WO2008096093A1 - Dérivés d'oxazole et de thiazole et leurs utilisations - Google Patents

Dérivés d'oxazole et de thiazole et leurs utilisations Download PDF

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Publication number
WO2008096093A1
WO2008096093A1 PCT/GB2007/000395 GB2007000395W WO2008096093A1 WO 2008096093 A1 WO2008096093 A1 WO 2008096093A1 GB 2007000395 W GB2007000395 W GB 2007000395W WO 2008096093 A1 WO2008096093 A1 WO 2008096093A1
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WIPO (PCT)
Prior art keywords
phenyl
hydroxy
methyl
ammonium
dimethyl
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PCT/GB2007/000395
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English (en)
Inventor
Nicholas Charles Ray
Richard James Bull
Harry Finch
Marco Van Den Heuvel
Jose Antonio Bravo
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Argenta Discovery Ltd.
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Priority to PCT/GB2007/000395 priority Critical patent/WO2008096093A1/fr
Publication of WO2008096093A1 publication Critical patent/WO2008096093A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to oxazole and thiazole derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of diseases where enhanced M3 receptor activation is implicated.
  • Anti-cholinergic agents prevent the passage of, or effects resulting from the passage of, impulses through the parasympathetic nerves. This is a consequence of the ability of such compounds to inhibit the action of acetylcholine (Ach) by blocking its binding to the muscarinic cholinergic receptors.
  • mAChRs muscarinic acetylcholine receptors
  • M1-M5 muscarinic acetylcholine receptors
  • M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Then, 58, 319 - 379).
  • muscarinic receptors M1 , M2 and M3 have been demonstrated to be important and are localized to the trachea, the bronchi, submucosal glands and parasympathetic ganglia (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) S 154 - 160).
  • M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.
  • vagal tone may either be increased (Gross et a/. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross et al. 1984, Am Rev Respir Dis; 129:856-870).
  • M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
  • Tiotropium (Spiriva TM) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.
  • ipratropium is a muscarinic antagonist marketed for the treatment of COPD.
  • WO97/30994 describes oxadiazoles and thiadiazoles as muscarinic receptor antagonists.
  • EP0323864 describes oxadiazoles linked to a mono- or bicyclic ring as muscarinic receptor modulators.
  • R 1 is Ci-C 6 -alkyl or hydrogen; and R 2 is hydrogen or a group -R 7 , -Z-Y-R 7 , -Z-NR 9 R 10 ; -Z-CO-NR 9 R 10 , -Z-NR 9 -C(O)O-R 7 , or ; -Z-C(O)-R 7 ; and R 3 is a lone pair, or C-
  • R 1 and R 3 together with the nitrogen to which they are attached form a , heterocycloalkyl ring, and R 2 is a lone pair or a group -R 7 , -Z-Y-R 7 , -Z-NR 9 R 10 , -Z-CO-NR 9 R 10 , -Z-NR 9 -C(O)O-R 7 ; or -Z-C(O)-R 7 ; or
  • R 1 and R 2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group -Y-R 7 , -Z-Y-R 7 , -Z- NR 9 R 10 ; -Z-CO-NR 9 R 10 ; -Z-NR 9 -C(O)O-R 7 ; or ; -Z-C(O)-R 7 ; and R 3 is a lone pair, or C-rCe-alkyl; R 4 and R 5 are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, C r C 6 -alkyl, cycloalkyl;
  • R 6 is -OH, C r C 6 -alkyl, C r C 6 -alkoxy hydroxy-C r C 6 -alkyl, nitrile, a group CONR 8 2 or a hydrogen atom;
  • A is an oxygen or a sulfur atom;
  • X is an alkylene, alkenylene or alkynylene group;
  • R 7 is an Ci-C 6 -alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(CrC 8 -alkyl)-, heteroaryl(C r C 8 -alkyl)-, cycloalkyl or heterocycloalkyl group;
  • R 8 is C r C 6 -alkyl or a hydrogen atom;
  • Z is a Ci-C-i6-alkylene, C 2 -C 16 -alkenylene or C 2 -C 16 -alkynylene group;
  • Y is a bond or oxygen atom;
  • R 9 and R 10 are independently a hydrogen atom, CrCe-alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C r C 6 -alkyl)-, or heteroaryl (C 1 - C 6 -alkyl)- group; or R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom; or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof.
  • the present invention provides compounds falling within the scope of, but not specifically disclosed in, our copending application PCT/GB2006/002956 referred to above.
  • the present invention provides a quaternary ammonium compound of formula
  • D is a pharmaceutically acceptable anion selected from the group comprising chloride, bromide, sulfate, methanesulfonate, benzenesulfonate, toluenesulfonate
  • the present invention covers all permissible ratios of cationic ammonium species to anion D, for example hemi-napadisylate and napadisylate.
  • Suitable pharmaceutically acceptable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate.
  • D is a pharmaceutically acceptable anion selected from the group comprising bromide and napadisylate (for example naphthalene-1 , 5-disulfonate); wherein the number of quaternary ammonium species balances the anion D such that compound of formula (I) has no net charge.
  • bromide and napadisylate for example naphthalene-1 , 5-disulfonate
  • Compounds of the invention may be useful in the treatment or prevention of diseases in which activation of muscarinic receptors are implicated, for example the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease, COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'whez- infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy, pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacos
  • a compound of present invention is useful in the treatment or prevention of respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease, COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'whez-infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy or pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis).
  • respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is implicated.
  • the present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention.
  • Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
  • the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
  • the invention includes a combination of an agent of the invention as hereinbefore described with one or more anti-inflammatory, bronchodilator, antihistamine, decongestant or anti-tussive agents, said agents of the invention hereinbefore described and said combination agents existing in the same or different pharmaceutical compositions, administered separately or simultaneously.
  • Preferred combinations would have two or three different pharmaceutical compositions.
  • Suitable therapeutic agents for a combination therapy with compounds of the invention include: One or more other bronchodilators such as PDE3 inhibitors; Methyl xanthines such as theophylline; Other muscarinic receptor antagonists;
  • a corticosteroid for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
  • a non-steroidal glucocorticoid receptor agonist for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
  • a ⁇ 2-adrenoreceptor agonist for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK-597901 , GSK-159802, GSK-64244, GSK-678007, TA-2005 and also compounds of EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651 , US2005/0133417, US2005/5159448, WO00/075114, WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204, WO03
  • a leukotriene modulator for example montelukast, zafirlukast or pranlukast
  • protease inhibitors such as inhibitors of matrix metalloprotease for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333
  • MMP12 matrix metalloprotease
  • TACE inhibitors such as marimastat, DPC-333, GW-3333
  • Human neutrophil elastase inhibitors such as sivelestat and those described in WO04/043942, WO05/021509, WO05/021512, WO05/026123, WO05/026124, WO04/024700, WO04/024701 , WO04/020410, WO04/020412, WO05/080372, WO05/082863, WO05/082864, WO03/053930; Phosphodiesterase-4 (PDE4) inhibitors, for example roflumilast, arofylline, cilomilast,
  • An antitussive agent such as codeine or dextramorphan
  • Kinase inhibitors particularly P38 MAPKinase inhibitors
  • P2X7 anatgonists P2X7 anatgonists; iNOS inhibitors;
  • NSAID non-steroidal anti-inflammatory agent
  • ibuprofen or ketoprofen for example ibuprofen or ketoprofen
  • dopamine receptor antagonist for example ibuprofen or ketoprofen
  • TNF- ⁇ inhibitors for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel;
  • A2a agonists such as those described in EP1052264 and EP1241176;
  • A2b antagonists such as those described in WO2002/42298; Modulators of chemokine receptor function, for example antagonists of CCR1 , CCR2,
  • Th1 or Th2 function Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterleukin 10 agonists, such as llodecakin;
  • HMG-CoA reductase inhibitors for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin; Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-
  • Antiinfective agents antibiotic or antiviral
  • antiallergic drugs including, but not limited to, antihistamines.
  • the weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • the active compound may be administered by any convenient, suitable or effective route.
  • Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.
  • prophylactic or therapeutic dose of a compound of the invention will, of course, vary depending upon a range of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment.
  • the daily dose range for inhalation will lie within the range of from about ⁇ 0.1 ⁇ g to about 10 mg per kg body weight of a human, preferably 0.1 ⁇ g to about 0.5 mg per kg, and more preferably 0.1 ⁇ g to 50 ⁇ g per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions.
  • the composition may contain 0.01-99% by weight of active compound.
  • a unit dose comprises the active compound in an amount of 1 ⁇ g to 10 mg.
  • suitable doses are 10 ⁇ g per kg to 100mg per kg, preferably 40 ⁇ g per kg to 4 mg per kg.
  • compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids, and salts of quaternary ammonium compounds with pharmaceutically acceptable counter-ions.
  • the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation.
  • a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI).
  • PMDI pressurised metered dose inhaler
  • Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI 2 F 2 ) and HFA-152 (C 2 H 4 F 2 ) and isobutane.
  • a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • Microparticles for delivery by administration may be formulated with excipients that aid delivery and release.
  • microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung.
  • Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 ⁇ m.
  • the active compounds may be dosed as described depending on the inhaler system used.
  • the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • the compounds of the invention can be prepared by using or adapting the methods described in the Examples, or by adapting methodology described in the art (eg common general knowledge, patent literature or chemical journals).
  • NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5mm inverse detection triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 5mm inverse detection triple resonance TXI probe operating at 400MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300MHz. Shifts are given in ppm relative to tetramethylsilane.
  • 'flash silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution.
  • thin layer chromatography TLC
  • it refers to silica gel TLC using plates, typically 3 * 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm), (e.g. Fluka 60778). All solvents and commercial reagents were used as received.
  • MS ionisation method Electrospray (positive and negative ion)
  • MS ionisation method Electrospray (positive and negative ion)
  • MS ionisation method Electrospray (positive and negative ion).
  • DIPEA di-isopropylethylamine
  • DMAP dimethylaminopyridine
  • DMF dimethylformamide
  • EtOAc ethyl acetate
  • EtOH ethanol
  • Oxalyl chloride (6.1g, 48mmol) was added to a solution of phenylglyoxylic acid (6.Og, 40mmol) and 3 drops of DMF in dry DCM (50ml). The reaction mixture was stirred at room temperature for 3 hours then the solvent was removed. The residue was taken up in dry DCM (50ml) and the solution.was cooled to 0 0 C. A mixture of propargyl amine (2.2g, 40 mmoi) and triethylamine (4.05g, 40mmol) was added cautiously over a period of 10 minutes then the mixture was allowed to warm to room temperature. Stirring was continued for 2.5 hours then water (10ml) was added.
  • reaction mixture was cooled to O 0 C again and treated cautiously with sat. ammonium chloride solution (aq) (1OmL).
  • aq ammonium chloride solution
  • the mixture was stirred at room temperature for 10mins then diluted with water (1 OmL).
  • the phases were separated and the organic phase was washed with brine.
  • the combined aqueous phase was extracted with DCM (3 x 2OmL) and the combined organic phase was dried (MgSO 4 ) and concentrated in vacuo to give the crude product which was triturated with ether (1OmL), filtered off and dried.
  • Methanesulfonic acid 3-phenoxy-propyl ester Prepared according to the method used for Intermediate 19 but using 3-phenoxy- propanol in place of 2-(4-methoxy-benzyloxy)-ethanol.
  • Example 6 (s, 1H), 5.00 (s, 2H), 7.20 (t, 1 H), 7.23-7.30 (m, 4H), 7.31-7.41 (m, 5H), 7.43 (s, 1 H).
  • Example 9 1 H), 3.11 (s, 3H), 3.12 propyl]-dimethyl- (s, 3H) 1 3.42 (m, 2H), ammonium 4.00 (m, 2H), 4.77 (s, bromide. (from 2H), 6.88 (dd, 1 H), second enantiomer) 7.11 (d, 1 H), 7.21 (t, 1 H), 7.29 (t, 2H), 7.42 (d, 1 H), 7.51 (m, 3H).
  • Example 10 dimethyl-ammonium 3H), 3.13 (s, 3H), 3.45 bromide. (from (m, 3H), 4.07 (m, 2H), second enantiomer) 4.77 (s, 2H), 6.98 (m, 2H), 7.21 (t, 1 H), 7.28 (m, 2H), 7.39 (m, 2H), 7.52 (s, 1 H), 7.86 (m, 2H).
  • Example 11 benzyloxy)-ethyl]- (s, 3H), 3.94 (m, 2H), dimethyl-ammonium 4.00 (m, 2H), 4.67 (s, bromide. 2H), 5.14 (dd AB , 2H), 7.24 (t, 1 H), 7.32 (t, 2H), 7.48 (m, 3H), 7.56 (d, 2H), 7.76 (d, 2H).
  • Example 13 ethyl)-ammonium 2H), 2.95 (s, 6H), 3.41 bromide. (from (m, 1 H), 3.47 (m, 2H), second enantiomer) 3.77 (t, 2H), 3.85 (m, 2H), 4.55 (dd AB , 2H), 7.12 (m, 1H), 7.21 (m, 4H), 7.25 (t, 1 H), 7.32 (m, 2H), 7.37 (s, 1 H), 7.40 (m, 2H).
  • Example 27 ethoxy]-ethyl ⁇ - 2H), 3.72 (t, 2H), 3,81- dimethyl-ammonium 3.87 (m, 2H), 4.58 (s, bromide 2H), 6.65-6.70 (m, 2H), 7.00-7.05 (m, 2H), 7.23-7.28 (m, 1 H), 7.31-7.36 (m, 2H), 7.38 (s, 1 H), 7.50-7.55 (m, 2H).
  • Example 28 phenoxy)-propyl]- 3.38-3.57 (m, 2H), dimethyl ammonium 3.89-4.05 (m, 2H) 1 bromide 4.77 (s, 2H), 6.66- 6.81 (m, 4H), 7.17- 7.37 (m, 3H), 7.47- 7.59 (m, 3H).
  • the RM was concentrated to dryness, redissolved in a mixture of DCM and acetonitrile, absorbed onto isolute HMN and purified by chromatography using a 5g isolute silica gel cartridge eluting with a gradient of 0-7% methanol in DCM.
  • the material was treated with tetrahydrofuran (2.5ml_) and 2.5ml_ of a mixture of HBr (48%, 0.4ml_) and water (4ml_). The mixture was stirred at RT for 3 days.
  • the RM was concentrated in vacuo, treated with methanol and re-evaporated (x 2).
  • Example 38 ammonium 4.00 (s, 1H), 4.03 (t, bromide. (from 2H), 5.19 (d, 1 H), 5.30 second enantiomer) (d, 1H), 6.85 (d, 2H), 6.97 (t, 1 H), 7.19 (t, 1 H), 7.25-7.31 (m, 4H), 7.57 (m, 3H).
  • Example 39 ammonium (m, 2H), 3.97 (s, 1 H), bromide, (from first 4.04 (t, 2H), 5.17 (d, enantiomer) 1H), 5.32 (d, 1H), 6.85 (d, 2H), 6.97 (t, 1 H), 7.20 (t, 1H), 7.25-7.31 (m, 4H), 7.58 (m, 3H).
  • Example 40 ammonium (m, 2H), 3.91 (s, 1 H), bromide. (from 4.04 (t, 2H), 5.18 (d, second enantiomer) 1 H) 1 5.33 (d, 1 H) 1 6.85 (d, 2H), 6.98 (t, 1 H), 7.20 (t, 1 H), 7.25-7.31 (m, 4H), 7.58 (m, 3H).
  • Example 45 tosylate from 2H), 4.43 (s, 2H), 4.63 second enantiomer) (s, 1H), 4.74-4.91 (dd, 2H), 7.06 (d, 2H), 7.14-7.30 (m, 5H), 7.32 (s, 1 H), 7.56 (d, 2H), 7.68 (d, 2H), 7.79 (d, 2H).
  • Radioligand binding studies utilising [ 3 H]-N-methyl scopolamine ([ 3 H]-NMS) and commercially available cell membranes expressing the human muscarinic receptors (M2 and M3) were used to assess the affinity of muscarinic antagonists for M2 and M3 receptors.
  • Membranes in TRIS buffer were incubated in 96-well plates with [ 3 H]- NMS and M3 antagonist at various concentrations for 3 hours. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Canberra Packard Topcount scintillation counter
  • the half-life of antagonists at each muscarinic receptor was measured using the alternative radioligand [ 3 H]-QNB and an adaptation of the above affinity assay.
  • Antagonists were incubated for 3 hours at a concentration 10-fold higher than their Ki, as determined with the [ 3 H]-QNB ligand, with membranes expressing the human muscarinic receptors. At the end of this time, [ 3 H]-QNB was added to a concentration 25-fold higher than its Kd for the receptor being studied and the incubation continued for various time periods from 15 minutes up to 180 minutes. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Canberra Packard Topcount scintillation counter.
  • the rate at which [3H]-QNB is detected binding to the muscarinic receptors is related to the rate at which the antagonist dissociates from the receptor, ie. to the half life of the antagonists on the receptors.
  • Example 2 had a Ki value of 0.09nM
  • Example 13 had a ki value of 0.06nM.
  • CHO cells expressing the human M3 receptor were seeded and incubated overnight in 96 well collagen coated plates (black-wall, clear bottom) at a density of 50000 / 75 ⁇ l of medium in 3% serum.
  • a calcium-sensitive dye (Molecular Devices, Cat # R8041) was prepared in HBSS buffer with the addition of 5mM probenecid (pH 7.4).
  • An equal volume of the dye solution (75 ⁇ l) was added to the cells and incubated for 45 minutes followed by addition of 50 ⁇ l of muscarinic antagonists or vehicle. After a further 15 minutes the plate was read on a FLEXstationTM (excitation 488nm, emission 525nm) for 15 seconds to determine baseline fluorescence.
  • the muscarinic agonist Carbachol was then added at an EC 8O concentration and the fluorescence measured for a further 60 seconds.
  • the signal was calculated by subtracting the peak response from the mean of the baseline fluorescence in control wells in the absence of antagonist. The percentage of the maximum response in the presence of antagonist was then calculated in order to generate IC 50 curves.
  • Tracheae were removed from adult male Dunkin Hartley Guinea pigs and dissected free of adherent tissue before being cut open longitudinally in a line opposite the muscle. Individual strips of 2-3 cartilage rings in width were cut and suspended using cotton thread in 10ml water-jacketed organ baths and attached to a force transducer ensuring that the tissue is located between two platinum electrodes. Responses were recorded via a MPIOOW/Ackowledge data acquisition system connected to a PC. Tissues were equilibrated for one hour under a resting tone of 1g and were then subjected to electrical field stimulation at a frequency of 80Hz with a pulse width of 0.1ms, a unipolar pulse, triggered every 2 minutes.
  • a "voltage-response" curve was generated for each tissue and a submaximal voltage then applied to every piece of tissue according to its own response to voltage. Tissues were washed with Krebs solution and allowed to stabilize under stimulation prior to addition of test compound. Concentration response curves were obtained by a cumulative addition of test compound in half-log increments. Once the response to each addition had reached a plateau the next addition was made. Percentage inhibition of EFS-stimulated contraction is calculated for each concentration of each compound added and dose response curves constructed using Graphpad Prism software and the EC 50 calculated for each compound.
  • Methacholine Induced Bronchoconstriction in vivo Male Guinea pigs (Dunkin Hartley), weighing 500-60Og housed in groups of 5 were individually identified. Animals were allowed to acclimatize to their local surroundings for at least 5 days. Throughout this time and study time animals were allowed access to water and food ad libitum. Guinea pigs were anaesthetized with the inhaled anaesthetic Halothane (5%). Test compound or vehicle (0.25 - 0.50 ml/kg) was administered intranasally. Animals were placed on a heated pad and allowed to recover before being returned to their home cages.
  • guinea pigs were terminally anaesthetized with Urethane (250 ⁇ g/ml, 2ml/kg).
  • Urethane 250 ⁇ g/ml, 2ml/kg.
  • the jugular vein was cannulated with a portex i.v. cannula filled with heparinised phosphate buffered saline (hPBS) (10U/ml) for i.v. administration of methacholine.
  • hPBS heparinised phosphate buffered saline
  • the trachea was exposed and cannulated with a rigid portex cannula and the oesophagus cannulated transorally with a flexible portex infant feeding tube.
  • the spontaneously breathing animal was then connected to a pulmonary measurement system (EMMS, Hants, UK) consisting of a flow pneumotach and a pressure transducer.
  • the tracheal cannula was attached to a pneumotach and the oesophageal cannula attached to a pressure transducer.
  • the oesophageal cannula was positioned to give a baseline resistance of between 0.1 and 0.2cmH20/ml/s.
  • a 2 minute baseline reading was recorded before i.v. administration of methacholine (up to 30 ⁇ g/kg, 0.5ml/kg).
  • a 2 minute recording of the induced constriction was taken from the point of i.v. administration.
  • the software calculated a peak resistance and a resistance area under the curve (AUC) during each 2 minute recording period which were used to analyse the bronchoprotective effects of test compounds.
  • Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK and acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs were randomly assigned into treatment groups and weighed. Each animal was lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally (0.5ml/kg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs were terminally anaesthetised with urethane (25% solution in H20, 1.5g/kg).
  • Saliva production was calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period could be analysed in addition to the whole 15 minute recording period. Baseline production of saliva was assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes.

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Abstract

L'invention concerne un composé d'ammonium quaternaire de formule (I) ayant une activité antagoniste du récepteur M3; une composition comprenant ce composé; l'utilisation de ce composé en thérapie (telle que le traitement de l'asthme ou de COPD (maladie pulmonaire obstructive chroniquesdu cheval)); et une méthode visant à traiter un patient avec ce composé.
PCT/GB2007/000395 2007-02-06 2007-02-06 Dérivés d'oxazole et de thiazole et leurs utilisations WO2008096093A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110046191A1 (en) * 2007-02-07 2011-02-24 Argenta Discovery Ltd. Combination of a muscarinic receptor antagonist and a beta-2-adrenoceptor agonist
US8207193B2 (en) 2006-11-14 2012-06-26 Astrazeneca Ab Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323864A2 (fr) * 1988-01-08 1989-07-12 Merck Sharp & Dohme Ltd. Oxadiazoles lipophiles
WO1997030994A1 (fr) * 1996-02-22 1997-08-28 Pfizer Research And Development Company, N.V./S.A. Oxa- et thia-diazoles utilises comme antagonistes des recepteurs muscariniques
WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323864A2 (fr) * 1988-01-08 1989-07-12 Merck Sharp & Dohme Ltd. Oxadiazoles lipophiles
WO1997030994A1 (fr) * 1996-02-22 1997-08-28 Pfizer Research And Development Company, N.V./S.A. Oxa- et thia-diazoles utilises comme antagonistes des recepteurs muscariniques
WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8207193B2 (en) 2006-11-14 2012-06-26 Astrazeneca Ab Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists
US20110046191A1 (en) * 2007-02-07 2011-02-24 Argenta Discovery Ltd. Combination of a muscarinic receptor antagonist and a beta-2-adrenoceptor agonist
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists

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