WO2008096094A1 - Bicyclor[2.2.1]hept-7-ylamine derivatives as muscarinic m3 receptor modulators - Google Patents

Bicyclor[2.2.1]hept-7-ylamine derivatives as muscarinic m3 receptor modulators Download PDF

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WO2008096094A1
WO2008096094A1 PCT/GB2007/000410 GB2007000410W WO2008096094A1 WO 2008096094 A1 WO2008096094 A1 WO 2008096094A1 GB 2007000410 W GB2007000410 W GB 2007000410W WO 2008096094 A1 WO2008096094 A1 WO 2008096094A1
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hydroxy
hept
bicyclo
phenyl
ammonium
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PCT/GB2007/000410
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French (fr)
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Nicholas Charles Ray
Richard James Bull
Harry Finch
Monique Bodil Van Niel
Andrew Stephen Robert Jennings
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Argenta Discovery Ltd.
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Publication of WO2008096094A1 publication Critical patent/WO2008096094A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/32—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and esterified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • This invention relates to bicyclo[2.2.1]hept-7-ylamine derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of M3 muscarinic receptor mediated diseases, for example respiratory diseases.
  • 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.
  • M1-M5 muscarinic acetylcholine receptors
  • M1-M5 muscarinic acetylcholine receptors
  • M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 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 al. 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 a/. 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.
  • heterocycloalkyl ring said ring being substituted by a group -Y-R 5 , or a group -Z-Y- R 5 , or a group -Z-NR 9 R 10 ; or a group -Z-CO-NR 9 R 10 ; or a group -Z-NR 9 -CO-R 5 ; or a group -Z-CO 2 -R 5 ; or a group -Z-CO 2 H and R 3 is a lone pair, or C-i-Ce-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
  • R 4 is selected from one of the groups of formula (a), (b), (c) or (d);
  • Z is a CrC ⁇ -alkylene, C 2 -C 16 -alkenylene or C 2 -C 16 -alkynylene group;
  • Y is a bond or oxygen atom;
  • R 5 is an C-
  • R 6 is C r C 6 -alkyl or a hydrogen atom;
  • R 7a and R 7b are a C r C 6 -alkyl group or halogen;
  • n and m are independently 0, 1 , 2 or 3;
  • R 8a and R 8b are independently selected from the group consisting of aryl, aryl-fused- hetero
  • R 8c is -OH, d-Ce-alkyl, hydroxy-CrC 6 -alkyl, nitrile, a group CONR 8d 2 or a hydrogen atom;
  • R 8d is C r C 6 -alkyl or a hydrogen atom;
  • R 9 and R 10 are independently a hydrogen atom, CrC ⁇ -alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryKd-Ce-alkyl)-, or heteroaryl(d- 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;
  • R 12 is Ci-C 6 -alkyl or a hydrogen atom;
  • Ar 1 is aryl, heteroaryl or cycloalkyl;
  • Ar 2
  • the present invention provides compounds falling within the scope of, but not specifically disclosed in, our copending application PCT/GB2006/002957 referred to above.
  • the present invention provides a compound which has a quaternary ammonium species: anf/-[(1S,2R)-8-(tert-Butoxycarbonyl-methyl-amino)-octyl]-[2-(2-hydroxy-2,2-di- thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium; a/?f/-(1S,2R)-[2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(3- phenyl-propyl)-ammonium; a/if/-(1S,2R)-[2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(4- phenyl-butyl)-ammonium; a
  • the present invention covers all permissible ratios of quaternary ammonium species to pharmaceutically acceptable anion, for example hemi-napadisylate and napadisylate.
  • a pharmaceutically acceptable anion is bromide or napadisylate (for example naphthalene-1 ,5-disulfonate), wherein the number of quaternary ammonium species balances the pharmaceutically acceptable anion such that compound of the invention has no net charge.
  • 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.
  • the substituent on position 2 couid be orientated endo- or exo-, and the substituent on position 7 could be orientated syn- or anti-.
  • the compounds of the present invention have anti- endo- orientation as shown below (where A and T are substituent groups).
  • 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 the invention is useful in the treatment or prevention of a respiratory-tract disorder 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, tabacosis and byssinosis).
  • a respiratory-tract disorder such as chronic obstructive lung disease (also known as chronic o
  • quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose.
  • parenteral route usually the oral route, may be preferred.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier 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.
  • Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
  • 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:
  • 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; A ⁇ 2-adrenoreceptor agonist, for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arform
  • 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
  • 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; iNOS inhibitors;
  • NSAID non-steroidal anti-inflammatory agent
  • ibuprofen or ketoprofen 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, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB-
  • DP1 or CRTH2 a thromboxane A 2 antagonist eg ramatroban
  • 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 Ilodecakin;
  • 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- 333, MSI-1956, gefitinib;
  • Antiinfective agents antibiotic or antiviral
  • antiallergic drugs including, but not limited to, anti-histamines.
  • 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.
  • an example is: Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister Trichlorofluoromethane, NF 4.025 g / canister
  • the active compounds may be closed 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 according to the procedures of the Examples, or by modifying procedures described in the art (such as in common general knowledge, the patent literature or the chemical journal literature).
  • 'flash silica 1 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 x 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.
  • Phenyl hexyl column (250 x 21.20 mm Luna column with 5 ⁇ m particle size), eluting with a gradient of A: water + 0.1 % TFA; B: acetonitrile + 0.1 % TFA at a flow rate of 5 ml/min with UV detection at 254 nm.
  • Micromass Platform LCT with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 ⁇ m particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid.
  • MS ionisation method Electrospray (positive and negative ion)
  • MS ionisation method Electrospray (positive and negative ion)
  • Example 20 anW-tiS ⁇ RJ- ⁇ -Hydroxy- ⁇ H-xanthene- ⁇ -carboxylic acid 7-[methyl-(4-pyrim ⁇ din-5- yl-but-3-ynyl)-amino]-bicyclo[2.2.1]hept-2-yl ester
  • Example 22 anf/ ' -f1S,2R)-f2-(2-Hvdroxy-2,2-di-thiophen-2-yl-acetoxy)-bicvclor2.2.nhept-7-v ⁇ - dimethvir3(3-methvI-1,2,4-oxadiazol-5-yl)-propyll-ammonium bromide
  • 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 TRlS 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.
  • 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 5 mM 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.
  • the plate was read on a FLEXstationTM (excitation 488 nm, emission 525 nm) 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.
  • the inhibitory effects of compounds of the present invention at the M3 muscarinic Receptor may be evaluated in the following ex-viva and in vivo assays:
  • mice Male Guinea pigs (Dunkin Hartley), weighing 500-600 g 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, 2 mL/kg).
  • Urethane 250 ⁇ g/mL, 2 mL/kg.
  • the jugular vein was cannulated with a portex i.v. cannula filled with heparinised phosphate buffered saline (hPBS) (10 U/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.
  • EMMS pulmonary measurement system
  • Hants UK
  • 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 0.2 cmH20/mL/s. A 2 minute baseline reading was recorded before i.v. administration of methacholine (up to 30 ⁇ g/kg, 0.5 mL/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 was used to analyse the bronchoprotective effects of test compounds.

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Abstract

Representatives of compounds of formula (I) having M3 receptor antagonist activity; a composition comprising such a compound; the use of such a compound in therapy (such as asthma or COPD); and a method of treating a patient with such a compound.

Description

BICYCLO [2 . 2 . 1] HEPT- 7 -YLAMINE DERIVATIVES AS MUSCARINIC M3 RECEPTOR MODULATORS
Field of the Invention
This invention relates to bicyclo[2.2.1]hept-7-ylamine derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of M3 muscarinic receptor mediated diseases, for example respiratory diseases.
Background to the invention
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.
There are five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M1-M5, and each is the product of a distinct gene and each displays unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract, M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319 - 379).
In the lungs, 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.
Increased signalling through muscarinic acetylcholine receptors has been noted in a variety of different pathophysiological states including asthma and COPD. In COPD, vagal tone may either be increased (Gross et al. 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 a/. 1984, Am Rev Respir Dis; 129:856-870). In addition, inflammatory conditions can lead to a loss of inhibitory M2 receptor activity which results in increased levels of acetylcholine release following vagal nerve stimulation (Fryer et al, 1999, Life ScL, 64, (6-7) 449-455). The resultant increased activation of M3 receptors leads to enhanced airway obstruction. Thus the identification of potent muscarinic receptor antagonists would be useful for the therapeutic treatment of those disease states where enhanced M3 receptor activity is implicated. Indeed, contemporary treatment strategies currently support regular use of M3 antagonist bronchodilators as first-line therapy for COPD patients (Pauwels et al. 2001 , Am Rev Respir Crit Care Med; 163:1256-1276)
Incontinence due to bladder hypercontractility has also been demonstrated to be mediated through increased stimulation of M3 mAChRs. Thus M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for treatment of airway disease states, relatively few anti-muscarinic compounds are in use in the clinic for pulmonary indications. Thus, there remains a need for novel compounds that are capable of causing blockade at M3 muscarinic receptors, especially those compounds with a long duration of action, enabling a once-daily dosing regimen. Since muscarinic receptors are widely distributed throughout the body, the ability to deliver anticholinergic drugs directly to the respiratory tract is advantageous as it allows lower doses of the drug to be administered. The design and use of topically active drugs with a long duration of action and that are retained on the receptor or in the lung would allow reduction of unwanted side effects that could be seen with systemic administration of the same drugs.
Tiotropium (Spiriva ™) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.
Figure imgf000003_0001
Tiotropium
Additionally ipratropium is a muscarinic antagonist marketed for the treatment of COPD.
Figure imgf000004_0001
ĨI)
heterocycloalkyl ring, said ring being substituted by a group -Y-R5, or a group -Z-Y- R5, or a group -Z-NR9R10; or a group -Z-CO-NR9R10; or a group -Z-NR9-CO-R5; or a group -Z-CO2-R5; or a group -Z-CO2H and R3 is a lone pair, or C-i-Ce-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
R4 is selected from one of the groups of formula (a), (b), (c) or (d);
Figure imgf000005_0001
(a) (b) (C) (d)
Z is a CrC^-alkylene, C2-C16-alkenylene or C2-C16-alkynylene group; Y is a bond or oxygen atom; R5 is an C-|-C6-alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(CrC8-alkyl)-, heteroaryl(CrC8-alkyl)-, cycloalkyl or heterocycloalkyl group; R6 is CrC6-alkyl or a hydrogen atom; R7a and R7b are a CrC6-alkyl group or halogen; n and m are independently 0, 1 , 2 or 3; R8a and R8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, CrC6-alkyl, cycloalkyl;
R8c is -OH, d-Ce-alkyl, hydroxy-CrC6-alkyl, nitrile, a group CONR8d 2 or a hydrogen atom; R8d is CrC6-alkyl or a hydrogen atom; R9 and R10 are independently a hydrogen atom, CrCβ-alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryKd-Ce-alkyl)-, or heteroaryl(d- C6-alkyl)- group; or R9 and R10 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; R12 is Ci-C6-alkyl or a hydrogen atom; Ar1 is aryl, heteroaryl or cycloalkyl; Ar2 are independently aryl, heteroaryl or cycloalkyl; and Q is an oxygen atom, -CH2-, -CH2CH2- or a bond; or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. Summary of the Invention
The present invention provides compounds falling within the scope of, but not specifically disclosed in, our copending application PCT/GB2006/002957 referred to above.
Thus, the present invention provides a compound which has a quaternary ammonium species: anf/-[(1S,2R)-8-(tert-Butoxycarbonyl-methyl-amino)-octyl]-[2-(2-hydroxy-2,2-di- thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium; a/?f/-(1S,2R)-[2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(3- phenyl-propyl)-ammonium; a/if/-(1S,2R)-[2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(4- phenyl-butyl)-ammonium; a/?f/-(1S,2R)-[2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7-yl]- dimethyl-(3-phenyl-propyl)-ammonium; anti-{λ S,2R)-[2-(9-Hydroxy-9H-fluorene-9-carbonyloxy)bicyclo[2.2.1 ]hept-7-yl]- dimethyl-(3-phenoxy-propyl)-ammonium; anti-{\ S,2R)-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-ethyl]-[2-(2-hydroxy-2,2-di- thiophen-2-yl-acetoxy)bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium; anf/-(1S,2R)-(3-Ethoxycarbonyl-propyl)-[2-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)- bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium; a/7f/-(1S,2R)-[2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7-yl]- dimethyl-(4-phenyl-butyl)-ammonium; a/rt/-(1 S,2R)-[2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-bicyclo[2.2.1 ]hept-7-yl]- dimethyl-(5-phenyl-pentyl)-ammonium;
(+)a/7f/-(1S,2R)-[2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)bicycIo[2.2.1]hept-7-yl]-(4- hydroxy-4-phenyl-butyl)-dimethyl-ammonium; anf/-(1S,2R)-[2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]- dimethyl-(4-phenyl-but-3-ynyl)-ammonium; or, aπf/-(1S,2R)-[2-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-bicyclo[2.2.1]hept-7-yl]- dimethyl-(4-phenyl-butyl)-ammonium; and a pharmaceutically acceptable anion selected from the group comprising chloride, bromide, sulfate, methanesulfonate, benzenesulfonate, toluenesulfonate
(tosylate), napadisylate (naphthalene-1 ,5-disulfonate or naphthalene-1 -(sulfonic acid)- 5-sulfonate), edisylate (ethane-1 ,2-disulfonate or ethane-1 -(sulfonic acid)-2- sulfonate), isethionate (2-hydroxyethylsulfonate), phosphate, acetate, citrate, lactate, tartrate, mesylate, maleate, malate, fumarate, xinafoate, p-acetamidobenzoate and succinate; wherein the number of quaternary ammonium species balances the pharmaceutically acceptable anion such that the compound of the invention has no net charge; or a pharmaceutically acceptable salt thereof.
The present invention covers all permissible ratios of quaternary ammonium species to pharmaceutically acceptable anion, for example hemi-napadisylate and napadisylate.
In one aspect a pharmaceutically acceptable anion is bromide or napadisylate (for example naphthalene-1 ,5-disulfonate), wherein the number of quaternary ammonium species balances the pharmaceutically acceptable anion such that compound of the invention has no net charge.
According to the invention, there is also provided a compound selected from the group consisting of: anti-i^ S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(4-phenyl-butyl)- amino]bicyclo[2.2.1]hept-2-yl ester; anti-{\ S,2R)-[9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(5-phenyl-pentyl)- amino]-bicyclo[2.2.1 ]hept-2-yl ester; a/7#-(1 S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-cyano-phenyl)-but-3- ynyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; an#-(1 S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-cyano-phenyl)-butyl]- methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; anti-{\ S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-methoxy-phenyl)-but- 3-ynyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; a/?f/-(1 S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(4-pyrimidin-5-yl-but-
3-ynyl)-amino]-bicyclo[2.2.1]hept-2-yl ester; or, an#-(1 S,2R)-Hydroxy-di-thiophen-2-yl-acetic acid 7-{methyl-[3-(3-methyl-
[1 ,2,4]oxadiazol-5-yl)-propyl]-amino}-bicyclo[2.2.1]hept-2-yl ester; an#-(1S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-methoxy-phenyl)-but-
3-ynyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; anti-{λ S,2R)-Hydroxy-di-thiophen-2-yl-acetic acid 7-{[4-(4-methoxy-phenyl)-butyl]- methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; or a pharmaceutically acceptable salt thereof.
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.
For the compounds of the invention the following ring numbering, shown below, is employed.
7
Figure imgf000008_0001
The substituent on position 2 couid be orientated endo- or exo-, and the substituent on position 7 could be orientated syn- or anti-. The compounds of the present invention have anti- endo- orientation as shown below (where A and T are substituent groups).
Figure imgf000008_0002
anti-, endo-
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; 'wheezy- 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, tabacosis and byssinosis); gastrointestinal-tract disorders such as irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders including neurogenic pollakisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria; motion sickness; and cardiovascular disorders such as vagally induced sinus bradycardia.
In one aspect off the invention a compound of the invention is useful in the treatment or prevention of a respiratory-tract disorder 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; 'wheezy-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, tabacosis and byssinosis).
For treatment of respiratory conditions, administration by inhalation will often be preferred, and in such cases administration of compounds (I) which are quaternary ammonium salts will often be preferred. In many cases, the duration of action of quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose. For treatment of gastrointestinal-tract disorders and cardiovascular disorders, administration by the parenteral route, usually the oral route, may be preferred.
Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier 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. Thus 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. Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Accordingly 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; A β2-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, WO03/99764, WO04/16578, WO04/016601 , WO04/22547, WO04/32921 , WO04/33412, WO04/37768, WO04/37773, WO04/37807, WO0439762, WO04/39766, WO04/45618, WO04/46083, WO04/71388, WO04/80964, EP1460064, WO04/087142, WO04/89892, EP01477167,
US2004/0242622, US2004/0229904, WO04/108675, WO04/108676, WO05/033121 , WO05/040103, WO05/044787, WO04/071388, WO05/058299, WO05/058867, WO05/065650, WO05/066140, WO05/070908, WO05/092840, WO05/092841 , WO05/092860, WO05/092887, WO05/092861 , WO05/090288, WO05/092087, WO05/080324, WO05/080313, US20050182091 , US20050171147, WO05/092870, WO05/077361 , DE10258695, WO05/11 1002, WO05/111005, WO05/110990, US2005/0272769 WO05/110359, WO05/121065, US2006/0019991 , WO06/016245, WO06/014704, WO06/031556, WO06/032627, US2006/0106075, US2006/0106213,
WO06/051373, WO06/056471 ;
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;
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,
ONO-6126 or lC-485;
Phosphodiesterase-7 inhibitors;
An antitussive agent, such as codeine or dextramorphan;
Kinase inhibitors, particularly P38 MAPKinase inhibitors; P2X7 anatgonists; iNOS inhibitors;
A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen;
A dopamine receptor antagonist; TNF-α 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, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB-
265610, SB-225002, MCP-1 (9-76), RS-504393, MLN-1202, INCB-3284;
Compounds which modulate the action of prostanoid receptors, for example a PGD2
(DP1 or CRTH2), or a thromboxane A2 antagonist eg ramatroban;
Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterleukin 10 agonists, such as Ilodecakin;
HMG-CoA reductase inhibitors (statins); for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;
Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK- 333, MSI-1956, gefitinib;
Antiinfective agents (antibiotic or antiviral), and antiallergic drugs including, but not limited to, anti-histamines. 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. In therapeutic use, 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.
The magnitude of 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. In general, the daily dose range for inhalation will lie within the range of from about 0.1 μg to about 10 mg per kg body weight of a human, preferably 0.1 μg to about 0.5 mg per kg, and more preferably 0.1 μg to 50μg 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. Preferably, a unit dose comprises the active compound in an amount of 1 μg to 10 mg. For oral administration suitable doses are 10μg per kg to 100mg per kg, preferably 40μg per kg to 4 mg per kg.
Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical 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. Accordingly, 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.
The pharmaceutical 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. The term "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.
For delivery by inhalation, 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.
By way of example, 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). Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI2F2) and HFA-152 (C2H4F2) and isobutane.
In a preferred embodiment of the invention, a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI). Many types of DPI are known.
Microparticles for delivery by administration may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, 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 μm.
In the case of an aerosol-based formulation, an example is: Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister Trichlorofluoromethane, NF 4.025 g / canister
Dichlorodifluoromethane, NF 12.15 g / canister. The active compounds may be closed as described depending on the inhaler system used. In addition to the active compounds, 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.
For the purposes of inhalation, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321). Additionally, compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents.
Methods of Synthesis
The compounds of the invention can be prepared according to the procedures of the Examples, or by modifying procedures described in the art (such as in common general knowledge, the patent literature or the chemical journal literature).
General Experimental Details:
All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.
Where products were purified by column chromatography, 'flash silica1 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. Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using plates, typically 3 x 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.
All compounds containing a basic centre(s), which were purified by HPLC, were obtained as the TFA salt unless otherwise stated. Preparative HPLC conditions: HPLC system 1 :
C18-reverse-phase column (100 x 22.5 mm i.d Genesis column with 7 μm particle size), eluting with a gradient of A: water + 0.1% TFA; B: acetonitrile + 0.1 % TFA at a flow rate of 5 ml/min and gradient of 1 %/min increasing in B. UV detection at 230 nm.
HPLC system 2:
Phenyl hexyl column (250 x 21.20 mm Luna column with 5 μm particle size), eluting with a gradient of A: water + 0.1 % TFA; B: acetonitrile + 0.1 % TFA at a flow rate of 5 ml/min with UV detection at 254 nm.
LC/MS Systems
The Liquid Chromatography Mass Spectroscopy (LC/MS) systems used:
LC-MS method 1
Micromass Platform LCT with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:
Gradient - Time flow ml/min %A %B
0.00 1.0 95 5
1.00 1.0 95 5
15.00 1.0 5 95 20.00 1.0 5 95
22.00 1.0 95 5
25.00 1.0 95 5
Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive ion)
LC-MS method 2
Micromass Platform LCT with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:
Gradient - Time flow ml/min %A %B 0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
5.50 2.0 5 95
6.00 2.0 95 5
Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive and negative ion)
LC-MS method 3
Waters Micromass ZQ with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:
Gradient - Time flow ml/min %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
5.50 2.0 5 95
6.00 2.0 95 5
Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive and negative ion)
LC-MS method 4
Waters Micromass ZQ with a C18-reverse-phase column (Higgins Clipeus δmicron C18 100 x 3.0mm or equivalent), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:
Gradient — Time flow ml/min %A %B
0.00 1.0 95 5
1.00 . 1.0 95 5
15.0 1.0 5 95
20.0 1.0 5 95
22.0 1.0 95 5
25.0 1.0 95 5 Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive and negative ion)
Abbreviations used in the experimental section: DCM = dichloromethane; THF = tetrahydrofuran; MeOH = methanol; EtOH = ethanol; DMSO = dimethylsulfoxide; EtOAc = ethyl acetate; DIPEA = di- isopropylethylamine; EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP = dimethylaminopyridine; RT = ambient temperature; HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro phosphate; TFA = trifluoroacetic acid; Rt = retention time; Satd = saturated
Example 1 anf/-[(1S,2R)-8-(tert-Butoxycarbonyl-methyl-amino)-octyl]-[2-(2-hydroxy-2,2-dϊ- thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium bromide
Figure imgf000017_0001
a. anti-C\ S)-7-(Benzyl-methyl-amino)-5-bromo-bicvclof2.2.11heptan-2-one
A solution of (1S)-2,3-dibromo-bicyclo[3.2.0]heptan-6-one (7.1 g, 26.5 mmol) in 150 ml_ DCM was stirred under a N2 atmosphere and N-benzylmethylamine (7.06 g, 7.52 mmol) was added dropwise. The reaction was stirred at ambident temperature for 33h before being washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on an ISCO companion column of silica gel eluting with 0-15% Et2O-cyclohexanes gave 6.39 g (78%) of the title product as a yellow solid. 1H NMR (CDCI3, 400 MHz): δ 1.77-1.80 (1 H, m), 2.10 (3H, s), 2.20-2.30 (1 H, m), 2.65-2.73 (1 H, m), 2.80-3.00 (4H, m), 3.40-3.60 (2H, m), 4.75-4.85 (1 H, m), 7.20-7.40 (5H, m).
Figure imgf000017_0002
b. (1 S)-7-(Benzvl-methyl-aminoVbicvclor2.2.11heptan-2-one A solution of anf/-(1S)-7-(benzyl-methyl-amino)-5-bromo-bicyclo[2.2.1]heptan-2-one (5 g, 16.2 mmol) in 80 mL toluene was degassed prior to addition of 2,2'-azobis (2- methoxyproprionitrile) (266 mg, 1.6 mmol). The reaction was heated to 80 0C for 1.5h and allowed to cool to ambient temperature. The reaction was extracted into 1 N HCI (150 mL), washed with Et2O then cooled in an ice bath and neutralised with Na2CO3 (solid). Following addition of NaOH (1 N solution) to give a pH ~10, the reaction was extracted with ethyl acetate, the combined organics dried (Na2SO4), filtered and concentrated to an orange oil which solidified (3.5 g). 1H NMR (CDCI3, 400 MHz): δ 1.37-1.52 (2 H, m), 2.00-2.29 (7 H, m), 2.60-2.71 (3 H, m), 3.49 (2 H, dd, J = 13, 42 Hz), 7.21-7.34 (5 H, m).
Figure imgf000018_0001
c. anf/-(1 S,2R,)-7-(Benzylmethylamino)-bicyclor2.2.1 lheptan-2-ol A solution of (1S)-7-(benzyl-methyl-amino)-bicyclo[2.2.1]heptan-2-one (3.5 g, 15.28 mmol) in THF (80 mL) was cooled in an ice bath. Lithium tri(t-butoxy)aluminium hydride (5.8 g, 22.9 mmol) was added in portions over 15 min. The reaction was stirred at 0 °C for 1.5h then quenched with NH4CI (10 mL) and the solid removed by filtration. The solid was washed with EtOAc and the filtrate was washed with H2O, dried (Na2SO4), filtered and evaporated. Purification by chromatography using 30- 70% EtOAc-cyclohexane as eluent gave the title compound as a pale oil (3.0 g). LC- MS (Method 2): Rt 0.76 min, m/z 232 [MH]+.
Figure imgf000018_0002
d. anti-C\S, 2R)-Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R)-7-(benzylmethylamino)- bicyclor2.2.nhept-2-yl ester:
To a cooled (0 0C) solution of anfr-(1S,2R)-7-(benzylmethylamino)- bicyclo[2.2.1]heptan-2-ol (1 g, 4.3 mmol) was added sodium hydride (432 mg of 60 % suspension in mineral oil, 10.8 mmol) portion wise. The mixture was allowed to warm to ambient temperature for 10 minutes then re-cooled to 0 0C. Hydroxy-di-thiophen-2- yl-acetic acid ethyl ester (1.39 g, 5.2 mmol) was added portion wise and then the mixture was heated at 80 °C for 2 hours. After allowing the mixture to cool to ambient temperature the reaction was quenched by dropwise addition of aqueous ammonium chloride (sat. 50 ml_) then extracted with ethyl acetate (3 x 100 ml_). Combined organics were dried over Na2SO4, filtered and evaporated to a yellow oil. Purification by flash column over silica gel using 5-10 % ethyl acetate-hexane as eluent then by a further flash column using 0-5 % ethyl acetate in DCM gave 1.12 g (57 %) of the title compound as a yellow oil: LC-MS (Method 2): Rt 2.44 min, m/z 454 [MH]+.
Figure imgf000019_0001
e. a/7f/-Hvdroxy-di-thiophen-2-yl-acetic acid (1S,2R)-7-methylaminobicvclof2.2.1lhept-
2-yl ester:
To a solution of antf-hydroxy-di-thiophen-2-yl-acetic acid (1S,2R)-7-(benzylmethyl- amino)-bicyclo[2.2.1]hept-2-yl ester (400 mg, 0.88 mmol) in 1 ,2-dichloroethane (5 ml_) was added 1-chloroethyl chloroformate (0.57 ml_, 5.3 mmol) and the mixture was heated at 80 0C for 8 hours. The solvent and excess 1-chloroethyl chloroformate were removed under reduced pressure leaving a yellow/brown oil. This was re-dissolved in methanol (5 ml.) and stirred at ambient temperature for 1 hour then evaporated to a yellow foam. The residue was suspended in water (10 mL) and basified using sodium hydroxide (0.1 N) then extracted with ethyl acetate (4 x 20 mL). The combined organics were dried over Na2SO4, filtered and evaporated to a brown solid. Purification by flash chromatography over silica gel using 5-10 % methanol in DCM as eluent gave 180 mg (56 %) of the title compound as a yellow solid: LC-MS (Method 2): Rt 2.20 min, m/z 364 [MH]+.
Figure imgf000019_0002
f. anf/-Hydroxy-di-thiophen-2-yl-acetic acid 7-{f8-(tert-butoxycarbonyl-methyl-amino)- octvn-methyl-amino)-bicyclor2.2.1lhept-2-yl ester:
To a solution of anfr-hydroxy-di-thiophen^-yl-acetic acid (1S,2R)-7-methylamino- bicyclo[2.2.1]hept-2-yl ester (43 mg, 0.12 mmol) in acetonitrile (3 ml_) was added methanesulfonic acid 8-(tert-butoxycarbonyl-methyl-amino)-octyl ester (60 mg, 0.18 mmol) and triethylamine (33 μl_, 0.24 mmol). The mixture was heated at 80 0C for 12 hours. The solvent was removed in vacuo then the residue was purified by flash chromatography over silica gel using 0-100 % ethyl acetate in DCM as eluent followed by further purification by flash chromatography over silica gel using 0-100 % ethyl acetate in cyclo-hexane as eluent to give the title compound (20 mg, 28 %). 1H NMR (CDCI3, 400 MHz): δ 1.07-1.15 (2 H, m), 1.20-1.31 (8 H, m), 1.35-1.53 (14 H, m), 1.56- 1.65 (1 H, m), 1.76-1.85 (1 H, m), 2.04-2.16 (5 H, m), 2.23 (1 H, s), 2.28 (2 H, t), 2.51 (1 H, m), 2.83 (3 H, s), 3.18 (2 H, m), 4.77 (1 H, s), 5.07 (1 H, m), 6.99 (2 H, m), 7.17- 7.21 (2 H, m), 7.27-7.30 (2 H, m).
Figure imgf000020_0001
g. aπf/-[(1S,2R)-8-(tert-Butoxycarbonyl-methyl-amino)-octvn-r2-(2-hydroxy-2,2-di- thiophen-2-yl-acetoxy)-bicycloF2.2.11hept-7-vπ-dimethyl-ammonium bromide A solution of anti-(1S, 2R)-hydroxy-di-thiophen-2-yl-acetic acid 7-{[8-(tert- butoxycarbonyl-methyl-amino)-octyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester (20 mg, 0.03 mmol) in a 30 % w/w solution of methyl bromide in acetonitrile (3 ml_) was heated in a sealed tube for 3 days at 60 °C. The solvent was removed and the residue purified by flash chromatography over silica gel using 5-10 % methanol in DCM as eluent to give 20 mg (87 %) of the title compound as a yellow foam: LC-MS (Method 1): Rt 9.14 min, m/z 619 [M]+; 1H NMR (CDCI3, 400 MHz) δ 1.20-1.82 (25 H, m), 1.92-2.02 (1 H, m), 2.48-2.59 (1 H, m), 2.79 (1 H, s), 2.81 (3 H, m), 3.08 (1 H, s), 3.18 (2 H, t), 3.33 (3 H, s), 3.39 (3 H, s), 3.60-3.75 (2 H, m), 4.16 (1 H, s), 4.70 (1 H, s), 5.21 (1 H, m), 6.95-7.02 (2 H, m), 7.12-7.19 (2 H, m), 7.27-7.30 (2 H, m).
The following examples were prepared in a similar manner to that described for Example 1. Ex. Name Structure 1H NMR (400 MHz) Rt/min (Method 1); [M]+ a/7tf-(1S,2R)-[2-(2- (CDCI3) δ 1.01 (1 H, dd), 1.25-1.35 (1 H, m), 1.40- 8.42; 484
Hydroxy-2,2-diphenyl- 1.52 (2 H, m), 1.73-1.84 (1 H, m), 2.13 (2 H, m), acetoxy)- 2.42 (1 H, m), 2.61 (1 H, m), 2.73 (2 H, m), 2.91 (1 bicyclo[2.2.1]hept-7-yl]- H, m), 3.28 (3 H, s), 3.31 (3 H, s), 3.61-3.76 (2 H, dimethyl-(3-phenyl-propyl)-
Figure imgf000021_0001
m), 4.01 (1 H, s), 4.14 (1 H, s), 5.20 (1 H, m), ammonium bromide 7.19-7.23 (3 H1 m), 7.25-7.41 (12 H, m).
aA?f/-(1S,2R)-[2-(2- (CDCI3) δ 1.00-1.10 (1 H, m), 1.20-1.40 (2 H1 m), 8.28; 498
Hydroxy-2,2-diphenyl- 1.40-1.50 (2 H, m), 1.70-1.90 (4 H, m), 2.35-2.50 acetoxy)- (1 H, m), 2.60-2.65 (1 H, m), 2.70-2.80 (2 H1 m), bicyclo[2.2.1]hept-7-yl]- 2.90-3.00 (1 H, m), 3.25 (3 H, s), 3.30 (3 H, s), dimethyl-(4-phenyl-butyl)- 3.60-3.80 (2 H, m), 4.03 (1 H, s), 4.10 (1 H, s), ammonium bromide 5.10-5.20 (1 H, m), 7.10-7.20 (3 H, m), 7.23-7.30
Figure imgf000021_0002
(3 H, m), 7.30-7.40 (7 H, m), 7.40-7.50 (2 H, m).
Figure imgf000023_0001
anf/-(1S,2R)-[2-(9- Br (CDCI3) δ 1.60-1.70 (1 H, m), 1.05-1.40 (4 H, m), 8.62; 512
Hydroxy-9H-xanthene-9- 1.60-1.80 (4 H1 m), 2.15-2.05 (1 H, m), 2.50 (1 H, carbonyloxy)bicyclo[2.2.1 ] m), 2.65-2.75 (3 H, m), 3.20 (3 H, s), 3.25 (3 H, s), hept-7-yl]-dimethyl-(4- 3.50-3.70 (2 H, m), 3.85 (1 H, s), 4.75 (1 H, s), phenyl-butyl)-ammonium
Figure imgf000024_0001
4.80-4.90 (1 H1 m), 7.10-7.30 (9 H, m), 7.35-7.40 bromide (2 H, m), 7.50-7.60 (2 H, m).
10 anfr-(1S,2R)-[9-Hydroxy- (CDCI3) δ1.60-1.75 (2 H, m), 1.75-1.85 (1 H, m), 8.78; 512 9H-xanthene-9-carboxylic 1.20-1.40 (6 H, m), 1.50-1.60 (2 H, m), 1.80-1.90 acid 7-[methyl-(5-phenyl- (1 H, m), 1.90 (1 H, s), 2.0 (3 H, s), 2.10 (1 H, s), pentyl)-amino]-
Figure imgf000024_0002
2.50-2.60 (2 H1 m), 4.75-4.80 (1 H, m), 4.90 (1 H, bicyclo[2.2.1]hept-2-yl S), 7.10-7.20 (7 H1 m), 7.20-7.30 (2 H, m), 7.30- ester 7.40 (2 H, m), 7.40-7.60 (2 H, m).
11 anfr-(1S,2R)-[2-(9- (CDCI3) δ 0.65-0.70 (1 H, m), 1.05-1.40 (6 H, m), 8.92; 526
Hydroxy-9H-xanthene-9- 1.60-1.80 (4 H, m), 2.15-2.25 (1 H, m), 2.55-2.63 carbonyloxy)- (3 H, m), 2.70-2.75 (1 H, m), 3.15-3.30 (6 H, m), bicyclo[2.2.1]hept-7-yl]- 2.45-2.60 (2 H, m), 3.90 (1 H, s), 4.85 (1 H, s),
Figure imgf000024_0003
dimethyl-(5-phenyl-pentyl)- 4.90-4.95 (1 H, m), 7.10-7.20 (7 H, m), 7.22-7.30 ammonium bromide (2 H, m), 7.35-7.40 (2 H, m), 7.50-7.58 (2 H, m).
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Example 20 anW-tiS^RJ-θ-Hydroxy-ΘH-xanthene-θ-carboxylic acid 7-[methyl-(4-pyrimϊdin-5- yl-but-3-ynyl)-amino]-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000028_0001
a. anf/-(1S,2RV9-Hvdroxy/methoxy-9H-xanthene-9-carboχylic acid 7-methylamino- bicvclof2.2.nhept-2-yl ester
To a solution of θ-Hydroxy-ΘH-xanthene-θ-carboxylic acid 7-(benzyl-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester (683 mg, 1.50 mmol) in 1 ,2-dichloroethane (7 mL) was added 1-chloroethyl chloroformate (0.97 mL, 8.99 mmol) and the mixture was heated at 80 0C for 8 hours. The solvent and excess 1-chloroethyl chloroformate were removed under reduced pressure leaving a yellow/brown oil. This was re-dissolved in methanol (5 mL) and stirred at ambient temperature for 1 hour then evaporated to a yellow foam. The residue was suspended in water (10 mL) and basified using sodium hydroxide (0.1 N) then extracted with ethyl acetate (4 x 20 mL). The combined organics were dried over Na2SO4, filtered and evaporated to a brown solid. Purification by flash chromatography over silica gel using 0-3 % methanol in DCM as eluent gave 235 mg (43 %) of a mixture of the title compounds as a gum: Hydroxy 1H NMR (CDCI3, 400 MHz) : δ 0.54-0.6 (1 H, m), 0.70-0.82 (1 H, m), 0.90-1.03 (1 H, m), 1.13-1.23 (1 H, m), 1.45-1.55 (1 H, m), 1.80-1.89 (2 H, m), 2.15-2.20 (1 H, m), 2.23 (3 H, s), 2.52-2.55 (1 H, m), 4.73-4.82 (1 H, m), 7.10-7.21 (4 H, m), 7.30-7.40 (2 H, m), 7.49-7.55 (2 H, m). LC-MS (Method 2): Rt 2.24 min, m/z 366 [MH]+. Methoxy 1H NMR (CDCI3, 400 MHz) : δ 0.54-0.6 (1 H, m), 0.70-0.82 (1 H, m), 0.90-1.03 (1 H, m), 1.13- 1.23 (1 H, m), 1.45-1.55 (1 H, m), 1.80-1.89 (2 H, m), 2.15-2.20 (1 H, m), 2.23 (3 H, s), 2.52-2.55 (1 H, m), 2.28 (3 H, s), 4.73-4.82 (1 H, m), 7.10-7.21 (4 H, m), 7.30-7.40 (2 H, m), 7.49-7.55 (2 H, m). LC-MS (Method 2): Rt 2.44 min, m/z 380 [MH]+.
Figure imgf000029_0001
b. anti-iλ S, 2R)-9-Hvdroxy-9H-xanthene-9-carboxylic acid 7-(but-3-vnyl-methyl-amino)- bicvclor2.2.1lhept-2-yl ester
A solution of 9-Hydroxy/methoxy-9H-xanthene-9-carboxylic acid 7-methylamino- bicyclo[2.2.1]hept-2-yl ester (87 mg, 0.238 mmol), 4-bromo-but-1-yne (200 mg, 1.504 mmol) and triethylamine (165 μl_, 1.190 mmol) in acetonitrile (1 ml_) in a sealed tube was heated for 18 hours at 80 0C. The solvent was removed and the residue purified by flash chromatography over silica using 0-0.5 % methanol in DCM as eluent. The resulting compound was dissolved into THF (1 ml_) and 1 M HCI (1 ml_), stirred for 4 hours and then evaporated to a gum. The residue was partitioned between DCM and NaHCO3 (gq). The organic layer was collected, dried over MgSO4 and solvent removed to give 17mg (17 %) of the title compound as a gum. 1H NMR (CDCI3, 400 MHz): δ 0.59-0.75 (2 H, m), 0.79-0.91 (1 H, m), 1.23-1.38 (1 H, m), 1.50-1.65 (1 H, m), 1.70- 1.92 (2 H, m), 1.94-2.00 (1 H, m), 2.08 (3 H, s), 2.18-2.30 (4 H, m), 2.47-2.55 (2 H, m), 4.75-4.83 (1 H, m), 4.90 (1 H, s), 7.10-7.22 (4 H, m), 7.31-7.40 (2 H, m), 7.48-7.55 (2 H, m).
Figure imgf000029_0002
c. a/7f/-(1S,2R)-9-Hvdroxy-9H-xanthene-9-carboxylic acid 7-rmethyl-(4-pyrimidin-5-yl- but-3-vnyl)-aminol-bicyclof2.2.1lhept-2-yl ester A solution of 9-Hydroxy-9H-xanthene-9-carboxylic acid 7-(but-3-ynyl-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester (27 mg, 0.065 mmol), 5-bromopyrimidine (15 mg, 0.097 mmol) and copper iodide (2 mg, 0.006 mmol) in triethylamine (1mL) and acetonitrile (1 ml.) was degassed using argon. Palladium tetrakis (7 mg, 0.006 mmol) was then added, the tube sealed and degassed using argon. The reaction was heated at 50 0C for 4 hours. The solvent was removed and residue dissolved into DCM, washed with water, dried over MgSO4 and solvent removed. The residue was purified by flash chromatography over silica using 0-1 % methanol in DCM as eluent to give 17 mg of the title compound as a gummy solid. LC-MS (method2) Rt 2.15 min, m/z 496 [M+H]+ Example 21 anf/-(1S,2R)-Hvdroxy-di-thiophen-2-yl-acetic acid 7-{methyl-r3-(3-methyl- ri,2,41oxadiazol-5-yl)-propyn-amino)-bicvclof2.2.1lhept-2-yl ester
Figure imgf000030_0001
a. 5-(3-Bromo-propyl)-3-methyl-M ,2,41oxadiazole
A partial solution of N-hydroxy acetamidine (780 mg, 10.5 mmol) was formed in THF
(20 ml_). Sodium hydride (505 mg of 60 % in mineral oil, 12.6 mmol) was added portionwise then the mixture was stirred at room temperature for 1 hour. Ethyl 4- bromobutyrate (1.8 mL, 12.6 mmol) was added and the mixture heated at 50 0C for 5 hours then allowed to cool to room temperature. The mixture was carefully quenched with aqueous ammonium chloride and then diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were dried over sodium sulphate, filtered and evaporated. The residue was purified through an ISCO companion column of silica gel eluting with a gradient of 0-100% ethyl acetate in cyclohexane gave the title compound as a pale yellow oil (210 mg, 10 %). 1H NMR (CDCI3, 400 MHz): δ 2.34-2.41 (5 H, m), 3.06 (2 H, t), 3.52 (2 H1 1).
Figure imgf000030_0002
b. a/7f/-(1S,2R)-Hvdroxy-di-thiophen-2-yl-acetic acid 7-|methyl-f3-(3-methyl- π ,2,41oxadiazol-5-yl)-propyll-aminoVbicvclor2.2.nhept-2-yl ester anf/-Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-methylamino-bicyclo[2.2.1 ]hept-2- yl ester was reacted with 5-(3-bromo-propyl)-3-methyl-[1 ,2,4]oxadiazole using a method analogous to that in example 1 to give the title compound as a pale yellow oil. Rt 6.51 min, m/z 488 [M+H]+; 1H NMR (CDCI3, 400 MHz) δ 1.07-1.18 (2 H, m), 1.39- 1.46 (1 H, m), 1.50-1.59 (1 H, m), 1.71-1.79 (1 H, m), 1.88-1.99 (2 H, m), 2.03-2.15 (5 H, m), 2.25 (1 H, s), 2.35-2.42 (5 H, m), 2.48 (1 H, m), 2.83 (2 H, t), 4.77 (1 H, s), 5.02-5.10 (1 H, m), 6.97-7.00 (2 H, m), 7.15-7.21 (2 H, m), 7.28-7.30 (2 H, m). Example 22 anf/'-f1S,2R)-f2-(2-Hvdroxy-2,2-di-thiophen-2-yl-acetoxy)-bicvclor2.2.nhept-7-vπ- dimethvir3(3-methvI-1,2,4-oxadiazol-5-yl)-propyll-ammonium bromide
Figure imgf000031_0001
aA7W-(1S,2R)-Hydroxy-di-thiophen-2-yl-acetic acid 7-{methyl-[3-(3-methyl-
[1 ,2,4]oxadiazol-5-yl)-propyl]-amino}-bicyclo[2.2.1]hept-2-yl ester was reacted with methyl bromide using a method analogous to that in example 1 to give the title compound as a white solid. Rt 6.92 min, m/z 502 [M]+; 1H NMR (d6-DMSO, 400 MHz) δ 1.02 (1 H1 dd), 1.32-1.40 (1 H, m), 1.64-1.78 (2 H, m), 1.91-2.01 (1 H, m), 2.18-2.23 (3 H, m), 2.31 (3 H, s), 2.67 (1 H, m), 2.95-3.00 (3 H, m), 3.08 (3 H1 s), 3.09 (3 H, s), 3.42-3.49 (2 H, m), 3.57 (1 H, s), 4.99-5.04 (1 H, m), 7.00-7.02 (2 H, m), 7.09-7.11 (2 H, m), 7.39 (1 H, s), 7.48-7.52 (2 H, m).
BIOLOGICAL EXAMPLES The inhibitory effects of compounds of the present invention at the M3 muscarinic receptor, were determined by the following binding assays:
Muscarinic Receptor Radioligand Binding Assays
Radioligand binding studies utilising [3H]-N-methyl scopolamine ([3H]-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 TRlS buffer were incubated in 96-well plates with [3H]- 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 [3H]-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 [3H]-QNB ligand, with membranes expressing the human muscarinic receptors. At the end of this time, [3H]-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.
Figure imgf000032_0001
M3 Binding Ki <2nM "+++"; K, 2-1OnM "++"; K, > 1OnM "+"; NT - Not Tested All compounds that were tested in the binding assay exhibited Kj potencies higher than 5OnM. As a further illustration of the invention, a Kj binding affinity of 0.78nM was obtained for Example 7 and 0.3OnM for Example 5.
Analysis of Inhibition of M3 Receptor Activation via Calcium Mobilization
IN an alternative M3 receptor binding assay, 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 μl_ of medium in 3 % serum. The following day, a calcium-sensitive dye (Molecular Devices, Cat # R8041) was prepared in HBSS buffer with the addition of 5 mM probenecid (pH 7.4). An equal volume of the dye solution (75 μl_) was added to the cells and incubated for 45 minutes followed by addition of 50 μl_ of muscarinic antagonists or vehicle. After a further 15 minutes the plate was read on a FLEXstation™ (excitation 488 nm, emission 525 nm) for 15 seconds to determine baseline fluorescence. The muscarinic agonist Carbachol was then added at an EC8O 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 IC50 curves.
The inhibitory effects of compounds of the present invention at the M3 muscarinic Receptor may be evaluated in the following ex-viva and in vivo assays:
Evaluation of potency and duration of action in Isolated Guinea Pig Trachea Experiments were carried out at 370C in modified Krebs-Henseleit solution, (114 mM NaCI, 15 mM NaHCO3, 1 mM MgSO4, 1.3 mM CaCI2, 4.7 mM KCI, 11.5 mM glucose and 1.2 mM KH2PO4 , pH 7.4) gassed with 95 % O2/5 % CO2. lndomethacin was added to a final concentration of 3 μM 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 10 ml 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 1 g and were then subjected to electrical field stimulation at a frequency of 80 Hz with a pulse width of 0.1 ms, 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 EC50 calculated for each compound.
Onset time and duration of action studies were performed by adding the previously determined EC50 concentration of compound to EFS contracted tissues and the response allowed to plateau. The time taken to reach 50 % of this response was determined to be the onset time. Tissues were then washed free of compound by flushing the tissue bath with fresh Krebs solution and the time taken for the contraction in response to EFS to return to 50 % of the response in the presence of compound is measured. This is termed the duration of action.
Methacholine Induced Bronchoconstriction in vivo
Male Guinea pigs (Dunkin Hartley), weighing 500-600 g 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. Up to 24 hrs post dosing guinea pigs were terminally anaesthetized with Urethane (250 μg/mL, 2 mL/kg). At the point of surgical anaesthesia, the jugular vein was cannulated with a portex i.v. cannula filled with heparinised phosphate buffered saline (hPBS) (10 U/mL) for i.v. administration of methacholine. 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 0.2 cmH20/mL/s. A 2 minute baseline reading was recorded before i.v. administration of methacholine (up to 30 μg/kg, 0.5 mL/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 was used to analyse the bronchoprotective effects of test compounds.

Claims

1. A compound which has a quaternary ammonium species: anf/-[(1S,2R)-8-(tert-Butoxycarbonyl-methyl-amino)-octyl]-[2-(2-hydroxy-2,2-di- thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium; aπf/-(1 S,2R)-[2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1 ]hept-7-yl]- dimethyl-(3-phenyl-propyl)-ammonium; anti-iλ S,2R)-[2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1 ]hept-7-yl]- dimethyl-(4-phenyl-butyl)-ammonium; a/7f/-(1S,2R)-[2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7- yl]-dimethyl-(3-phenyl-propyl)-ammonium; anW-(1S,2R)-[2-(9-Hydroxy-9H-fluorene-9-carbonyloxy)bicyclo[2.2.1]hept-7-yl]- dimethyl-(3-phenoxy-propyl)-ammonium; anti-0 S,2R)-[2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-ethyl]-[2-(2-hydroxy-2,2-di- thiophen-2-yl-acetoxy)bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium; anf/-(1S,2R)-(3-Ethoxycarbonyi-propyl)-[2-(2-hydroxy-2,2-di-thiophen-2-yl- acetoxy^bicycloβ^.ilhept^-ylj-dimethyl-ammonium; anf/-(1S,2R)-[2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7- yl]-dimethyl-(4-phenyl-butyl)-ammonium; aπf/-(1S,2R)-[2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-bicyclo[2.2.1]hept-7- yl]-dimethyl-(5-phenyl-pentyl)-ammonium;
(+)aπf/-(1S,2R)-[2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)bicyclo[2.2.1]hept-
7-yl]-(4-hydroxy-4-phenyl-butyl)-dimethyl-ammonium; a/?f/-(1S,2R)-[2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7- yl]-dimethyl-(4-phenyl-but-3-ynyl)-ammonium; or, aπf/-(1S,2R)-[2-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-bicyclo[2.2.1]hept-7-yl]- dimethyl-(4-phenyl-butyl)-ammonium; and a pharmaceutically acceptable anion selected from the group comprising chloride, bromide, sulfate, methanesulfonate, benzenesulfonate, toluenesulfonate (tosylate), napadisylate (naphthalene-1 ,5-disulfonate or naphthalene-1 -(sulfonic acid)-5-sulfonate), edisylate (ethane-1 ,2-disulfonate or ethane-1 -(sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethylsulfonate), phosphate, acetate, citrate, lactate, tartrate, mesylate, maleate, malate, fumarate, xinafoate, p-acetamidobenzoate and succinate; wherein the number of quaternary ammonium species balances the pharmaceutically acceptable anion such that the compound of the invention has no net charge; or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 wherein the pharmaceutically acceptable anion is bromide or napadisylate, wherein the number of quaternary ammonium species balances the pharmaceutically acceptable anion such that compound of the invention has no net charge.
3. A compound selected from the group consisting of: anf/-(1 S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(4-phenyl- butyl)-amino]bicyclo[2.2.1]hept-2-yl ester; anf/-(1S,2R)-[9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(5-phenyl- pentyl)-amino]-bicyclo[2.2.1]hept-2-yl ester; anti-{\ S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-cyano-phenyl)- but-3-ynyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester; anf/-(1 S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-cyano-phenyl)- buty!]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; a/7f/-(1 S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-methoxy- phenyl)-but-3-ynyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; anfr-(1 S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(4-pyrimidin-
5-yl-but-3-ynyl)-amino]-bicyclo[2.2.1]hept-2-yl ester; or, a/7tf-(1S,2R)-Hydroxy-di-thiophen-2-yl-acetic acid 7-{methyl-[3-(3-methyl-
[1 ,2,4]oxadiazol-5-yl)-propyl]-amino}-bicyclo[2.2.1]hept-2-yl ester; anti-{λ S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-{[4-(4-methoxy- phenyl)-but-3-ynyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester; anti-(\ S,2R)-Hydroxy-di-thiophen-2-yl-acetic acid 7-{[4-(4-methoxy-phenyl)- butyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; or a pharmaceutically acceptable salt thereof.
4. A compound as claimed in claim 1 , 2 or 3 wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p- toluenesulfonate.
5. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.
6. A pharmaceutical composition as claimed in claim 5 in a form suitable for inhalation.
7. A compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.
8. A compound as claimed in any of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of prevention of a disease or condition in which M3 muscarinic receptor activity is implicated.
9. A method of treatment of a disease or condition in which M3 muscarinic receptor activity is implicated comprising administration to a subject in need thereof of an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 4.
10. Use as claimed in claim 7 or 8 or a method of treatment as claimed in claim 9, wherein the disease or condition is a respiratory-tract disorder.
11. Use as claimed in claim 7 or 8 or a method of treatment as claimed in claim 9, wherein the disease or condition is a gastrointestinal-tract disorder.
12. Use as claimed in claim 7 or 8 or a method of treatment as claimed in claim 9, wherein the disease or condition is a cardiovascular disorder.
13. Use as claimed in claim 7 or 8 or a method of treatment as claimed in claim 9, wherein the disease or condition is chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, or allergic rhinitis;
14. Use as claimed in claim 7 or 8 or a method of treatment as claimed in claim 9, wherein the disease or condition is irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders including neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria; motion sickness; and cardiovascular disorders such as vagally induced sinus bradycardia.
15. Use as claimed in claim 7 or 8 or a method of treatment as claimed in claim 9, wherein the disease or condition is vagally induced sinus bradycardia.
PCT/GB2007/000410 2007-02-06 2007-02-06 Bicyclor[2.2.1]hept-7-ylamine derivatives as muscarinic m3 receptor modulators WO2008096094A1 (en)

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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
US20170029400A1 (en) * 2014-12-30 2017-02-02 Shinhao Materials LLC Leveler, Leveler Composition and Method for Electrodeposition of Metals in Microelectronics

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WO2003087094A2 (en) * 2002-04-16 2003-10-23 Almirall Prodesfarma Ag Pyrrolidinium derivatives as antagonists of m3 muscarinic receptors
WO2007017670A1 (en) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Bicyclo[2.2.]hept-7-ylamine derivatives and their uses

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WO2003033495A1 (en) * 2001-10-17 2003-04-24 Ucb, S.A. Quinuclidine derivatives, processes for preparing them and their uses as m2 and/or m3 muscarinic receptor inhibitors
WO2003087094A2 (en) * 2002-04-16 2003-10-23 Almirall Prodesfarma Ag Pyrrolidinium derivatives as antagonists of m3 muscarinic receptors
WO2007017670A1 (en) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Bicyclo[2.2.]hept-7-ylamine derivatives and their uses

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* 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
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
US20170029400A1 (en) * 2014-12-30 2017-02-02 Shinhao Materials LLC Leveler, Leveler Composition and Method for Electrodeposition of Metals in Microelectronics
US10323015B2 (en) * 2014-12-30 2019-06-18 Shinhao Materials LLC Leveler, leveler composition and method for electrodeposition of metals in microelectronics
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