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WO2008149053A1 - Dérivés de la bicyclo[2.2.1]hept-2-ylamine et leur utilisation - Google Patents

Dérivés de la bicyclo[2.2.1]hept-2-ylamine et leur utilisation Download PDF

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Publication number
WO2008149053A1
WO2008149053A1 PCT/GB2007/002130 GB2007002130W WO2008149053A1 WO 2008149053 A1 WO2008149053 A1 WO 2008149053A1 GB 2007002130 W GB2007002130 W GB 2007002130W WO 2008149053 A1 WO2008149053 A1 WO 2008149053A1
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Prior art keywords
hydroxy
hept
bicyclo
phenyl
thiophen
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PCT/GB2007/002130
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English (en)
Inventor
Harry Finch
Andrew Stephan Robert Jennings
Monique Bodil Van Niel
Nicholas Charles Ray
Philip Smith
Original Assignee
Argenta Discovery Ltd.
Astrazeneca Ab
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Publication date
Application filed by Argenta Discovery Ltd., Astrazeneca Ab filed Critical Argenta Discovery Ltd.
Priority to PCT/GB2007/002130 priority Critical patent/WO2008149053A1/fr
Publication of WO2008149053A1 publication Critical patent/WO2008149053A1/fr

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    • 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
    • C07C219/24—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • 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-2-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. 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 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 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.
  • muscarinic receptor modulators have been referred to. For example:
  • US4353922 describes muscarinic modulators based upon a [2.2.1]azabicycloheptane ring system.
  • EP418716 and US005610163 describe various [3.2.1]azabicyclooctane ring systems.
  • WO06/017768 describes [3.3.1]azabicyclononane ring systems.
  • [2.2.2]azabicyclooctane systems (quinuclidines) have been previously described, for example in US2005/0209272 and WO06/048225.
  • [3.1.0]azabicyclohexane systems have been described in, for example in WO06/035282.
  • [3.2.1]azabicyclooctane systems have been described in for example WO06/035303.
  • R 1 is C r C 6 -alkyl or a hydrogen atom
  • R 2 is a hydrogen atom or a group -R 5 , or a group, -Z-Y-R 5 , or a group -Z-NR 9 R 10 , or a group -Z-N(R 9 )C(O)R 11
  • R 3 is a lone pair, or d-C 6 -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 Ci-C 16 -alkylene, C 2 -C 16 -alkenylene or C 2 -Ci 6 -alkynylene group;
  • Y is a bond or oxygen atom
  • R 5 is an Ci-C 6 -alkyl, aryl, arylalkyl; aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, heteroaryl(Ci-C 8 -alkyl)-, cycloalkyl or heterocycloalkyl group;
  • R 6 is CVC ⁇ -alkyl or a hydrogen atom
  • R 7a and R 7b are a 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- heterocycloalkyl, heteroaryl, Ci-C ⁇ -alkyI, cycloalkyl and hydrogen;
  • R 80 is -OH, Ci-C ⁇ -alkyI, hydroxy-CVCe-alkyl, or a hydrogen atom;
  • R 9 and R 10 are independently a hydrogen atom, Ci-C 6 -alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(Ci-C 6 -alkyl)-, or heteroary ⁇ CV 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 11 is Ci-C 6 -alkyl or a hydrogen atom
  • Ar 1 is aryl, heteroaryl or cycloalkyl
  • Ar 2 are independently aryl, heteroaryl or cycloalkyl; and Q is an oxygen atom, -CH 2 -, -CH 2 CH 2 - or a bond;
  • the present invention provides compounds falling within the scope of, but not specifically disclosed in, our co-pending application PCT/GB2006/004675 referred to above.
  • the present invention provides a compound which has a quaternary ammonium species selected from the group consisting of:
  • Anti ⁇ S, 2S [7-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-2-yl]- dimethyl-(4-p-tolyl-butyl) ammonium; Anti-( 1 S, 2S) ⁇ -( ⁇ -Hydroxy- ⁇ H-xanthene- ⁇ -carbonyloxyJ-bicyclo ⁇ .1 ]hept-2-yl]- dimethyl-(3-phenoxy-propyl)-ammonium;
  • 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
  • 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 compounds of the invention be predominantly in the anti-endo configuration.
  • Compounds of the invention can also exist as optical isomers since substituted bicyclic ring systems can lack a plane of symmetry.
  • the absolute configuration of the molecule can be defined using Cahn-lngold-Prelog rules to assign the R or S designation to each position. To avoid confusion the ring numbering used below is employed.
  • compounds of the invention include racemates, single enantiomers and mixtures of the enantiomers in any ratio, since all such forms have muscarinic M3 receptor modulating activity to varying extents.
  • a preferred class of compounds of the invention consists of quaternary ammonium salts of formula (I) wherein the nitrogen shown in formula (I) is quaternary nitrogen, carrying a positive charge.
  • 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, 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); gastrointestinal-tract disorders
  • 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.
  • Another aspect of the invention is 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 the invention.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts, pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable quaternary ammonium salts.
  • pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, ⁇ /-methyl-glucamine, diethanolamine or amino acids (e.g.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that may be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, fumarates, succinates and the like
  • a compound contains a quaternary ammonium group acceptable counter- ions may be, for example, chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates (besylates), toluenesulfonates (tosylates), napthalene- bissuifonates (napadisylates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, fumarates, succinates and the like.
  • Prodrug refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention.
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of the invention containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of the invention containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
  • ester prodrug of a compound of the invention containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and frans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).
  • 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:
  • 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
  • WO05/080324 WO05/080313, US20050182091 , US20050171147, WO05/092870, WO05/077361, DE10258695, WO05/111002, 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
  • MMP12 matrix metalloprotease
  • TACE inhibitors such as marimastat, DPC-333, GW-3333
  • 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 Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterieukin 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, 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.
  • 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 ingredients), and the inert ingredients) (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.
  • Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister
  • 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.
  • 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.
  • adaptors spacers, expanders
  • pear-shaped containers e.g. Nebulator®, Volumatic®
  • automatic devices emitting a puffer spray Autohaler®
  • 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 ).
  • compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents.
  • 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).
  • 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 ne CJI gative ion)
  • MS ionisation method Electrospray (positive and negative ion)
  • Micromass Platform LCT with a C18-reverse-phase column (100 * 3.0 mm Higgins Clipeus with 5 ⁇ m particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid.
  • DCM dichloromethane
  • EtOH ethanol
  • DIPEA di-isopropylethylamine
  • EDCI 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • DMAP dimethylaminopyridine
  • RT room temperature
  • HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate
  • TFA trifluoroacetic acid
  • MgSO 4 magnesium sulphate
  • THF tetrahydrofuran
  • Et 2 O diethyl ether
  • DCE 1 ,2- dichloroethane
  • NaHCO 3 sodium hydrogen carbonate
  • EtOAc ethyl acetate
  • Na 2 SO 4 sodium s
  • the title compound was prepared from a ⁇ tf-(1S, 2S) hydroxy-di-thiophen-2-yl-acetic acid 2- ⁇ methyl-[4-(1-methyl-2-oxo-1 ,2-dihydropyridin-4-yl)-butyl]-amino ⁇ - bicyclo[2.2.1]hept-7-yl ester using the method described in example 1.
  • the title compound was prepared from antf-(1S, 2S) )-[7-(2S-cyclohexyl-hydroxy- phenyl-acetic acid 2-[methyl-(4-phenyl-butyl)-amino]-bicyclo[2.2.1]hept-7-yl ester using the method described in example 1.
  • 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.
  • Recombinant human M3 receptor was expressed in CHO-K1 cells.
  • Cell membranes were prepared and binding of [3H]-N-methyl scopolamine ([3H]-NMS) and compounds was assessed by a scintillation proximity assay (SPA).
  • SPA scintillation proximity assay
  • the incubation time was 16 hours at room temperature in the presence of 1 % (v/v) DMSO.
  • the assay was performed in white 96 well clear-bottomed NBS plates (Corning). Prior to the assay, the CHO cell membranes containing M3 receptor were coated onto SPA WGA (Wheat germ agglutinin) beads (GE Healthcare). Non specific binding was determined in the presence of 1 ⁇ M Atropine.
  • Radioactivity was measured on a Microbeta scintillation counter (PerkinElmer) using a 3H protocol with a 2 minutes per well read time.
  • Compound inhibition of [3H]-NMS binding was determined typically using concentrations in the range 0.03 nM to 1 ⁇ M and expressed as percent inhibition relative to the plate specific radioligand binding for the plate. Concentration dependent inhibition of [3H]-NMS binding by compounds was expressed as plC50
  • Example compounds that were tested in these assays showed binding affinity (K 1 or IC 50 ) values of ⁇ 10nM.
  • Examples 3, 9, 21 , 27 and 47 exhibited IC 50 values of 2.26nM, 3.65nM, 1.15nM, 0.13nM and 0.59nM respectively.
  • the inhibitory effects of compounds of the present invention at the M3 muscarinic receptor may be determined using the following assays:
  • 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 ⁇ o 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 mUkg) was administered intranasally. Animals were placed on a heated pad and allowed to recover before being returned to their home cages.
  • 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
  • the software calculated a peak resistance and a resistance area under the curve

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Abstract

La présente invention concerne un composé nommé de formule (I) : ayant une activité antagoniste du récepteur M3 ; une composition comprenant un tel composé ; l'utilisation d'un tel composé en thérapie (telle que pour l'asthme ou la bronchopneumopathie chronique obstructive) ; et un procédé de traitement d'un patient avec un tel composé.
PCT/GB2007/002130 2007-06-08 2007-06-08 Dérivés de la bicyclo[2.2.1]hept-2-ylamine et leur utilisation WO2008149053A1 (fr)

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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
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
US10683275B2 (en) * 2014-12-30 2020-06-16 Shinhao Materials LLC Leveler, leveler composition and method for electrodeposition of metals in microelectronics

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017670A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Dérivés bicyclo[2,2]hept-7-ylamine et leurs utilisations

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017670A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Dérivés bicyclo[2,2]hept-7-ylamine et leurs utilisations

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
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
US10683275B2 (en) * 2014-12-30 2020-06-16 Shinhao Materials LLC Leveler, leveler composition and method for electrodeposition of metals in microelectronics

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