US20100216769A1 - Substituted glycinamides, process for their manufacture and use thereof as medicaments - Google Patents

Substituted glycinamides, process for their manufacture and use thereof as medicaments Download PDF

Info

Publication number
US20100216769A1
US20100216769A1 US11/993,426 US99342606A US2010216769A1 US 20100216769 A1 US20100216769 A1 US 20100216769A1 US 99342606 A US99342606 A US 99342606A US 2010216769 A1 US2010216769 A1 US 2010216769A1
Authority
US
United States
Prior art keywords
group
alkyl
groups
methyl
substituted
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
US11/993,426
Other languages
English (en)
Inventor
Henning Priepke
Georg Dahmann
Kai Gerlach
Roland Pfau
Wolfgang Wienen
Annette Schuler-Metz
Sandra Handschuh
Herbert Nar
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: NAR, HERBERT, GERLACH, KAI, PFAU, ROLAND, DAHMANN, GEORG, HANDSCHUH, SANDRA, PRIEPKE, HENNING, SCHULER-METZ, ANNETTE, WIENEN, WOLFGANG
Publication of US20100216769A1 publication Critical patent/US20100216769A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • 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
    • 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
    • A61P25/28—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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • 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
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to new substituted glycinamides of general formula (I)
  • the compounds of the above general formula (I) as well as the tautomers, enantiomers, diastereomers, mixtures and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and the stereoisomers thereof, have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity.
  • the present application relates to new compounds of the above general formula (I), the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation and use thereof.
  • a 1st embodiment of the present invention includes those compounds of general formula (I) wherein
  • Examples of monocyclic heteroaryl groups are the pyridyl, N-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1,2,3]triazinyl, [1,3,5]triazinyl, [1,2,4]triazinyl, pyrrolyl, imidazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolyl or [1,2,5]thiadiazolyl group.
  • bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo[c]furanyl, benzothiophenyl, benzo[c]thiophenyl, benzothiazolyl, benzo[c]-isothiazolyl, benzo[d]isothiazolyl, benzooxazolyl, benzo[c]isoxazolyl, benzo[d]-isoxazolyl, benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,3]thia-diazolyl, benzo[d][1,2,3]triazinyl, benzo[1,2,4]triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, N-oxy-quinolinyl, isoquinolinyl, quinazolinyl, N-oxy-quinazolinyl, quinoxalinyl
  • Examples of the C 1-6 -alkyl groups mentioned hereinbefore in the definitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2-dimethyl-3-butyl or 2,3-dimethyl-2-butyl group.
  • C 1-6 -alkyloxy groups mentioned hereinbefore in the definitions are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.
  • Examples of the C 2-5 -alkenyl groups mentioned hereinbefore in the definitions are the ethenyl, 1-propen-1-yl, 2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl, 1-penten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-hexen-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 4-hexen-1-yl, 5-hexen-1-yl, but-1-en-2-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, pent-1-en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1-en-3-yl, pent-2-en-3-yl, 2-methyl-but-1-en-1
  • Examples of the C 2-5 -alkynyl groups mentioned hereinbefore in the definitions are the ethynyl, 1-propynyl, 2-propynyl, 1-butyn-1-yl, 1-butyn-3-yl, 2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1-yl, 1-pentyn-3-yl, 1-pentyn-4-yl, 2-pentyn-1-yl, 2-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 2-methyl-1-butyn-4-yl, 3-methyl-1-butyn-1-yl or 3-methyl-1-butyn-3-yl group.
  • a 2nd embodiment of the present invention includes those compounds of general formula (I), wherein
  • a 3rd embodiment of the present invention includes those compounds of general formula (I), wherein
  • a 4th embodiment of the present invention includes those compounds of general formula (I), wherein
  • a 5th embodiment of the present invention includes those compounds of general formula (I), wherein
  • a 6th embodiment of the present invention includes those compounds of general formula (I), corresponding to embodiments 1, 2, 3, 4 or 5, wherein the group
  • a 7th embodiment of the present invention includes those compounds of general formula (I), corresponding to embodiments 1, 2, 3, 4, 5 or 6, wherein neither
  • R 4 nor R 5 may represent a hydrogen atom, the tautomers, enantiomers, diastereomers, mixtures and salts thereof.
  • An 8th embodiment of the present invention includes those compounds of general formula (I), corresponding to embodiments 1, 2, 3, 4, 5 or 6, wherein
  • the invention also relates to physiologically acceptable salts of the compounds according to the embodiments defined above and the Examples.
  • the invention also relates to pharmaceutical compositions containing a compound or a physiologically acceptable salt of a compound according to the embodiments defined above and the Examples, optionally together with one or more inert carriers and/or diluents.
  • the invention also relates to the use of a compound or a physiologically acceptable salt of a compound according to the embodiments defined above and the Examples, for preparing a pharmaceutical composition with an inhibitory effect on factor Xa and/or an inhibitory effect on related serine proteases.
  • the invention also relates to a process for preparing a pharmaceutical composition, characterised in that by a non-chemical method a compound or a physiologically acceptable salt of a compound according to the embodiments defined above and the Examples is incorporated in one or more inert carriers and/or diluents.
  • a compound of general formula (IV) wherein R 3 denotes a hydrogen atom and A1, A2, A3, K1, K2, K3, K4 and X are defined as in embodiment 1, may be prepared by reduction of the nitro group of a compound of general formula (III)
  • any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protective groups which are cleaved again after the reaction.
  • a protecting group for a hydroxy group might be the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert.-butyl, trityl, benzyl or tetrahydropyranyl group.
  • Protecting groups for a carboxyl group might be the trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl or tetrahydropyranyl group.
  • a protecting group for an amino, alkylamino or imino group might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, the phthalyl group.
  • a protecting group for an ethynyl group might be the trimethylsilyl, diphenylmethylsilyl, tert.butyldimethylsilyl or a 1-hydroxy-1-methyl-ethyl group.
  • Any protective group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. In water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by means of ether splitting, e.g. In the presence of iodotrimethylsilane, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.
  • an aqueous solvent e.g. In water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved by hydrogenolysis, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50° C., but preferably at room temperature, and under a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar.
  • a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • a methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50° C., but preferably at room temperature.
  • an oxidising agent such as cerium(IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50° C., but preferably at room temperature.
  • a methoxy group is conveniently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between ⁇ 35 and ⁇ 25° C.
  • a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol.
  • a tert.-butyl or tert.-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
  • a phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50° C.
  • An allyloxycarbonyl group is cleaved by treatment with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100° C., preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris-(triphenylphosphine)-rhodium(I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2,2,2]octane at temperatures between 20 and 70° C.
  • a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0) preferably in a solvent such as tetrahydrofuran and preferably in the presence of
  • the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.
  • the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. And Eliel E. L. In “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical enantiomers and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. By chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • the enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. Esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • Optically active acids in common use are e.g.
  • An optically active alcohol may be, for example, (+) or ( ⁇ )-menthol and an optically active acyl group in amides, for example, may be a (+)- or ( ⁇ )-menthyloxycarbonyl.
  • the compounds of formula (I) obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula (I) may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
  • Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the compounds of general formula (I) and the tautomers, enantiomers, diastereomers and physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and on an inhibitory effect on related serine proteases such as e.g. urokinase, factor Vila, factor IX, factor XI and factor XII.
  • an antithrombotic activity which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and on an inhibitory effect on related serine proteases such as e.g. urokinase, factor Vila, factor IX, factor
  • Enzyme-kinetic measurement with chromogenic substrate The quantity of p-nitroaniline (pNA) released from the colourless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (in relation to the solvent control) is determined at various concentrations of test substance and from this the IC 50 is calculated, as the concentration which inhibits the factor Xa used by 50%.
  • pNA p-nitroaniline
  • Tris(hydroxymethyl)-aminomethane buffer 100 mMol and sodium chloride (150 mMol), pH 8.0 plus 1 mg/ml Human Albumin Fraction V, protease-free Factor Xa (Calbiochem), spec. Activity: 217 IU/mg, final concentration: 7 IU/ml for each reaction mixture
  • Test substance final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 ⁇ Mol/l
  • the compounds prepared according to the invention are generally well tolerated.
  • the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the prevention and treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe sepsis, for preventing and treating DVT in patients with exacerbated COPD, for treating ulcerative colitis, for preventing and treating coronary thrombosis, for preventing stroke and the occlusion of shunts.
  • venous and arterial thrombotic diseases such as for example the prevention and treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe seps
  • the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT(C)A, for the prevention and treatment of ischaemic events in patients with all forms of coronary heart disease, for preventing metastasis and the growth of tumours and inflammatory processes, e.g. In the treatment of pulmonary fibrosis, for preventing and treating rheumatoid arthritis, for preventing and treating fibrin-dependent tissue adhesions and/or the formation of scar tissue and for promoting wound healing processes.
  • the new compounds and the physiologically acceptable salts thereof are also suitable for the treatment of Alzheimer's and Parkinson's disease.
  • One explanation for this arises for example from the following findings, from which it can be concluded that thrombin inhibitors or factor Xa inhibitors, by inhibiting thrombin formation or thrombin activity, may be valuable drugs for treating Alzheimer's and Parkinson's disease.
  • Clinical and experimental studies indicate that neurotoxic mechanisms, for example the inflammation which is associated with the activation of proteases of the clotting cascade, are involved in the dying of neurones following brain injury.
  • Various studies point to the involvement of thrombin in neurodegenerative processes, for example following a stroke, repeated bypass operations or traumatic brain injury.
  • thrombin causes a neurite retraction, as well as glia proliferation, and apoptosis in primary cultures of neurones and neuroblastoma cells (for a summary see: Neurobiol. Aging 2004, 25(6), 783-793).
  • a concentration of immune-reactive thrombin has been detected in neurite plaques in the brains of Alzheimer's patients.
  • thrombin also plays a part in the regulation and stimulation of the production of the “Amyloid Precursor Protein” (APP) as well as in the cleaving of the APP into fragments which can be detected in the brains of Alzheimer's patients.
  • APP Amyloid Precursor Protein
  • thrombin-induced microglial activation leads in vivo to the degeneration of nigral dopaminergic neurones.
  • the dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times a day.
  • the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, 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 hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
  • inert conventional carriers and/or diluents e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glyce
  • the new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the clotting system and the recombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. Clopidogrel, ticlopidine), with P 2 T receptor antagonists (e.g. Cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. Terbogrel).
  • fibrinogen receptor antagonists e.g. abciximab, eptifibatide, tirofiban, roxifiban
  • R f values were determined using ready-made silica gel 60 F 254 TLC plates (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation.
  • the R f values given under the heading Alox were determined using ready-made aluminium oxide 60 F 254 TLC plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation.
  • the R f values given under the heading Reversed-phase-8 (RP-8) were determined using ready-made RP-8 F 254s TLC plates (E. Merck, Darmstadt, Item no. 1.15684) without chamber saturation.
  • the ratios given for the eluants refer to units by volume of the solvents in question.
  • silica gel made by Messrs Millipore MATREXTM, 35-70 ⁇ m was used. Unless more detailed information is provided as to the configuration, it is not clear whether the products are pure stereoisomers or mixtures of enantiomers and diastereomers.
  • thiophen-2-yl or “thien-2-yl” denotes the group shown in the box:
  • HPLC-MS data were obtained under the following conditions:
  • the mobile phase used was:
  • the stationary phase used was an X-Terra MS C18 column, 3.5 ⁇ m, 4.6 mm ⁇ 50 mm.
  • the diode array detection was carried out at a wavelength range of 210-500 nm.
  • the mobile phase used was:
  • the stationary phase used was a Waters X-Terra MS C18 column, 2.5 ⁇ m, 4.6 mm ⁇ 30 mm
  • the mobile phase used was:
  • the stationary phase used was a Varian Microsorb 100 C18 column; 3.5 ⁇ m; 4.6 mm ⁇ 50 mm
  • the mobile phase used was:
  • the stationary phase used was a Varian Microsorb 100 C18 column; 2.5 ⁇ m; 4.6 mm ⁇ 30 mm
  • the mobile phase used was:
  • A water with 0.10% formic acid
  • B acetonitrile with 0.10% formic acid
  • the stationary phase used was a Zorbax StableBond C18 column; 3.5 ⁇ m; 4.6 mm ⁇ 75 mm
  • the mobile phase used was:
  • the stationary phase used was an Interchim HS Strategy 5 C18-2 column; 5 ⁇ m; 4.6 mm ⁇ 50 mm
  • the mobile phase used was:
  • the stationary phase used was a MerckChromolith SpeedRod RP-18e column; 4.6 mm ⁇ 50 mm
  • the methanol is distilled off using the rotary evaporator, the residue is combined with water and extracted with tert.-butylethylether.
  • the organic phase is washed with NaOH solution (50%) and sat. Sodium chloride solution, dried on sodium sulphate and evaporated to dryness i. vac.
  • the residue is combined with water and 2-molar sodium carbonate solution and washed with diethyl ether.
  • the aqueous phase is adjusted to pH 1 with 20 ml conc. Hydrochloric acid, the precipitate is suction filtered and dried at 50° C. in the vacuum drying cupboard.
  • Example 2(a) Prepared analogously to Example 2(a) from 3-[(5-chloro-thiophen-2-yl)-carbonylamino]-tetrahydro-furan-3-carboxylic acid and 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with TBTU and TEA in THF at room temperature with subsequent purification by chromatography with aluminium oxide (eluant: dichloromethane/ethanol 100:0 to 97:3).
  • Example 2-c Prepared analogously to Example 2-c from 2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid and 3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amine with TBTU and NMM in DMF at room temperature with subsequent filtration through aluminium oxide.
  • reaction mixture is stirred overnight at room temperature, evaporated down i. vac., the residue is combined with ethyl acetate and washed with ammonia solution (5%) and water.
  • the organic phase is dried on sodium sulphate and evaporated to dryness i. vac.
  • the residue is combined with diethyl ether, the precipitate is suction filtered and dried.
  • Example 2 Prepared analogously to Example 1 from 2-[(5-chloro-thiophen-2-yl)-carbonylamino-2-methyl-propionic acid with HATU, NMM and 8-amino-1,3,4,5-tetrahydro-benzo[d]azepin-2-on/7-amino-1,3,4,5-tetrahydro-benzo[d]azepin-2-one in DMF with subsequent purification by chromatography on silica gel with the eluant (dichloromethane/ethanol 100:0 to 92:8).
  • Example 2 0.117 g (0.60 mmol) (R)-3-benzyloxy-2-tert.-butoxycarbonylamino-propionic acid are reacted analogously to Example 2 (a) with 0.116 g (0.66 mmol) 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine, TBTU, DIPEA in THF. Then the BOC protective group is cleaved analogously to Example 1 (d), made basic with sodium hydroxide and extracted with ethyl acetate.
  • aluminium oxide eluant: dichloromethane/ethanol 98:2
  • Example 1 Prepared analogously to Example 1 (b) from 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and aqueous formalin solution in formic acid.
  • Example 1 Prepared analogously to Example 1 (b) from 7-benzyloxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and aqueous formalin solution in formic acid.
  • the reaction is washed with 5% sodium hydrogen carbonate solution and the organic phase is dried with sodium sulphate and concentrated by evaporation.
  • Example 52 was isolated as a by-product in the preparation of Example 52.
  • Example 1e/1f The title compound was prepared analogously to the synthesis sequence in Example 1e/1f from 3-amino-pyrrolidin-1-tert.butoxycarbonyl-3-carboxylic acid, 5-chlorothiophene-2-carboxylic acid chloride and 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine.
  • THF N,N,N,N-tetramethyl-ethylenediamine
  • reaction mixture is combined with aqueous ammonium chloride solution and concentrated by evaporation i.vac.
  • the residue is combined with 1 M hydrochloric acid and THF and extracted with ethyl acetate.
  • Example 69 is prepared from Example 69 by saponification with lithium hydroxide analogously to Example 8 (d).
  • a mixture of the two title compounds may be prepared by the synthesis sequence of Leuckart-Wallach reaction analogously to Example 1(b), nitrogenation analogously to Example 9(a) and reduction analogously to Example 9(d), and the mixture may be purified by chromatography (silica gel, methylene chloride/(ethanol: ammonia 95:5) 99/1->8/2): 3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
  • R f value 0.70 (silica gel; methylene chloride/methanol/ammonia 80/20/2)
  • R f value 0.75 (silica gel; methylene chloride/methanol/ammonia 80/20/2)
  • R f value 0.6 (silica gel; methylene chloride/methanol/ammonia 80/20/2)
  • Example 71a is prepared from 3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-8-ylamine (see Example 71a) analogously to Example 1(f).
  • R f value 0.8 (silica gel; methylene chloride/methanol/ammonia 80/20/2)
  • R f value 0.35 (silica gel; methylene chloride/methanol/ammonia 95/5/0.5)
  • R f value 0.6 (aluminium oxide; methylene chloride/ethanol 95/5)
  • R f value 0.42 (silica gel; methylene chloride/methanol 80/20)
  • R f value 0.05 (silica gel; methylene chloride/methanol 80/20)
  • the title compound is prepared from methyl 2-(5-chlorothiophen-2-yl)carbonylamino-3-(2-methoxyethyloxy)propionate by lithium hydroxide saponification and subsequent reaction with 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with EEDQ analogously to Example 58(c).
  • the title compound was prepared from methyl 1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-dihydroxy-cyclopentane-1-carboxylate by methylation analogously to Example 61 and subsequent saponification with LiOH and reaction with 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine.
  • Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.
  • Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.
  • the product is dissolved in water.
  • Diameter of the tablets 9 mm.
  • Diameter of the tablets 12 mm.
  • Capsules containing 50 mg of active substance Composition (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
  • This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
  • Capsules containing 350 mg of active substance Composition (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
  • This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.
  • Suppositories containing 100 mg of active substance 1 suppository contains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg
  • the polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40° C. the ground active substance is homogeneously dispersed in the melt. It is cooled to 38° C. and poured into slightly chilled suppository moulds.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US11/993,426 2005-06-30 2006-06-28 Substituted glycinamides, process for their manufacture and use thereof as medicaments Abandoned US20100216769A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05014270 2005-06-30
EP05014270.2 2005-06-30
PCT/EP2006/063611 WO2007003536A1 (de) 2005-06-30 2006-06-28 Substituierte glycinamide mit antithrombotischer und faktor xa-inhibierender wirkung

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/063611 A-371-Of-International WO2007003536A1 (de) 2005-06-30 2006-06-28 Substituierte glycinamide mit antithrombotischer und faktor xa-inhibierender wirkung

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/785,176 Continuation US9062034B2 (en) 2005-06-30 2013-03-05 Substituted glycinamides, process for their manufacture and use thereof as medicaments

Publications (1)

Publication Number Publication Date
US20100216769A1 true US20100216769A1 (en) 2010-08-26

Family

ID=35907001

Family Applications (3)

Application Number Title Priority Date Filing Date
US11/993,426 Abandoned US20100216769A1 (en) 2005-06-30 2006-06-28 Substituted glycinamides, process for their manufacture and use thereof as medicaments
US13/785,176 Active US9062034B2 (en) 2005-06-30 2013-03-05 Substituted glycinamides, process for their manufacture and use thereof as medicaments
US14/716,227 Active US9676781B2 (en) 2005-06-30 2015-05-19 Substituted glycinamides, process for their manufacture and use thereof as medicaments

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/785,176 Active US9062034B2 (en) 2005-06-30 2013-03-05 Substituted glycinamides, process for their manufacture and use thereof as medicaments
US14/716,227 Active US9676781B2 (en) 2005-06-30 2015-05-19 Substituted glycinamides, process for their manufacture and use thereof as medicaments

Country Status (33)

Country Link
US (3) US20100216769A1 (ko)
EP (1) EP1899330B9 (ko)
JP (1) JP4768016B2 (ko)
KR (1) KR101321722B1 (ko)
CN (1) CN101213195B (ko)
AR (1) AR054627A1 (ko)
AT (1) ATE489381T1 (ko)
AU (1) AU2006265216B2 (ko)
BR (1) BRPI0612580A8 (ko)
CA (1) CA2613059C (ko)
CY (1) CY1111627T1 (ko)
DE (1) DE502006008392D1 (ko)
DK (1) DK1899330T3 (ko)
EA (1) EA015188B1 (ko)
EC (1) ECSP078058A (ko)
ES (1) ES2357029T3 (ko)
HK (1) HK1116190A1 (ko)
HR (1) HRP20110044T2 (ko)
IL (1) IL188323A (ko)
MX (1) MX2007016253A (ko)
MY (1) MY145883A (ko)
NO (1) NO340670B1 (ko)
NZ (1) NZ565440A (ko)
PE (1) PE20070171A1 (ko)
PL (1) PL1899330T3 (ko)
PT (1) PT1899330E (ko)
RS (1) RS51572B (ko)
SG (1) SG163540A1 (ko)
SI (1) SI1899330T1 (ko)
TW (1) TWI392495B (ko)
UA (1) UA94910C2 (ko)
WO (1) WO2007003536A1 (ko)
ZA (1) ZA200708525B (ko)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110166125A1 (en) * 2007-11-15 2011-07-07 Boehringer Ingelheim International Gmbh Substituted amides, manufacturing and use thereof as medicaments

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1799684B1 (en) 2004-10-04 2014-12-03 Millennium Pharmaceuticals, Inc. Lactam compounds useful as protein kinase inhibitors
PE20080145A1 (es) 2006-03-21 2008-02-11 Janssen Pharmaceutica Nv Tetrahidro-pirimidoazepinas como moduladores de trpv1
US20090312306A1 (en) * 2006-07-20 2009-12-17 Guangri Sun Tetrahydro-5h-pyrido[2,3-d]azepines as 5-ht2c ligands
PE20081834A1 (es) * 2006-12-31 2009-01-16 Boehringer Ingelheim Int Proceso para la sintesis de derivados de acido 3-amino-tetrahidrofuran-3-carboxilico y uso de los mismos como medicamentos
EP1975165A1 (de) 2007-03-27 2008-10-01 Boehringer Ingelheim Pharma GmbH & Co. KG Substituierte Pyrrolidinamide, deren Herstellung und deren Verwendung als Arzneimittel
PE20091102A1 (es) 2007-12-17 2009-07-25 Janssen Pharmaceutica Nv Moduladores imidazolo-, oxazolo-, y tiazolopirimidina del trpv1
AR074487A1 (es) 2008-12-05 2011-01-19 Millennium Pharm Inc Tiolactamas inhibidoras de proteinquinasas plk, composiciones farmaceuticas que las contienen y usos de las mismas para el tratamiento de trastornos proliferativos e inflamatorios, en particular cancer.
US20120015938A1 (en) * 2009-02-17 2012-01-19 Msd K.K. 1,4-benzodiazepin-2-on derivatives
EP3248615A1 (en) 2010-03-30 2017-11-29 Mount Sinai School of Medicine of New York University Influenza virus vaccines and uses thereof
IN2014CN02114A (ko) 2011-09-20 2015-05-29 Sinai School Medicine
EP4154907A1 (en) 2012-12-18 2023-03-29 Icahn School of Medicine at Mount Sinai Influenza virus vaccines and uses thereof
US9499532B2 (en) * 2014-02-07 2016-11-22 eXIthera Pharmaceuticals Inc. Therapeutic compounds and compositions
CN105622511B (zh) * 2014-11-03 2018-01-23 北京瑞都医药科技有限公司 一种减肥药物及其制备方法
EP3078378B1 (en) 2015-04-08 2020-06-24 Vaiomer Use of factor xa inhibitors for regulating glycemia
PL3818050T3 (pl) 2018-07-05 2023-07-24 Bayer Aktiengesellschaft Podstawione tiofenokarboksyamidy i analogi jako środki przeciwbakteryjne
CN111196772B (zh) * 2018-11-16 2022-09-30 沈阳化工研究院有限公司 一种芳酰氨基异丁酰衍生物及其应用
CN115038698A (zh) 2019-12-20 2022-09-09 拜耳公司 噻吩基噁唑酮及类似物
US11691960B2 (en) 2020-11-06 2023-07-04 Boehringer Ingelheim International Gmbh 2-[thiophen-2-yl)formamido]-N-(phenyl)-2-methylpropanamide derivatives and the use thereof as medicament

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060069082A1 (en) * 2004-09-29 2006-03-30 Boehringer Ingelheim International Gmbh Novel substituted thiophenecarboxamides, their preparation and their use as medicaments
US20060293300A1 (en) * 2004-05-13 2006-12-28 Boehringer Ingelheim International Gmbh New substituted thiophene carboxamides, process for their preparation and their use as medicaments
US7476663B2 (en) * 2004-05-13 2009-01-13 Boehringer Ingelheim International Gmbh Substituted thiophene carboxamides

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2248084T3 (es) * 1999-06-14 2006-03-16 Eli Lilly And Company Inhibidores de serinproteasa.
DE19962924A1 (de) * 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
EA005893B1 (ru) 2000-03-21 2005-06-30 Смитклайн Бичам Корпорейшн Ингибиторы протеаз
DE10063008A1 (de) 2000-12-16 2002-06-20 Merck Patent Gmbh Carbonsäureamidderivate
US20040157828A1 (en) 2001-05-17 2004-08-12 Ren Xie Protease inhibitors
JP2004300133A (ja) * 2002-11-19 2004-10-28 Takeda Chem Ind Ltd アミン誘導体
EP1562898A1 (en) 2002-11-19 2005-08-17 Takeda Pharmaceutical Company Limited Indole derivatives as somatostatin agonists or antagonists
DE10254336A1 (de) * 2002-11-21 2004-06-03 Merck Patent Gmbh Carbonsäureamide
US7250415B2 (en) 2003-06-04 2007-07-31 Bristol-Myers Squibb Company 1,1-Disubstitutedcycloalkyl-, glycinamidyl-, sulfonyl-amidino-, and tetrahydropyrimidinyl-containing diaminoalkyl, β-aminoacids, α-aminoacids and derivatives thereof as factor Xa inhibitors
CA2562714A1 (en) 2004-05-13 2005-11-24 Boehringer Ingelheim International Gmbh Substituted thiophene-2-carboxylic acid amides, the production thereof and the use thereof as drugs
PE20081834A1 (es) 2006-12-31 2009-01-16 Boehringer Ingelheim Int Proceso para la sintesis de derivados de acido 3-amino-tetrahidrofuran-3-carboxilico y uso de los mismos como medicamentos

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060293300A1 (en) * 2004-05-13 2006-12-28 Boehringer Ingelheim International Gmbh New substituted thiophene carboxamides, process for their preparation and their use as medicaments
US7476663B2 (en) * 2004-05-13 2009-01-13 Boehringer Ingelheim International Gmbh Substituted thiophene carboxamides
US20060069082A1 (en) * 2004-09-29 2006-03-30 Boehringer Ingelheim International Gmbh Novel substituted thiophenecarboxamides, their preparation and their use as medicaments

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110166125A1 (en) * 2007-11-15 2011-07-07 Boehringer Ingelheim International Gmbh Substituted amides, manufacturing and use thereof as medicaments
US8741890B2 (en) 2007-11-15 2014-06-03 Boehringer Ingelheim International Gmbh Substituted amides, manufacturing and use thereof as medicaments

Also Published As

Publication number Publication date
US9062034B2 (en) 2015-06-23
CN101213195B (zh) 2012-05-09
ES2357029T3 (es) 2011-04-15
DE502006008392D1 (de) 2011-01-05
NO340670B1 (no) 2017-05-29
PE20070171A1 (es) 2007-03-08
NZ565440A (en) 2011-04-29
TW200738692A (en) 2007-10-16
BRPI0612580A2 (pt) 2010-11-23
WO2007003536A1 (de) 2007-01-11
NO20075186L (no) 2008-02-14
ZA200708525B (en) 2009-08-26
BRPI0612580A8 (pt) 2017-12-26
SI1899330T1 (sl) 2011-03-31
CA2613059A1 (en) 2007-01-11
IL188323A (en) 2013-08-29
CA2613059C (en) 2013-12-24
DK1899330T3 (da) 2011-02-21
KR20080033318A (ko) 2008-04-16
SG163540A1 (en) 2010-08-30
EA200702620A1 (ru) 2008-06-30
ATE489381T1 (de) 2010-12-15
CN101213195A (zh) 2008-07-02
PT1899330E (pt) 2011-01-11
AU2006265216A1 (en) 2007-01-11
EP1899330B1 (de) 2010-11-24
US20130184256A1 (en) 2013-07-18
JP2008546741A (ja) 2008-12-25
HRP20110044T2 (hr) 2012-02-29
MX2007016253A (es) 2008-03-07
AU2006265216B2 (en) 2011-09-29
JP4768016B2 (ja) 2011-09-07
EP1899330B9 (de) 2011-11-09
HRP20110044T1 (en) 2011-02-28
AR054627A1 (es) 2007-07-04
MY145883A (en) 2012-05-15
RS51572B (en) 2011-08-31
US9676781B2 (en) 2017-06-13
TWI392495B (zh) 2013-04-11
KR101321722B1 (ko) 2013-10-25
EA015188B1 (ru) 2011-06-30
HK1116190A1 (en) 2008-12-19
UA94910C2 (ru) 2011-06-25
EP1899330A1 (de) 2008-03-19
IL188323A0 (en) 2008-04-13
CY1111627T1 (el) 2015-10-07
US20150252050A1 (en) 2015-09-10
ECSP078058A (es) 2008-01-23
PL1899330T3 (pl) 2011-05-31

Similar Documents

Publication Publication Date Title
US9676781B2 (en) Substituted glycinamides, process for their manufacture and use thereof as medicaments
US7476663B2 (en) Substituted thiophene carboxamides
US7807693B2 (en) Substituted prolinamides, manufacturing, and the use thereof as medicaments
US7563786B2 (en) Substituted thiophenecarboxamides, their preparation and their use as medicaments
US7615549B2 (en) Substituted pyrrolidinones, their manufacture and their use as medicaments
US8003639B2 (en) Substituted prolinamides, the preparation thereof and the use thereof as pharmaceutical compositions
US20050256107A1 (en) New substituted thiophene carboxamides, process for their preparation and their use as medicaments
US20070032473A1 (en) Substituted amides and their use as medicaments
WO2008135525A2 (en) Substituted azetidines, manufacturing and use thereof as medicaments
US7732466B2 (en) Substituted thiophene carboxamides, process for their preparation and their use as medicaments
US8741890B2 (en) Substituted amides, manufacturing and use thereof as medicaments

Legal Events

Date Code Title Description
AS Assignment

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PRIEPKE, HENNING;DAHMANN, GEORG;GERLACH, KAI;AND OTHERS;SIGNING DATES FROM 20080215 TO 20080226;REEL/FRAME:024360/0367

STCB Information on status: application discontinuation

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