EP1003748A2 - Derives de pyrrolopyrrolone en tant qu'inhibiteurs de neutrophile elastase - Google Patents

Derives de pyrrolopyrrolone en tant qu'inhibiteurs de neutrophile elastase

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Publication number
EP1003748A2
EP1003748A2 EP98951348A EP98951348A EP1003748A2 EP 1003748 A2 EP1003748 A2 EP 1003748A2 EP 98951348 A EP98951348 A EP 98951348A EP 98951348 A EP98951348 A EP 98951348A EP 1003748 A2 EP1003748 A2 EP 1003748A2
Authority
EP
European Patent Office
Prior art keywords
pyrrolo
hexahydro
methanesulfonyl
carbonyl
pyrrol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98951348A
Other languages
German (de)
English (en)
Inventor
Geoffrey Duke Edward Clarke
Michael Dennis Dowle
Harry Finch
Lee Andrew Harrison
Graham George Adam Inglis
Martin Redpath Johnson
Simon John Fawcett Macdonald
Pritom Shah
Robin Andrew Smith
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.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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
Priority claimed from GBGB9719189.4A external-priority patent/GB9719189D0/en
Priority claimed from GBGB9719183.7A external-priority patent/GB9719183D0/en
Priority claimed from GBGB9719290.0A external-priority patent/GB9719290D0/en
Priority claimed from GBGB9803611.4A external-priority patent/GB9803611D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1003748A2 publication Critical patent/EP1003748A2/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to therapeutically active bicyclic compounds, processes for their manufacture, pharmaceutical formulations containing them and their use in chemotherapy.
  • novel bicyclic compounds which are effective in treating inflammatory diseases.
  • Inflammation is a primary response to tissue injury or microbial invasion and is characterised by circulating leukocytes binding to and extravasation through vascular endothelium. Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes.
  • the inflammatory process can be triggered in a number of ways, including by infection, tissue damage and autoimmune reactions.
  • neutrophils move from the bloodstream into the tissue at the site of tissue lesion.
  • the neutrophils contain large numbers of different intracellular granules and when activated at the site of inflammation the contents of these granules are secreted into the tissue.
  • the different granules contain a variety of enzymes and other proteins, many of which have antibacterial properties.
  • neutrophil elastase One of the enzymes found in the azurophilic granules is neutrophil elastase.
  • Neutrophil elastase has a wide spectrum of activities in the body. For example, within the lung the enzyme increases mucus production and changes the cellular composition of the epithelium The enzyme also causes vascular permeability changes within the microcirculation of many tissues and it is a potent destructive agent against a number of connective tissue components.
  • elastase activity has been implicated in the pathogenesis of a number of disease states including inflammatory diseases of the airways, the joints and the skin.
  • the enzyme is also responsible for some or most of the symptoms of acute respiratory distress syndrome (ARDS) and other acute inflammatory states brought about by trauma and/or sepsis.
  • ARDS acute respiratory distress syndrome
  • R 1 represents C 1-6 alkyl
  • R 2 represents C 2-4 alkyl or C 2- alkenyl
  • X represents CO or SO 2 ;
  • Het represents an optionally substituted 5 to 10 membered monocylic or bicyclic aromatic ring system containing 1 to 4 heteroatoms selected from O, N and S; n represents an integer 0 to 4;
  • R 3 and R 4 independently represent hydrogen, C 1-8 alkyl, -(CH 2 ) CONR 5 R 6 , COC ⁇ alkyl or (CH 2 ) 0-2 Ph where Ph represents phenyl optionally substituted by one or more C 1-4 alkyl or halogen groups or NR 3 R 4 together represents azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl optionally N- substituted by C 1-6 alkyl, phenyl (optionally substituted by halogen or C 1-4 alkyl) or benzyl (optionally substituted on the benzene ring by halogen or C 1-4 alkyl) or NR 3 R 4 together represents a ring as just described save that it is substituted on carbon by one or more C ⁇ alkyl, CONR 5 R 6 or COOR 6 groups; R 5 and R 6 independently represent hydrogen or C 1-4 alkyl; and salts and solvates thereof
  • Formula (I) shows the relative stereochemistry of the chiral centres.
  • the invention embraces compounds of the invention in racemic form as well as in a form in which one enantiomer predominates or is present exclusively.
  • the present invention also covers the physiologically acceptable salts of the compounds of formula (I).
  • physiologically acceptable salts of the compounds of formula (I) include inorganic and organic acid salts such as hydrochloride and tartrate.
  • alkyl includes branched as well as straight chain alkyl and may also include cycloalkyl when 3 or more carbon atoms are present.
  • Suitable R ⁇ alkyl groups include methyl, ethyl and propyl.
  • Het groups include furanyl, imidazolyl, thiophenyl, pyrrolyl, thiazolyl, isoxazolyl, pyrazolyl, pyridinyl and pyrazinyl.
  • Het may be connected to the pyrrolidine ring via X in any position.
  • connectivities include furan-2-yl, furan-3-yl, imidazol-2-yl, imidazol-4-yl, thiophen-2-yl, pyrrol-2-yl, thiazol-4-yl, isoxazol-3-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-3-yl, l-methyl-pyrrol-2-yl, 1-methyl-pyrazol-3-yl, 1-methyl-pyrazol-5-yl and pyrazin-2-yl.
  • substituents for Het include C 1-6 alkyl (e.g. methyl, ethyl), C ⁇ alkoxy (e.g. methoxy), nitro and halogen (e.g. chlorine, bromine, fluorine, iodine).
  • the substituent(s) may be on carbon or nitrogen.
  • substituted Het examples include 1 -methyl pyrrolyl, 1 -methyl pyrazolyl.
  • positions for the sidechain shown in formula (I) include for furan-2- yl the 5 position, for furan-3-yl the 2 position, for thiophen-2-yl the 5 position, for pyrrol-2-yl the 4 or 5 position, for 1 -methyl pyrrol-2-yl the 5 position, for thiazol-4- yl the 2 position, for isoxazol-3-yl the 5 position, for 1-methyl-pyrazol-3-yl the 5 position, for 1-methyl-pyrazol-5-yl the 3 position, for pyridin-3-yl the 6 position and for pyrazin-2-yl the 5 position.
  • R 3 and R 4 independently represent C 1-8 alkyl, examples include methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, CH(iPr) 2 and cyclohexyl.
  • R 3 and R 4 independently represent (CH 2 ) 0-2 Ph, examples include phenyl, benzyl and (4-F-phenyl)methyl.
  • NR 3 R 4 together represents N-substituted piperazinyl, examples include N- phenyl-piperazinyl and N-methyl-piperazinyl.
  • NR 3 R 4 When NR 3 R 4 together represents a ring substituted on carbon, examples of substituents include methyl, CONH 2 and COOMe. Examples of such NR 3 R 4 include 4-methyl piperidin-1-yl.
  • R 1 to represent methyl or ethyl, especially methyl.
  • R 2 to represent isopropyl or propyl, especially isopropyl.
  • Het to represent a 5 or 6 membered monocyclic aromatic ring containing 1 or 2 heteroatoms selected from O, N and S which is more preferably thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl, especially thiazolyl (particularly thiazol-4-yl) or pyrazinyl.
  • Het to represent pyridinyl, especially 3-pyridinyl.
  • Het represents pyrazinyl.
  • Het represents pyrazin-2-yl in which the sidechain is in the 5-position.
  • Het to represent oxazolyl, particularly oxazol-4-yl.
  • n represents 1 to 3, particularly 1 or 2, especially 1.
  • R 3 and R 4 independently to represent hydrogen or C h alky! or for NR 3 R 4 to represent pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally N-substituted by C 1-8 alkyl or phenyl (optionally substituted by halogen or C 1-4 alkyl).
  • preferred NR 3 R 4 groups are NMe 2 , N(n-butyl) 2 , NHMe NH(cyclopropyl), NHCH(iPr) 2 and N(cyclohexyl) 2.
  • a set of compounds of formula (I) of particular interest are compounds of formula (IA) in which Het represents oxazol-4-yl with the sidechain in the 2- position:
  • X to represent CO.
  • R to represent isopropyl or propyl, especially isopropyl.
  • R 1 to represent methyl or ethyl, especially methyl.
  • n to represent 1 to 3, particularly 1 or 2, especially 1.
  • R 3 and R 4 independently to represent hydrogen or C ⁇ alkyl or for NR 3 R 4 to represent pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally N- substituted by C 1-8 alkyl or phenyl (optionally substituted by halogen or C 1-4 alkyl).
  • -NR 3 R 4 to represent pyrrolidinyl, piperidinyl, N- phenylpiperazinyl, N(butyl) 2 , NMe(cyclopropyl) or N(cyclohexyl) 2 , most particularly pyrrolidinyl.
  • the potential for compounds of the invention to inhibit neutrophil elastase activity may be demonstrated, for example, using the following in vitro and in vivo assays:
  • Suitable concentrations of compound under test diluted with water from a 10mM stock solution in dimethylsulphoxide are final concentrations after the addition of substrate solution (see below).
  • Enzyme activity is plotted against concentration of inhibitor and an IC50 determined using curve fitting software.
  • Intracellular elastase is prepared from neutrophils collected by lavage and from femoral bone marrow . This is achieved by sonication of the neutrophils and centrifugation to yield intracellular granules. These are disrupted by freeze/thawing and sonication. Elastase and myeloperoxidase assays are then performed on these samples to assess the efficacy of the compounds and to normalise for neutrophil recovery.
  • the wash is with saline (300 ⁇ l), followed by centrifugation at 100g for 10 minutes at 4°C. Pellets are washed twice more, before resuspension of the final cell pellet in buffer (200 ⁇ l of 100mM Tris, 300mM NaCI, 1% (w/v) HTAB, pH 8.6). Samples are stored at -20 °C. After freeze-thawing of the samples four times, elastase activity is determined by a colorimetric assay in 50mM Tris, 150mM NaCI, 0.6mM MeO-Succ-Ala-Ala-Ala-Pro-Val-pNA at pH 8.6, measuring the rate of increase in absorbance at 405nm.
  • the compounds of the invention are of potential therapeutic benefit in the treatment and amelioration of symptoms of diseases where elastase activity is implicated.
  • diseases particularly include bronchitis, including chronic bronchitis. Also any chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Examples of disease states in which the compounds of the invention have potentially beneficial effects include inflammatory diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma and hyper-reactivity states of the lung, acute respiratory distress syndrome and septic shock, inflammatory or destructive conditions of the lung such as emphysema and cystic fibrosis and inflammatory or destructive conditions of external tissue such as skin diseases (e.g. lupus and psoriasis) and periodontal disease including gingivitis.
  • inflammatory diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma and hyper-reactivity states of the lung, acute respiratory distress syndrome and septic shock, inflammatory or destructive conditions of the lung such as emphysema and cystic fibrosis and inflammatory or destructive conditions of external tissue such as skin diseases (e.g. lupus and psoriasis) and periodontal disease including ging
  • cardiovascular diseases such as myocardial infarction and stroke, peripheral vascular disease including intermittent claudication, atherosclerosis, reperfusion injury, cardiovascular changes occurring during cardiopulmonary bypass surgery and septicemia.
  • Compounds of the invention may also be useful in the treatment of connective tissue disorders such as rheumatoid arthritis, osteoarthritis and spondylitis and inflammatory conditions of the kidney such as glomerulonephritis. They may also be useful in the treatment of certain leukemias including acute myelogenous leukemia, acute myelomonocytic leukemia and the chronic monocytic leukemias and in prevention or inhibition of metastasis of solid tumours e.g. lung, breast, prostate and stomach cancers and melanomas.
  • a particular aspect of the present invention is the use of compounds of formula (I) in the treatment of chronic bronchitis.
  • Chronic bronchitis is a condition which results from the exposure of the airway surface to noxious chemicals or agents or is secondary to another disease. The symptoms of the condition are caused by the excessive secretion of mucus onto the surface of the airways. This excess mucus cannot be cleared effectively and the result is reduced gas exchange within the lungs resulting in laboured breathing and hypoxemia, recurrent microbial infections and persistent cough associated with the expectoration of mucoid material.
  • the proposed mechanism for the excessive secretion of mucus involves the recruitment of neutrophils into the airways following the exposure of the epithelium to irritant materials; the neutrophils secrete elastase onto the surface of the airways and the enzyme brings about both an increase in the amount of mucus secreted onto the airway surfaces and a dramatic change in the cellular composition of the airway epithelium.
  • Inhibition of elastase activity by the administration of compounds of this invention is therefore an approach to the treatment of chronic bronchitis.
  • Reduced lung function in COPD eg in chronic bronchitics with airflow obstruction
  • an elastase inhibitor will improve lung function.
  • compounds of the invention are useful in human or veterinary medicine, in particular as inhibitors of the enzyme neutrophil elastase.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine, particularly in the treatment of conditions where elastase activity is implicated such as chronic bronchitis.
  • references herein to treatment extend to prophylaxis as well as the treatment of established conditions.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of conditions where elastase activity is implicated, particularly in chronic bronchitis.
  • a method for the treatment of a human or animal subject with a condition caused or mediated by elastase activity comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • compositions for use in therapy comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.
  • composition which comprises mixing the ingredients.
  • the compounds according to the invention may, for example, be formulated for oral, buccal, parenteral, topical or rectal administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disinteg rants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl £- hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or toxicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • topical administration as used herein, we include administration by insufflation and inhalation.
  • preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol.
  • Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.
  • Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1,2,3,3,3-heptafluoropropane, 1 ,1 ,1,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1,2,3,3,3-heptafluoropropane, 1 ,1 ,1,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • Capsules and cartridges for use in an inhaler or insufflator, of for example gelatin may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti- muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), lung surfactants and/or antimicrobial and anti-viral agents.
  • anti-inflammatory agents such as corticosteroids or NSAIDs
  • bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline)
  • mucolytic agents e.g. theophylline
  • anti-muscarinics e.g. theophylline
  • anti-leukotrienes e.g. the
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further aspect of the invention.
  • the compound of the invention may conveniently be administered in amounts of, for example, 0.01 to 50mg/kg body weight, suitably 0.05 to 25mg/kg body weight orally, one or more times a day.
  • the precise dose will of course depend on the age and condition of the patient, the particular route of administration chosen, and the disease being treated.
  • the compound is preferably administered orally for the treatment of bronchitis. Other routes of administration may be needed for other indications, for instance i.v. for ARDS.
  • the compounds of the invention have useful duration of action.
  • a process according to the invention for preparing a compound of formula (I) comprises:
  • the condensation reaction with R 4 R 3 N(CH 2 ) n HetCOOH is suitably carried out in the presence of a coupling agent such as 1-(3-N,N-dimethylaminopropyl)-3- ethylcarbodiimide, preferably also in the presence of HOBT, and a solvent such as dichloromethane, DMF, MeCN or tetrahydrofuran at a temperature of suitably between O°C and ambient.
  • a coupling agent such as 1-(3-N,N-dimethylaminopropyl)-3- ethylcarbodiimide
  • HOBT preferably also in the presence of HOBT
  • a solvent such as dichloromethane, DMF, MeCN or tetrahydrofuran
  • reaction conditions will be modified accordingly, for instance by inclusion of a base. If one or both of R 3 , R 4 represents hydrogen, it will generally be preferred to protect the nitrogen, e.g. with BOC.
  • reaction is suitably carried out in the presence of a base such as triethylamine and a solvent such as DCM, suitably at 0°C- ambient.
  • a base such as triethylamine
  • a solvent such as DCM
  • the sulphonylation reaction is suitably carried out in the presence of LHMDS or
  • R 3 and R 4 represents hydrogen, it may be necessary to protect the nitrogen, e.g. with BOC.
  • the cyclisation reaction is suitably carried out in the presence of 2-chioro-1- methylpyridinium iodide, or EDC, in a solvent such as dichloromethane, at a temperature of suitably 0°C - reflux.
  • This reaction may also be performed using a carboxylic acid thioester derivative of the compound of formula (IV).
  • another acid derivative such as an acid halide (e.g. acid chloride) may be used.
  • This oxidation reaction may be carried out in conventional manner such as by peracid oxidation.
  • Preferred leaving groups include halogen (such as chlorine, bromine or iodine), mesylate and tosylate.
  • the reaction may be performed by combining the reactants optionally in the presence of a base such as triethylamine or potassium carbonate in an inert solvent such as DMF or MeCN.
  • This reaction will take place on combining the reagents in an inert solvent, e.g. DCM at ambient or elevated temperature.
  • an inert solvent e.g. DCM at ambient or elevated temperature.
  • Reduction can be performed in situ using a conventional mild reducing agent such as NaBH 3 CN or NaBH(OAc) 3 .
  • Process (ix) Purification of a single enantiomer may be achieved by conventional methods such as chiral chromatography (e.g. chiral HPLC) and crystallisation with a homochiral acid (e.g. tartaric acid).
  • Physiologically acceptable acid salts of the compound of formula (I) such as the hydrochloride or tartrate may be prepared by treating a basic compound of formula (I) with the desired acid.
  • BOC may be performed by reacting with (BOC) 2 O in the presence of base (e.g.
  • This conversion may be performed on treatment with ammonium bicarbonate in the presence of a suitable solvent such as pyridine/DMF and in the presence of
  • CBZ may be performed by reaction with nBuLi followed by CBZ-CI in the presence of an inert solvent such as THF below -50 °C.
  • This reaction may be performed by treatment with RX where RX is a compound
  • R e.g. Mel, benzyl iodide or Me 2 SO 4
  • a suitable solvent e.g. propanone or acetonitrile.
  • R will represent alkyl or aralkyi and X will represent halide, especially iodide, or sulphate. Protection of the amide is convenient, although not essential, for this reaction.
  • Step (e) This ring closure reaction may be performed by treatment with Dowex 2 x 8 400 mesh OH " resin in a suitable solvent, e.g. MeCN.
  • the ring closure may be performed by treatment with potassium carbonate in a suitable solvent, e.g. MeCN.
  • Deprotection may be performed in a conventional manner, for example, a BOC protecting group may be removed by treatment with HCI, e.g. in dioxan.
  • This reaction may be performed by treatment with a trifluoroacetic acid alkyl ester (e.g. the methyl ester) or trifluoroacetic anhydride in the presence of a suitable base e.g. N-methylmorpholine.
  • a trifluoroacetic acid alkyl ester e.g. the methyl ester
  • a suitable base e.g. N-methylmorpholine.
  • This conversion will take place on treating the compound of formula (XV) with a reducing agent e.g. lithium borohydride, followed by treatment with concentrated sulphuric acid in the presence of an alkyl alcohol e.g. ethanol solvent.
  • a reducing agent e.g. lithium borohydride
  • concentrated sulphuric acid in the presence of an alkyl alcohol e.g. ethanol solvent.
  • the reaction of compounds of formula (XVI) and (XVII) takes place in the presence of a Lewis acid e.g. boron trifluoride dietherate and an inert solvent e.g. dichloromethane or MeCN.
  • a Lewis acid e.g. boron trifluoride dietherate
  • an inert solvent e.g. dichloromethane or MeCN.
  • the group "alkyl" in Oalkyl and OSi(alkyl) 3 generally represents C 1-6 alkyl.
  • suitable alkyl groups in the silyl alkyl moiety include methyl, isopropyl and t-butyl.
  • Preferred Oalkyl is OEt and preferred OSi(alkyl) 3 is OSi(i-Pr) 3 or OSi(Me) 2 (t-Bu).
  • the use of variants of compounds of formula (XVII) in which Oalkyl is replaced by OSi(aIkyl) 3 is also envisaged.
  • Compounds of formula (XVII) may be prepared by treatment of the corresponding carboxylic acid ester (R 2 CH 2 COOEt or another alkyl ester, which compounds are either known or may be prepared by known methods) with a strong base (eg LHMDS) followed by a trialkylsilylchloride (such as trimethylsilylchloride) or a trialkylsilyltriflate.
  • a strong base eg LHMDS
  • a trialkylsilylchloride such as trimethylsilylchloride
  • a trialkylsilyltriflate Typically the reaction will be performed at low temperature (less than 0 °C) in an inert solvent (such as THF) in the presence of DMPU.
  • Step (j) This deprotection reaction will take place on treatment with base, such as potassium carbonate.
  • This ring closure reaction may be performed on treatment with an alkyl Grignard reagent (e.g. t-butylmagnesium choride) in an inert solvent such as THF in the presence of tetramethylethylenediamine at a temperature of -20°C to 25°C.
  • an alkyl Grignard reagent e.g. t-butylmagnesium choride
  • an inert solvent such as THF
  • Step (m) This is a N-deprotection reaction, which can suitably be carried out in conventional manner.
  • P. is CBZ
  • it is suitably carried out by hydrogenation over Pd (OH) 2 catalyst in solvents such as ethyl acetate or THF.
  • R 13 is suitably a C 1-6 alkyl group, preferably methyl.
  • the cyclisation reaction will take place on stirring in water with Dowex 2X8 (preferably 400 mesh).
  • the TFA protected amine is formed by treating the compound of formula (XXIV) with methyl trifluoroacetate in a polar protic solvent, eg MeOH.
  • Suitable protecting groups P 1 include CBZ.
  • the compound of formula (XXV) may be treated with a strong base such as LHMDS or nBuLi in an inert solvent such as THF, followed by treatment with CBZ-CI.
  • a strong base such as LHMDS or nBuLi in an inert solvent such as THF
  • the compounds of formula (XXVI) are either known compounds or may be made in analogous manner to known compounds.
  • P- is a N-protecting group, preferably CBZ.
  • Step (a) is a further N-protection reaction.
  • P 2 in formula (XXVII) is a different N-protecting group, preferably BOC. When P 2 is BOC, the reaction is suitably carried out using BOC 2 O.
  • reaction is carried out in the presence of a base such as triethylamine or 4-dimethylaminopyridine in a solvent such as ethyl acetate, at temperature of suitably 0°-25° C.
  • a base such as triethylamine or 4-dimethylaminopyridine
  • a solvent such as ethyl acetate
  • Step (b) This conversion is suitably carried out with pyridinium p-toluenesulfonate, in a solvent such as acetone/water, at a temperature suitably between 25°-75° C.
  • Step (c) This is a condensation rearrangement reaction suitably carried out using a 2- phenylsulfinyl acetic acid ester (PhSOCH 2 CO 2 R 13 ) and piperidine, in a solvent such as acetonitrile, suitably at ambient temperature.
  • a 2- phenylsulfinyl acetic acid ester PhSOCH 2 CO 2 R 13
  • piperidine a solvent such as acetonitrile
  • R 13 is suitably a C 1-6 alkyl group, preferably methyl.
  • THF at a temperature of suitably 0°-40° C.
  • This is a deprotection reaction, preferably using a strong acid such as TFA in a solvent such as DCM, at a temperature of suitably 0°-40° C.
  • R 13 is suitably C 1-6 alkyl, preferably ethyl.
  • a cyclisation reaction suitably carried out as an intramolecular Michael reaction.
  • NaH is used, in a solvent such as THF, at a temperature such as 0° - 25° C.
  • N-deprotection and re-protection two reactions occur: N-deprotection and re-protection.
  • the phthalimido group is removed suitably with hydrazine hydrate in a solvent such as ethanol at a temperature between 0°C and reflux.
  • Protecting group P 3 is incorporated in a conventional manner. When P 3 is BOC, this is suitably achieved with BOC 2 O.
  • the R 2 side chain may be introduced by alkylation, using as reactant R 2 -Y, wherein Y is a reactive group such as bromo or iodo.
  • R 2 -Y wherein Y is a reactive group such as bromo or iodo.
  • the reaction is carried out using a base, preferably a strong base such as LHMDS.
  • LHMDS suitably a cosolvent DMPU in THF is used.
  • Suitable reaction temperatures are -78° to 50°C. Under these conditions the reaction generally takes place with good stereochemical control.
  • the former is carried out in a conventional manner, for example by using KOH in aqueous ethanol, at a temperature of suitably 25°-80°C .
  • the latter is carried out in a conventional manner, for example by using HCI in dioxan, at a temperature of suitably 0°-50°C or, if the protecting group is trifluoroacetate, by treatment with base.
  • a suitable base such as N, N-diisopropyl ethylamine
  • a solvent such as dichloromethane
  • the compounds of formula (XXXVI) are either known compounds or may be 5 prepared in analogous manner to known compounds.
  • P 3 is a protecting group as discussed above, and is suitably BOC.
  • the reaction is suitably carried out using PI FA (phenyl iodosylbis(trifluoroacetate)) and a base such as pyridine in an aqueous solvent, such as aqueous THF, dioxan or acetonitrile. This is the method of Stansfield, C.F. Organic Preparations and Procedures Int., 1990, 10 22(5), 593-603.
  • P ⁇ is a protecting group eg CBZ.
  • This protection reaction may be carried out in a conventional manner. For instance it is suitably carried out in a water miscible solvent such as THF, DMF or dioxan using N-
  • the compound of formula (XXXVIII) can be prepared in conventional manner from diaminobutyric acid.
  • Step (c) This reaction is suitably carried out in two stages.
  • the first stage involves reacting the compound of formula (XXXVIII) at reduced temperature with N- methylmorpholine and then an alkyl chloroformate such as ethyl chloroformate, in an organic solvent such as DCM, dioxan or THF.
  • an alkyl chloroformate such as ethyl chloroformate
  • the product is reduced, suitably with sodium borohydride at reduced temperature, such as -20° to 10°C, in a solvent such as THF.
  • This oxidation reaction may be carried out in any suitable manner, for instance using oxalyl chloride in DMSO and methylene dichloride under nitrogen at reduced temperature, such as -30° to -70°C, followed by triethylamine.
  • the intermediate (XXXX) suitably is not isolated.
  • a phosphonate in a Wadsworth-Emmons reaction.
  • Step (f) This Michael addition reaction is suitably carried out using LHMDS or other strong base in an organic solvent such as THF, ether or toluene, and preferably a complexing agent such as TMEDA is also present.
  • the intermediate compounds of formula (III) may be prepared by reacting a deprotected compound of formula (XX) from Scheme 1 with R 4 R 3 N(CH 2 ) n HetCOOH or R 4 R 3 N(CH 2 ) n HetXY in the manner described above in relation to main process (i) above.
  • the intermediate compounds of formula (IV) may be prepared from a compound of formula (XIX) (with the primary amine suitably protected) in an analogous manner to that described above for preparing a compound of formula (III) from a compound of formula (XX) together with main process (ii) above.
  • Compounds of formula (V) wherein X a represents S may be prepared by reaction of a corresponding compound of formula (III) with a compound of formula R 1 SSR 1 under standard conditions for nucleophilic displacement.
  • Compounds of formula (V) wherein X a represents SO may be prepared by peracid oxidation of a corresponding compound wherein X a represents S.
  • Compounds of formula (VI), (VII) and (VIII) may be prepared from compounds of formula (II) following conventional methods known perse.
  • Mesylate and tosylate derivatives may be prepared from the corresponding alcohol following treatment with MeSO 2 CI or paramethylbenzenesulphonylchloride.
  • Compounds of formula R 4 R 3 N(CH 2 ) n HetCOOH or an acid derivative thereof, and R 4 R 3 N(CH 2 ) n HetXY are either known or may be prepared by conventional methods known perse.
  • Schemes 1 , 2, 3 and 4 may be modified to produce homochiral products by using homochiral starting materials (e.g. S-methionine in Scheme 1 or S-diaminobutyric acid in Scheme 4) or by performing an additional chiral resolution step.
  • homochiral starting materials e.g. S-methionine in Scheme 1 or S-diaminobutyric acid in Scheme 4
  • Both enantiomers of the compound of formula (XIV) may also be produced from a synthesis based on S-methionine or R-methionine following similar procedures.
  • the compounds of the invention have the advantage that they may be more efficacious, show greater selectivity, have fewer side effects, have a longer duration of action, be more bioavailable by the preferred route have more attractive pharmacodynamic or pharmacokinetic properties or have other more desirable properties than similar known compounds.
  • the aqueous phase was extracted with further ethyl acetate (5x250ml), the combined organics were washed with 2M HCI (100ml) and saturated brine solution (100ml), dried (MgSO 4 ), filtered and the solvent evaporated in vacuo to leave a brown solid.
  • the solid was stirred in acetonitrile (900ml) and triethylamine (60ml) and cyclopropylamine (30ml) were added. After stirring for 20 hours at room temperature, further cyclopropylamine (30ml) was added and the mixture stirred for a further 15 minutes.
  • dihydrochloride salts are indicated by the qualification "(2:1)" after the chemical name.
  • Example 1 rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-ylmethyl-furan- 2-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • a mixture of Intermediate 11 (80mg) and pyrrolidine (17mg) in dichloromethane (6ml) was stirred for 2h.
  • Sodium triacetoxyborohydride (69mg) was added and stirring was continued overnight.
  • the reaction mixture was washed with 8% aqueous sodium bicarbonate solution and water.
  • Example 5 rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4-(2-morpholin-4-ylmethyl- furan-3-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • a mixture of Intermediate 12 (50mg) and morpholine (13mg) in dichloromethane (3.5ml) was stirred for 1.5h.
  • Sodium triacetoxyborohydride (43mg) was added and stirring was continued overnight.
  • the reaction mixture was diluted with dichloromethane and extracted with 2M hydrochloric acid.
  • aqueous extracts were made basic with 8% aqueous sodium bicarbonate solution and extracted with dichloromethane.
  • the dichloromethane extracts were washed with brine, dried (Na 2 SO 4 ) and the solvent removed in vacuo to leave a solid, which was treated with 1.0M. hydrogen chloride in diethyl ether to give the title compound as a cream solid (32mg).
  • Example 11 rel-(3R,3aR,6aS)-4-(5-Dimethylaminomethyl-thiophene-2-carbonyl)-3-isopropyl- 1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • the reaction mixture was diluted with dichloromethane and extracted with 2M hydrochloric acid.
  • the aqueous extracts were washed with dichloromethane then made basic with 2M sodium carbonate solution and extracted with dichloromethane.
  • Example 12 was prepared in a similar manner to Example 11 from Intermediate 13:
  • Example 13 rel-(3S,3aS,6aR)-3-lsopropyl-1-methanesulfonyl-4-(5-morpholin-4-ylmethyl-1 H- pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • the aqueous phase was further extracted with ethyl acetate (30ml).
  • the combined organic phases were dried (Na 2 SO 4 ) and the solvent evaporated in vacuo to leave a gum.
  • Example 15 rel-(3S, 3aS,6aR)-3-lsopropyl-1-methanesulfonyl-4-(5-piperidin-1 -ylmethyl-1 H- pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • Example 16 rel-(3S,3aS,6aR)-3-lsopropyl-1 -methanesulfonyl-4-(5-pyrrolidin-1 -ylmethyl-1 H- pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • Example 17 rel-(3S,3aS,6aR)-3-lsopropyl-1-methanesulfonyl-4-[5-(4-phenyl-piperazin-1- ylmethyl)-1H-pyrrole-2-carbonyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2) Cream powder, Melting Point 156-160°C
  • Example 23 rel-(3S,3aS,6aR)-4-(5-Dimethylaminomethyl-1-methyl-1H-pyrrole-2-carbonyl)-3- isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • Example 24 rel-(3S,3aS,6aR)-3-lsopropyl-1 -methanesulfonyl-4-(1 -methyl-5-pyrrolidin-1 - ylmethyl-1 H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • Example 26 rel-(3S,3aS,6aR)-4-(4-Dimethylaminomethyl-1 H-pyrrole-2-carbonyl)-3-isopropyl- 1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • a mixture of Intermediate 14 (80mg), paraformaldehyde (25mg), dimethylammonium chloride (38mg) and activated 4 Angstrom molecular sieves (200mg) in ethanol (10ml) was stirred and heated at reflux for 24h. The mixture was cooled to room temperature and the- solvent was evaporated in vacuo to leave a gum.
  • the gum was purified by flash column chromatography, using two columns (Merck 9385 silica; eluent dichloromethane:ethanol:ammonia; 80:8:1 for the first column, 100:8:1 for the second column) to isolate a white powder (16mg) which was treated with 1.0M. hydrogen chloride in diethyl ether to give the title compound as a white powder (16mg).
  • reaction mixture was stirred for 1.5h. An aliquot (7ml) was removed and added to a stirred solution of pyrrolidine (30mg) in dichloromethane (2ml). The solution was stirred for 2 days. Aqueous 8% sodium bicarbonate solution (12ml) was added, with vigorous stirring. The aqueous phase was separated and extracted with dichloromethane (15ml). The organic phases were combined and dried (Na 2 SO ). The solvent was removed in vacuo to leave a semi-solid, which was triturated in diethyl ether (10ml) to give a solid suspension. Cyclohexane (10ml) was added to the suspension and the solvent was decanted.
  • Example 30 rel-(3S,3aS,6aR)-3-lsopropyl-1-methanesulfonyl-4-[2-(4-methyl-piperazin-1- ylmethyl)-thiazole-4-carbonyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride (1 :2) White powder, Melting Point 153-158°C
  • Example 36 rel-(3S,3aS,6aR)-4-(2-Dimethylaminomethyl-thiazole-4-carbonyl)-3-isopropyl-1- methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • Oxalyl chloride (127mg) was added to a stirred suspension of Intermediate 19 (125mg) in dichloromethane (10ml), followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1.0h. then concentrated in vacuo. The residue was suspended in dichloromethane (15ml) and treated, with stirring, with Intermediate 10 (43mg) and sodium bicarbonate (175mg).
  • Example 37 rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4-(5-morpholin-4-ylmethyl- isoxazole-3-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • a mixture of Intermediate 21 (50mg) and morpholine (13mg) in dichloromethane (5ml) was stirred for 1.5h.
  • Sodium triacetoxyborohydride (43mg) was added and stirring was continued for 2.5h.
  • the reaction mixture was washed with 8% aqueous sodium bicarbonate solution.
  • Example 62 rel-(3R,3aR,6aS)-3-lsopropyl-4- ⁇ 6-[(1-isopropyl-2-methyl-propylamino)-methyl]- pyridine-3-carbonyl ⁇ -1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)
  • Example 65 rel-(3R,3aR,6aS)-4-(5-Cyclopropylaminomethyl-pyrazine-2-carbonyl)-3- 15 isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • reaction mixture was partitioned between 2M sodium carbonate solution (3ml) and dichloromethane (3ml). The phases were separated. The organic phase was passed through a Varian SPE cartridge (which had been pre-conditioned by eluting through a column volume of dichloromethane), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate,
  • Circular Dichroism ⁇ max 250.2nm ( ⁇ E -1.34M “1 cm “1 ) ⁇ max 285.4nm ( ⁇ E +0.99M “ 1 ), (MeCN/H 2 O)
  • Example 76 (alternative preparation) A mixture of Intermediate 46 (1.056g), cyclopropylamine (0.73ml) and potassium iodide (481 mg) in acetonitrile (25ml) was stirred for 3 hours. The solvent was evaporated in vacuo and the mixture partitioned between sat. sodium bicarbonate solution (20ml) and dichloromethane (20ml). The phases were separated. The aqueous phase was further extracted with dichloromethane (2x20ml) The combined organics were dried (MgSO 4 ), filtered and the solvent removed in vacuo to leave an oil.
  • the aqueous phase was separated and extracted with dichloromethane (150ml). The combined organics were washed with brine (250ml), dried (MgSO ) and concentrated in vacuo to leave a brown solid.
  • the solid was purified by flash column chromatography (Merck 9385 silica; eluent dichloromethane:ethanol:ammonia 150:8:1 to 135:8:1) to give a cream solid (29.3g).
  • the solid was dissolved in dichloromethane (150ml) and treated with 1.0M. hydrogen chloride in ether (75ml). The solvent was removed in vacuo to leave a solid which was again dissolved in dichloromethane (150ml) and treated with 1.0M.
  • Example 78 rel-(3S,3aS,6aR)-3-lsopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-ylmethyl- oxazole-4-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • a stirred suspension of Intermediate 56 (second preparation: 40mg) in dichloromethane (4ml) was treated with oxalyl chloride (63mg) followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1.5h. The solvent was removed in vacuo and replaced by toluene (10 ml). The resultant suspension was triturated vigorously for 10 min.
  • Example 80 rel-(3S,3aS,6aR)-3-lsopropyl-1-methanesulfonyl-4-[2-(4-phenyl-piperazin-1- ylmethyl)-oxazole-4-carbonyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride Cream solid, melting point 156-160°C.
  • Example 82 rel-(3S,3aS,6aR)-4- ⁇ 2-[(Cyclopropyl-methyl-amino)-methyl]-oxazole-4-carbonyl ⁇ -
  • Example 83 was prepared in a similar manner to Example 82 from Intermediate 10 and Intermediate 52:
  • Example 83 rel-(3S,3aS,6aR)-4- ⁇ 2-[(Dicyclohexylamino)-methyl]-oxazole-4-carbonyl ⁇ -3- isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • Example IC 50 ( ⁇ M) Example IC 50 ( ⁇ M)
  • Example ICso ( ⁇ M) Example IC 50 ( ⁇ M)

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Abstract

L'invention concerne des composés représentés par la formule (I) dans laquelle R?1, R2 et R3¿ sont tels qu'ils sont définis dans le descriptif. Ces composés sont utiles notamment pour traiter des maladies inflammatoires des voies respiratoires.
EP98951348A 1997-09-09 1998-09-07 Derives de pyrrolopyrrolone en tant qu'inhibiteurs de neutrophile elastase Withdrawn EP1003748A2 (fr)

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Application Number Priority Date Filing Date Title
GB9719189 1997-09-09
GBGB9719189.4A GB9719189D0 (en) 1997-09-09 1997-09-09 New therapeutic method
GBGB9719183.7A GB9719183D0 (en) 1997-09-09 1997-09-09 Compounds
GB9719183 1997-09-09
GB9719290 1997-09-10
GBGB9719290.0A GB9719290D0 (en) 1997-09-10 1997-09-10 Compounds
GB9803611 1998-02-21
GBGB9803611.4A GB9803611D0 (en) 1998-02-21 1998-02-21 Compounds
PCT/EP1998/005609 WO1999012933A2 (fr) 1997-09-09 1998-09-07 Derives de pyrrolopyrrolone en tant qu'inhibiteurs de neutrophile elastase

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US7429659B2 (en) 2004-03-31 2008-09-30 Janssen Pharmaceutica N.V. Furan compounds as histamine H3 modulators
DE102004024772A1 (de) * 2004-05-17 2005-12-22 Grünenthal GmbH Substituierte 5-Aminomethyl-1H-pyrrol-2-carbonsäureamide
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TWI355380B (en) 2004-05-27 2012-01-01 Nihon Nohyaku Co Ltd Substituted pyrazinecarboxanilide derivatives or s
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ATE439347T1 (de) 2004-11-23 2009-08-15 Warner Lambert Co 7-(2h-pyrazol-3-yl)-3,5-dihydroxy-heptansäure- derivate als hmg-co-a-reductase-inhibitoren zur behandlung von lipidemia
US8198288B2 (en) 2006-05-04 2012-06-12 Pulmagen Therapeutics (Inflammation) Limited Tetrahydropyrrolopyrimidinediones and their use in therapy
WO2007129060A1 (fr) 2006-05-04 2007-11-15 Argenta Discovery Limited Tétrahydropyrrolopyrimidinediones et leur utilisation comme inhibiteurs de l'élastase neutrophile humaine
US7662967B2 (en) 2007-08-02 2010-02-16 Cambridge Enterprise Limited Anti-inflammatory compounds and compositions
GB2452696B (en) 2007-08-02 2009-09-23 Cambridge Entpr Ltd 3-(2',2'-dimethylpropanoylamino)-tetrahydropyridin-2-one and its use in pharmaceutical compositions
WO2009060206A1 (fr) * 2007-11-07 2009-05-14 Argenta Discovery Limited 3,4,6,7-tétrahydro-1h-pyrrolo[3,4-d]pyrimidine-2,5-diones et leur utilisation thérapeutique
US20110212181A1 (en) * 2010-02-26 2011-09-01 The University Of Hong Kong Compositions and methods for treating chronic respiratory inflammation
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DK4106757T3 (da) 2020-04-16 2023-10-23 Mereo Biopharma 4 Ltd Fremgangsmåder der involverer neutrofil elastase-inhibitor alvelestat til behandling af luftvejssygdom medieret af alpha-1-antitrypsin-mangel
CA3234399A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'elastase neutrophile utilises dans le traitement de la fibrose

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