Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics

Definitions

• This invention relates to heterocycles, pharmaceutical compositions, methods for their 5 preparation and use in the treatment of diseases where enhanced M3 receptor activation is implicated.
• Anti-cholinergic agents prevent the passage of, or effects resulting from the passage of, 10 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- muscarinic acetylcholine receptors
• M5 15 M5
• mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions.
• M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319-
• 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 25 Med., 158 (5 part 3) S 154 - 160).
• M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.
• vagal tone may either be increased (Gross et a/. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross ef a/. 1984, Am Rev Respir Dis;
• M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
• Tiotropium (Spiriva TM) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.
• ipratropium is a muscarinic antagonist marketed for the treatment of COPD.
• WO97/30994 describes oxadiazoles and thiadiazoles as muscarinic receptor antagonists.
• EP0323864 describes oxadiazoles linked to a mono- or bicyclic ring as muscarinic receptor modulators.
• R 2 is a group H, -(Z) p -R 7 , -Z-Y-R 7 or -Y-R 7 ;
• p is 0 or 1 ;
• R 4 and R 5 are joined together to form a tricyclic ring so that the group R 4 R 5 R 6 C-
• R 6 represents the group , where R 6 : i,s -OH, Ci-Ce-alkyl, Ci-C 6 - alkoxy or a hydrogen atom, Q is an oxygen atom, -CH 2 -, -CH 2 CH 2 - or a bond, R 14 and R 15 are independently selected from halo, CrCe-alkyl and C r C 6 -alkoxy, and a and b are, independently, 0 or 1 ;
• one of W, V and A is N or NR 11 ; another of W, V and A is N, O, S or CR 8 ; and the last one of W, V and A is N or CR 8 ;
• X is an d-C ⁇ alkylene, C 2 -C 4 -alkenylene or C 2 -C 4 -alkynylene group;
• R 7 is an Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C r C 8 -alkyl)-, heteroaryKCrC ⁇ -alkyl)-, heterocycloalkyl orcycloalkyl group;
• t, u and v are independently selected from 1 , 2 or 3, with the proviso that t, u and v cannot all simultaneously be 1 ;
• Z is a C 1 -C 4 -alkylene, C 2 -C 4 -alkenylene or C 2 -C 4 -alkynylene group;
• Y is an oxygen atom, a group -OC(O)-, a group -N(H)C(O)- or a group -S(O) n ;
• n 0, 1 or 2;
• R 8 and R 11 are, independently, a hydrogen atom or Ci-C 6 -alkyl group.
• D ' is a pharmaceutically acceptable counter-ion
• each occurrence of alkyl, alkenyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted; and wherein each alkenylene chain contains, where possible, up to 2 carbon-carbon double bonds and each alkynylene chain contains, where possible, up to 2 carbon-carbon triple bonds.
• the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) as herein defined.
• the present invention provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
• the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
• the present invention provides a solvate (such as a hydrate) of a compound of formula (I) as herein defined, or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.
• the substituent R 2 can be attached to any carbon atom of the azabicyclic ring.
• the carbon atom to which R 4 , R 5 and R 6 are attached can be an asymmetric centre so compounds of the invention may be in the form of single enantiomers or mixtures of enantiomers.
• both enantiomers of the invention generally exhibit affinity at the M 3 receptor, although one enantiomer is generally preferred on criteria of potency at the M 3 receptor and/or selectivity against the M 2 receptor.
• W, V 1 A 1 Q, X, D " , R 14 , R 15 , R 6 , R 2 , a, b, t, u and v are as previously defined above.
• 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 or COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'whez- infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy, pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacos
• a compound of present invention is useful in the treatment or prevention of respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease, COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'whez- infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy or pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis).
• chronic obstructive lung disease also known as chronic obstructive pulmonary disease, COPD
• compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
• Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is implicated.
• Diseases or conditions in which muscarinic M3 receptor activity is implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
• Another aspect of the invention provides a compound of the invention for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is implicated.
• Diseases or conditions in which muscarinic M3 receptor activity is implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
• Another aspect of the invention provides 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 a therapeutically effective amount of a compound of the invention.
• Diseases or conditions in which muscarinic M3 receptor activity is implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders.
• Another aspect of the invention provides a compound of the invention for use in therapy.
• Alkoxy and “alkyloxy” means an -O-alkyl group in which alkyl is as described below.
• Exemplary alkoxy groups include methoxy (-OCH 3 ) and ethoxy (-OC 2 H 5 ).
• Alkyl as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, for example 1-8, such as 1 to 6, 1-4 or 1-2 carbon atoms, in the chain.
• Exemplary alkyl groups include methyl, ethyl, 1- propyl and 2-propyl.
• alkenyl as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one or more carbon-carbon double bonds in the chain.
• alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl.
• Alkylene means an -alkyl- group in which alkyl is as defined previously.
• exemplary alkylene groups include -CH 2 -, -(CH 2 )2- and -C(CH 3 )HCH 2 -.
• Alkenylene means an -alkenyl- group in which alkenyl is as defined previously.
• Alkynylene means an -alkynyl- group in which -alkynyl- refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain.
• exemplary alkynylene groups include ethynyl and propargyl.
• Aryl as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, conveniently from 6 to 10 carbon atoms, such as phenyl or naphthyl. Phenyl is a specifically convenient aryl group.
• aryl group specifically a phenyl group
• Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Convenient arylalkyl groups contain a C ⁇ alkyl moiety.
• arylalkyl groups include benzyl, phenethyl and naphthlenemethyl.
• Cyclic amine means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein).
• Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and ⁇ /-methylpiperazine.
• the cyclic amine group may be substituted by one or more substituent groups.
• Cycloalkyl means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, conveniently from 3 to 8 carbon atoms, and more conveniently from 3 to 6 carbon atoms.
• Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
• the cycloalkyl group may be substituted by one or more substituent groups.
• Halo or halogen means fluoro, chloro, bromo, or iodo. Convenient are fluoro or chloro.
• Haloalkoxy means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
• Haloalkyl means an alkyl group which is substituted by one or more halo atoms.
• exemplary haloalkyl groups include trifluoromethyl.
• Heteroaryl as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, conveniently from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
• Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, fury I, imidazoiyl, indolyi, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups.
• the heteroaryl group may be substituted by one or more substituent groups.
• the heteroaryl group may be attached to the remainder of the compound of the invention by any available carbon or nitrogen atom.
• ⁇ eterocycloalkyl means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR or CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl).
• the heterocycloalkyl group may be substituted by one or more substituent groups.
• the heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
• “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (propyl or /so-propyl) or butyl (butyl, /so-butyl or tert- butyl).
• “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, napadisylate (naphthalene-1 ,5-disulfonate or naphthalene-1 - (sulfonic acid)-5-sulfonate), edisylate (ethane-1 ,2-disulfonate or ethane-1 -(sulfonic acid)- 2-sulfonate), maleates, fumarates, succinates and the like; (iii) when R 3 is not a lone pair the compound of formula (I) has a quaternary ammonium group for which the pharmaceutically acceptable counter-ion may be, for example, chloride, bromide, sulf
• the present invention covers all permissible ratios of cationic ammonium species to counter-ion, for example hemi-napadisylate and napadisylate.
• references to the compounds of the invention are meant to also include the pharmaceutically acceptable salts.
• “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. Suitable groups for forming pro-drugs are described in The Practice of Medicinal Chemistry, 2 nd Ed. pp561-585 (2003) and in F. J. Leinweber, Drug Metab. Res., 18, 379. (1987) It will be understood that, as used in herein, references to the compounds of the invention are meant to also include the prodrug forms.
• “Saturated” pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
• cyclic groups referred to above namely, aryl, heteroaryl, cycloalkyl, and cyclic amine are unsubstituted or substituted by one or more of the same or different substituent groups.
• substituent groups include -Cl, -F, -CH 3 , -OCH 3 , -CN, More generally the substituents can be divided into two classes:
• a first class of substituent includes acyl (e.g. -COCH,), alkoxy (e.g., -OCH-), alkoxycarbonyl (e.g. -COOCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfinyl (e.g. -SOCH 3 ), alkylsulfonyl (e.g. -SO 2 CH 3 ), alkylthio (e.g. -SCH 3 ), -NH 2 , aminoacyl (e.g. -CON(CH 3 ) 2 ), aminoalkyl (e.g.
• a second class of substituent includes arylalkyl (e.g. -CH 2 Ph or
• aryl e.g. morpholine
• aryloxy, heteroaryloxy, arylalkyloxy e.g. benzyloxy
• heteroarylalkyloxy the cyclic part of any of which being optionally substituted by any of the first class of substituent referred to above (for example alkoxy, haloalkoxy, halogen, alkyl and haloalkyl).
• Alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g., -OCHJ, alkylamino (e.g. -NHCHJ, alkylsulfinyl
• alkylsulfonyl e.g. -SO 2 CH 3
• alkylthio e.g. -SCH 3
• -NH 2 aminoalkyl (e.g. - CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 0 -Ph), cyano, dialkylamino (e.g. -N(CH 3 J 2 ), halo, haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g. -CF 3 ), alkyl (e.g. -CH 3 or - CH CHJ, -OH, -CHO, and -NO 2 .
• aminoalkyl e.g. - CH 2 NH 2
• arylalkyl e.g. -CH 2 Ph or -CH 2 -CH 0 -Ph
• cyano dialkylamino
• 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 further comprises a subset of compounds formula (Ia) wherein:
• R 6 is -OH or C r C 6 -alkyl
• Q is an oxygen atom or a bond
• a and b are O; W is N, one of V and A is N, O or S, and the last one of V and A is N or CR 8 ;
• R 7 is aryl, aryKd-C ⁇ -alkyl)-, heteroaryl or heterocycloalkyl;
• R 2 , R 8 , D " , X, t, u, v, aryl, heteroaryl and heterocycloalkyl are as previously defined.
• the present invention further comprises another subset of compounds formula (I) wherein compounds of formula (I) may be depicted according to formula (Ib):
• R 2 is selected from -(Z) p -R 7 , -Z-Y-R 7 and -Y-R 7 ;
• R 6 is -OH or a methyl group
• Q is an oxygen atom or a bond
• W is N, V is CR 8 , and A is O;
• X is C ⁇ -alkylene
• R 7 is aryl, or an/Kd-Ce-alkyl)-;
• t, u and v are 2;
• Z is a CrC ⁇ alkylene;
• Y is an oxygen atom or a group -S(O) n ;
• n 0;
• aryl is as previously defined
• D ' is a pharmaceutically acceptable counter-ion
• each occurrence of each occurrence of alkyl may be optionally substituted with one or more substituent groups chosen from d-C ⁇ -haloalkyl, d-C ⁇ -haloalkoxy, CN and halo; and each occurrence of aryl or alkylene may be optionally substituted with one or more substituent groups chosen from Ci-C 6 -alkyl, d-C ⁇ -haloalkyl, C 1 -C 6 - haloalkoxy, CN and halo; and
• each alkenylene chain may contain, where possible, up to 2 carbon-carbon double bonds.
• the present invention provides compounds of formula (I) wherein R 2 is a group -(Z) p -R 7 , p is 1 and -Z- is a straight or branched alkylene radical linking the azabicyclic ring and -R 7 by a chain of up to 4, for example up to 2, carbon atoms.
• R 7 is typically a cyclic lipophilic group such as phenyl, benzyl, dihydrobenzofuryl or phenylethyl (wherein the phenyl rings are optionally substituted as described herein).
• the present invention provides compounds of formula (I) wherein R 2 is a group -Y-R 7 and Y is an oxygen or sulfur atom.
• R 7 is typically a cyclic lipophilic group such as phenyl, benzyl, dihydrobenzofuryl or phenylethyl (wherein the phenyl rings are optionally substituted as described herein).
• the present invention provides compounds of formula (I) wherein R 2 is selected from -(Z) p -R 7 , -Z-Y-R 7 and -Y-R 7 .
• the present invention provides compounds of formula (I) wherein R 2 is selected from -Z-Y-R 7 and -Y-R 7 .
• the present invention provides compounds of formula (I) wherein R 2 is -(Z) p -R 7 .
• the present invention provides compounds of formula (I) wherein R 2 is -Y-R 7 .
• the present invention provides a compound of formula (I) wherein R 4 and R 5 are joined together to form a tricyclic ring so that the group R 4 R 5 R 6 C-
• R 6 is -OH, Ci-C 4 -alkyl, C 1 -C 4 -BIkOXy or a hydrogen atom;
• Q is an oxygen atom, -CH 2 -, or a bond;
• R 14 and R 15 are independently selected from halo, Ci-C 6 -alkyl, Ci-C 6 -alkoxy and a and b are, independently, 0 or 1.
• the present invention provides a compound of formula (I) wherein R 6 is hydroxy or CrC 4 alkyl.
• the present invention provides a compound of formula (I) wherein a and b are 0.
• the present invention provides a compound of formula (I) wherein R 6 is -OH or a methyl group.
• the present invention provides a compound of formula (I) wherein Q is an oxygen atom or a bond.
• the present invention provides a compound of formula (I) wherein R 7 is an aryl group (for example phenyl), an aryl-fused-cycloalkyl group (for example indanyl) or an 8PyI(C 1 -C 8 -alkyl)- group (for example benzyl or 2-phenyleth-1-yl) group; wherein said groups may be optionally substituted with 1 or 2 substituents independently selected from Ci-C 6 -alkyl, and halo.
• R 7 is an aryl group (for example phenyl), an aryl-fused-cycloalkyl group (for example indanyl) or an 8PyI(C 1 -C 8 -alkyl)- group (for example benzyl or 2-phenyleth-1-yl) group; wherein said groups may be optionally substituted with 1 or 2 substituents independently selected from Ci-C 6 -alkyl, and halo.
• the present invention provides a compound of formula (I) wherein R 7 is selected from C 2 -C 6 -alkenyl (for example 3-methyl-but-2-enyl or allyl), aryl (for example phenyl), heteroaryl (for example thienyl), aryl(C r C 8 -alkyl)- (for example phenyl-CH 2 - or phenyl-CH 2 CH 2 -), or heteroaryl(d-C 8 -alkyl)- (for example thienyl-CH 2 -).
• R 7 is selected from C 2 -C 6 -alkenyl (for example 3-methyl-but-2-enyl or allyl), aryl (for example phenyl), heteroaryl (for example thienyl), aryl(C r C 8 -alkyl)- (for example phenyl-CH 2 - or phenyl-CH 2 CH 2 -), or heteroaryl(d-C 8 -al
• the present invention provides a compound of formula (I) wherein R 8 is hydrogen.
• the present invention provides a compound of formula (I) wherein R >11 is hydrogen or C 1 -C 3 alkyl.
• the present invention provides a compound of formula (I) wherein R 11 is methyl.
• the present invention provides a compound of formula (I) wherein Y is an oxygen atom or a group -S(O) n .
• the present invention provides a compound of formula (I) wherein Y is an oxygen atom.
• the present invention provides a compound of formula (I) wherein n is 1 or 2.
• the present invention provides a compound of formula (I) wherein n is 0.
• the present invention provides a compound of formula (I) wherein p is 1.
• the present invention provides a compound of formula (I) wherein t is 2.
• the present invention provides a compound of formula (I) wherein u is 1 or 2.
• the present invention provides a compound of formula (I) wherein u is 2
• the present invention provides a compound of formula (I) wherein v is 2.
• particular combinations of W, V and A in the compounds of formula (I) include:
• W is a group CR 8 , V is an oxygen atom and A is a nitrogen atom;
• W is a group CR 8 , V is a sulfur atom and A is a nitrogen atom;
• W is a group CR 8 , V is a nitrogen atom and A is an oxygen atom;
• W is a group CR 8 , V is a nitrogen atom and A is a sulfur atom;
• W is a nitrogen atom, V is a nitrogen atom and A is an oxygen atom;
• W is a nitrogen atom, V is an oxygen atom and A is a nitrogen atom;
• W is an oxygen atom, V is a nitrogen atom and A is a nitrogen atom;
• W is a nitrogen atom, V is a group CR 8 and A is an oxygen atom;
• W is a nitrogen atom, V is a group CR 8 and A is a sulphur atom;
• W is a group N-R 11 , V is a group CR 8 and A is a nitrogen atom;
• (k) W is a nitrogen atom, V is an oxygen atom and A is a group CR 8 ;
• W is a group NR 11 , V is a nitrogen atom and A is a group CR 8 ;
• W is an oxygen atom, V is a nitrogen atom and A is a group CR 8 ;
• W is a nitrogen atom
• V is a sulfur atom
• A is a nitrogen atom
• W is a nitrogen atom
• V is a nitrogen atom
• A is a sulfur atom
• W is a sulfur atom, V is a nitrogen atom and A is a nitrogen atom;
• the present invention provides a compound of formula (I) wherein the 5-membered ring containing W, V and A is selected from:
• the present invention provides a compound of formula (I) wherein the 5-membered ring containing W, V and A is selected from: wherein the bond marked * is attached to the group R 4 R 5 R 6 C-, and the bond marked ** is attached to the group -XN + .
• the present invention provides a compound of formula (I) wherein the 5-membered ring containing W, V and A is: wherein the bond marked * is attached to the group R 4 R 5 R 6 C-, and the bond marked ** is attached to the group -XN + .
• the present invention provides a compound of formula (I) wherein X is C ⁇ C ⁇ alkylene. In another alternative embodiment, the present invention provides a compound of formula (I) wherein X is CrC 3 alkylene.
• the present invention provides a compound of formula (I) wherein X is ethylene or methylene.
• the present invention provides a compound of formula (I) wherein X is methylene.
• the present invention provides a compound of formula (I) wherein Z is C 1 -C 4 alkylene being optionally substituted on up to three carbons in the chain by methyl.
• the present invention provides a compound of formula (I) wherein Z is ethylene or methylene.
• the present invention provides a compound of formula (I) wherein, the group
• the present invention provides a compound of formula (I) wherein, the group
• the group R 2 may be attached at any carbon atom of the azabicyclic group.
• the present invention provides compounds wherein particular attachment points are:
• Examples of compounds of the invention include those of the non-limiting Examples provided herein.
• the present invention provides a compound of formula (I) selected from: (R)-3-(3-Fluoro-phenoxy)- 1 -[2-(9-methyl-9H-xanthen-9-yl)-oxazol-5- ylmethyl]azonia-bicyclo[2.2.2]octane salt;
• Examples of pharmaceutically acceptable counter-ions that may be present in the salts according to this embodiment include chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), napadisylates (naphthalene-1 ,5- disulfonates or naphthalene-1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2- disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), isethionates (2- hydroxyethylsulfonates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, malates, fumarates, succinates, xinafoates, p-acetamidobenzoates. More specific examples include chloride, bromide
• 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 antiinflammatory, 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.
• Typical combinations would have two or three different pharmaceutical compositions.
• Suitable therapeutic agents for a combination therapy with compounds of the invention include: One or more other bronchodilators such as PDE3 inhibitors; Methyl xanthines such as theophylline; Other muscarinic receptor antagonists;
• a corticosteroid for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
• a non-steroidal glucocorticoid receptor agonist for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
• a ⁇ 2-adrenoreceptor agonist for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK-597901 , GSK-159802, GSK-64244, GSK- 678007, TA-2005 and also compounds of EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651 , US2005/0133417, US2005/5159448, WO00/075114, WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204, WO
• 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; Phosphodie
• An antitussive agent such as codeine or dextramorphan
• P2X7 anatgonists P2X7 anatgonists; iNOS inhibitors;
• NSAID non-steroidal anti-inflammatory agent
• ibuprofen or ketoprofen for example ibuprofen or ketoprofen
• a dopamine receptor antagonist A dopamine receptor antagonist
• 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,
• DP1 or CRTH2 a thromboxane A 2 antagonist eg ramatrobant
• TM or Th2 function Compounds which modulate TM or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterieukin 10 agonists, such as llodecakin; 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-
• 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.
• 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.
• 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, typically 0.1 ⁇ g to about 0.5 mg per kg, and more typically 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, typically 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 typically 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
• the active compounds may be dosed as described depending on the inhaler system used.
• the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
• the compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilising the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
• the compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds.
• reactive functional groups e.g. hydroxy, amino, thio or carboxy
• Conventional protecting groups for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry” John Wiley and Sons, 1999, may be used.
• + NR c R d R e represents ( and R R R C- represents the group wherein R 2 , R 6 , R 14 , R 15 , Q, t, u, v, a and b are as defined above for compounds of formula (I);
• LG represents a leaving group such as bromide, chloride, iodide, by reaction with an amine of formula (XVII): R c R d R e N (XVII)
• R c R d R e N represents an azabicyclic compound wherein t, u, v and R 2 are as described above
• the reaction is performed in a range of solvents, typically a mixture of THF/DCM or acetonitrile/chloroform at a range of temperatures, typically between 0 and the reflux temperature, or more typically, in acetonitrile at a temperature between 0 and 50° C, most typically at 50 0 C.
• solvents typically a mixture of THF/DCM or acetonitrile/chloroform at a range of temperatures, typically between 0 and the reflux temperature, or more typically, in acetonitrile at a temperature between 0 and 50° C, most typically at 50 0 C.
• reaction by reaction with a brominating agent such as N-bromosuccinimide in the presence of a radical initiator such as AIBN or benzoyl peroxide.
• a brominating agent such as N-bromosuccinimide
• a radical initiator such as AIBN or benzoyl peroxide.
• the reaction can be carried out in suitable solvents, such as CCI 4 , at a range of temperatures, typically between ambient temperature and the reflux temperature of the solvent.
• compounds of formula (III) can be prepared from compounds of general formula (IV) by palladium-catalysed cyclisation using a palladium catalyst such as bis(dibenzylideneacetone)palladium in the presence of a ligand such as triphenylphosphine and a base such as sodium tert-butoxide in a solvent such as THF from ambient temperature to the reflux temperature of the solvent.
• a palladium catalyst such as bis(dibenzylideneacetone)palladium
• a ligand such as triphenylphosphine
• a base such as sodium tert-butoxide
• R is a suitable alkyl group (such as ethyl or methyl) by reaction with an aqueous solution of an inorganic base such as lithium or potassium hydroxide in a suitable solvent such as methanol or ethanol or 1 ,4-dioxane at a temperature from 0°C to the reflux temperature of the solvent, typically at 50 0 C.
• an inorganic base such as lithium or potassium hydroxide
• a suitable solvent such as methanol or ethanol or 1 ,4-dioxane
• Compounds of general formula (XV) can be prepared from compounds of formula (XIII) by reaction with an alkylating agent of formula (XVIII):
• R a is C r C 6 -alkyl and LG is a leaving group such as halogen, tosylate, mesylate.
• the reaction is performed in the presence of a base such as sodium hydride in a solvent such as THF from O 0 C to the reflux temperature of the solvent.
• R a is CrC ⁇ -alkyl and LG is a leaving group such as halogen, tosylate, mesylate.
• the reaction is performed in the presence of a base such as potassium tert-butoxide in a solvent such as THF from O 0 C to the reflux temperature of the solvent.
• R f is CVC ⁇ -alkyl and LG is a leaving group such as halogen, tosylate, mesylate.
• the reaction is performed in the presence of a base such as sodium hydride in a solvent such as THF from O 0 C to the reflux temperature of the solvent.
• Compounds of formula (l-d) can be prepared from compounds of formula (l-b) by reaction with a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid in a solvent such as DCM from ambient temperature to the reflux temperature of the solvent.
• a reducing agent such as triethylsilane
• an acid such as trifluoroacetic acid
• a solvent such as DCM
• Compounds of formula (X) may be prepared from compounds of formula (Xl); by treatment with a non-nucleophilic base such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a compatible solvent, for example toluene, at a temperature from 0-60 0 C, typically 0-10 0 C.
• a non-nucleophilic base such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a compatible solvent, for example toluene, at a temperature from 0-60 0 C, typically 0-10 0 C.
• Compounds of formula (III) may be prepared from compounds of formula (X) or from compounds of formula (Xl) by treatment with a non-nucleophilic base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene (DBN) or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a compatible solvent, for example toluene, at a temperature from ambient temperature to the reflux temperature of the solvent, typically 80 0 C.
• a non-nucleophilic base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene (DBN) or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a compatible solvent, for example toluene, at a temperature from ambient temperature to the reflux temperature of the solvent, typically 80 0 C.
• reaction by cyclisation in the presence of iodine and a base such as potassium t-butoxide or potassium carbonate in a compatible solvent such as toluene.
• a base such as potassium t-butoxide or potassium carbonate
• a compatible solvent such as toluene.
• Compounds of formula (XII) may be prepared from compounds of formula (V) using methods analogous to those used in the preparation of compounds of formula (IV) from compounds of formula (V) as described above and using allylamine in place of propargylamine.
• R and R are suitable alkyl groups (such as methyl) by reaction with cyanogen bromide in a suitable solvent such as DCM at ambient temperature.
• compounds of formula (l-f) may be prepared from compounds of formula (XXIII) using methods described above for the preparation of compounds of formula (l-a) from compounds of formula (II), Scheme 9;
• Compounds of formula (XXIII) may be prepared from compounds of formula (XXIV) by reaction with chloroacetyl chloride in a solvent such as pyridine or a mixture of chloroform and pyridine at a temperature between 0° C and ambient temperature.
• Compounds of general formula (XXIV) can be prepared from compounds of formula (VII) by reaction with hydroxylamine hydrochloride in the presence of a base such as sodium bicarbonate or pyridine in a solvent such as methanol or ethanol at a temperature from ambient temperature to the reflux temperature of the solvent, preferably at the reflux temperature of the solvent.
• a base such as sodium bicarbonate or pyridine
• a solvent such as methanol or ethanol
• Scheme 11 illustrates an alternative method whereby the + NR c R d R e group can be introduced.
• Compounds of formula (l-e) may be prepared from compounds of formula (XXVIII) by reaction with a compound of formula (XVII), in a solvent such as a chloroform/acetonitrile mixture at elevated temperatures, for example at 180 0 C in a microwave reactor.
• Compounds of formula (XXVIII) can be prepared by the reaction of a compound of formula (XXII-a) with an alkylating agent, such as MeBr 1 in an aprotic solvent, such as THF, at elevated temperature.
• an alkylating agent such as MeBr 1
• an aprotic solvent such as THF
• the intermediate bromide is then treated with an alkylamine, such as dimethylamine, in a suitable aprotic solvent, such as THF at a temperature from 0° C to ambient temperature.
• Compounds of formula (l-h) may be prepared from compounds of formula (XXXI) by methods similar to those used for the preparation of compounds of formula (l-a) from compounds of formula (II).
• Compounds of formula (XXXI) can be prepared from compounds of formula (XXXII) by treatment with cyanogen bromide (von Braun reaction) in a suitable solvent such as dichloromethane at ambient temperature.
• Compounds of formula (XXXIII) may be prepared from compounds of formula (V) by reaction with compounds of formula (XXXIV) in the presence of a suitable coupling agent such as carbonyl diimidazole, in a suitable solvent, for example dichloromethane at ambient temperature.
• a suitable coupling agent such as carbonyl diimidazole
• a suitable solvent for example dichloromethane at ambient temperature.
• Compounds of formula (XXXIV) are known in the art or are commercially available.
• Isoxazoles of formula (l-i) may be prepared according to the methods outlined in Scheme 13;
• Compounds of formula (l-i) may be prepared from compounds of formula (XXXV) using a similar set of procedures as described for the preparation of compounds of formula (l-f) from compounds of formula (XXIII).
• Compounds of formula (XXXV) and their preparation from compounds of formula (XXXVI) are described in the literature, Medicinal Chemistry Research 2001, 10(9), 615-633.
• Compounds of general formula (XXXVI) can be prepared from compounds of formula (XXIX) by reaction with N-chlorosuccinimide in a suitable solvent.
• Compounds of general formula (XXIX) can be prepared from compounds of formula (V) by standard methods such as conversion of the carboxylic acid to the Weinreb amide followed by reduction of the Weinreb amide to the aldehyde using a reducing agent such as lithium aluminium hydride in a suitable solvent such as diethyl ether of THF followed by conversion to the oxime with hydroxylamine hydrochloride and pyridine in a solvent such as ethanol at reflux.
• a reducing agent such as lithium aluminium hydride in a suitable solvent such as diethyl ether of THF
• Compounds of formula (l-j) may be prepared from compounds of formula (XXXVII) using a similar set of procedures as described for the preparation of compounds of formula (l-f) from compounds of formula (XXIII).
• Compounds of general formula (XXXVII) can be prepared from compounds of formula (V) by reaction with 2-chloro-N-hydroxy- acetamidine (XXXVIII) in the presence of a coupling agent such as CDI in a suitable solvent such as DMF or 1 ,4-dioxane followed by heating in the presence of an acid such as acetic acid.
• a coupling agent such as CDI
• a suitable solvent such as DMF or 1 ,4-dioxane
• Compounds of formula (XXXVIII) are known in the art or are commercially available.
• compounds of formula (1-j) can be prepared from compounds of formula (XXXVII-a) using a similar set of procedures as described for the preparation of compounds of formula (l-f) from compounds of formula (XXIII).
• Compounds of formula (XXXVII-a) can be prepared from compounds of formula (XXXIX) using a similar method (von Braun reaction) to that described for the preparation of compounds of formula (XXXI) from compounds of formula (XXXII).
• Compounds of formula (XXXIX) can be prepared from compounds of formula (V) using a compound of formula (XL) using similar methods to those described above for the preparation of compounds of formula (XXXVII) from compounds of formula (V).
• R 1 and R 2 are either methyl or ethyl in the presence of a suitable reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as 1 ,2- dichloroethane at ambient temperature.
• a suitable reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as 1 ,2- dichloroethane at ambient temperature.
• XLV by reaction with a vinyl tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) in a suitable solvent such as toluene at a suitable temperature such as the reflux temperature of the solvent.
• a vinyl tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0)
• a suitable solvent such as toluene
• R 7 are described in EP413545; and compounds of formula (XVII) may be prepared according to methods described above.
• 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
• TLC 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.
• MS ionisation method Electrospray (positive and negative ion).
• MS ionisation method Electrospray (positive and negative ion).
• AIBN 2,2'-azobis(2-methylpropionitrile);
• DCM dichloromethane
• DEA diethylamine
• DIPEA diisopropylethylamine
• DMAP diisopropylethylamine
• EtOH ethanol
• HATU O-(7-azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate
• HOBT 1 -hydroxybenzotriazole
• IMS industrial methylated spirit
• IPA 2-propanol
• MeOH methanol
• RT ambient temperature
• Rt retention time
• TFA trifluoroacetic acid
• THF tetrahydrofuran
• Sat saturated
• MeCN acetonitrile
• Trifluoromethanesulfonic acid (1.15 mL, 10.8mmol) was added dropwise to a solution of 9-methyl-9H-xanthene-9-carboxylic acid prop-2-ynylamide (3.0 g, 10.8mmol) in 1 ,4- dioxane (30 mL). The resulting solution was heated at 90 0 C for 16 hours. The reaction mixture was cooled and the solvent was removed. The residue was partitioned between DCM (30 mL) and cone, ammonia solution (20 mL). The phases were separated and the aqueous phase was extracted with DCM (2x40 mL). The combined organic phase was washed with 10% citric acid, sat.
• Potassium tert-butoxide (4.48 g, 40.0mmol) was added to a suspension of 9-Hydroxy- 9H-fluorene-9-carboxylic acid allylamide (7.06 g, 26.6mmol) in toluene (140 mL) under N 2 , followed by portionwise addition of I 2 .
• the reaction mixture was stirred at 0 0 C for ten minutes, then allowed to warm up to ambient temperature and stirred for 3 hours.
• the reaction mixture was treated with 20% w/w aqueous solution of Na 2 S 2 O 3 (140 mL) and stirred vigorously for 15 minutes before filtration.
• HATU (16.54 g, 43.5mmol) was added to a solution of 9-Hydroxy-9H-xanthene-9- carboxylic acid (7.20 g, 29.7mmol) in dry DMF (130 ml.) followed by DIPEA (7.42 ml_, 43.5mmol) and allylamine (2.23 ml_, 29.7 mmol). The mixture was allowed to stir at ambient temperature for 24 hours then the solvent was evaporated in vacuo and the residue partitioned between H 2 O (80 ml.) and EtOAc (100 ml.) . The phases were separated and the aqueous layer was extracted with EtOAc (2x60 ml_).
• Step 1 A solution of borane-THF (1.0 M in THF, 82.6 mL, 82.55 mmol) was added dropwise to a solution of (R)-1 -aza-bicyclo[2.2.2]octan-3-ol (10.00 g, 78.62 mmol) in THF (50 mL) at 0 0 C. The reaction mixture was allowed to warm to room temperature, stirred for 24 h, and evaporated in vacuo. The resulting residue was diluted with chloroform, washed with water, brine, dried (MgSO 4 ), filtered and evaporated in vacuo.
• Step 2 A solution of the foregoing compound (1.50 g, 10.64 mmol) in DMF (30 mL) was treated with NaH (0.64 g , 15.96 mmol of 60% dispersion in mineral oil), stirred for 5 mins and then treated with 3,3-dimethylallyl bromide (2.45 ml_, 21.27 mmol). The reaction mixture was stirred overnight at room temperature, evaporated in vacuo and purified by silica gel chromatography (eluting with 0-100% DCM in cyclohexane) to give (R)-3-(3- methyl-but-2-enyloxy)-1-azonia-bicyclo[2.2.2]octane borane complex (1.95 g, 88%).
• Step 1 A solution of 9-methyl-9H-xanthene-9-carboxylic acid (3.5 g, 13.76 mmol) in anhydrous THF (40 ml_) was added dropwise to a stirred solution of 2M LAH in THF (8.94 mL, 17.89 mmol) cooled to -15 0 C under a nitrogen atmosphere. Upon addition the reaction was allowed to reach room temperature. After stirring for 2 hours at room temperature, the reaction was cooled ' to -15 0 C and quenched by the addition of water (1.3 mL), 4M NaOH (1.3 mL) and water (1.3 mL). The formed precipitate was removed by filtration through hi-flo, eluting with ethyl acetate.
• Step 2 A solution of oxalyl chloride (1.6 mL, 18.36 mmol) in dry DCM (90 mL) was cooled to -78 0 C under a nitrogen atmosphere. A solution of DMSO (2.61 mL, 36.72 mmol) in
• Step 3 A solution of 9-methyl-9H-xanthene-9-carbaldehyde oxime (2.76 g, 11.53 mmol) was formed in dry DCM (150 mL) and cooled to -78 0 C. Under reduced lighting, a solution of tert-butylhypochlorite (2.50 g, 23.06 mmol) in DCM (6 mL) was added drop wise. After 2 hours at -78 0 C triethylamine (2.40 mL, 17.30 mmol) was added drop wise. After a further 10 mins at -78 0 C the mixture was allowed to warm to 0 0 C.
• Step 1 A solution of 9-hydroxy-9-fluorene carboxylic acid (8.7 g, 38.46 mmol) in anhydrous THF (50 mL) was added dropwise to a stirred solution of 2M LAH in THF (25.00 mL, 50.00 mmol) cooled to -15 0 C under a nitrogen atmosphere. Upon addition the reaction was allowed to reach room temperature. After stirring for 2 hours at room temperature, the reaction was cooled to -15 0 C and quenched by the addition of water (3.6 mL), 4M NaOH (3.6 mL) and water (3.6 mL). The formed precipitate was removed by filtration through hi-flo, eluting with ethyl acetate.
• Step 2 A solution of oxalyl chloride (2.47 mL, 28.34 mmol) in dry DCM (130 mL) was cooled to -78 C C under a nitrogen atmosphere. A solution of DMSO (4.03 mL, 56.68 mmol) in DCM (15 mL) was added drop wise then the mixture stirred at -78 0 C for 10 mins. A solution of 9-hydroxymethyl-9H-fluoren-9-ol (4.01 g, 18.89 mmol) in DCM (40 mL) was added drop wise over the course of 1 hour giving a thick slurry. The internal temperature was allowed to reach -45 0 C.
• Triethylamine 13.10 mL, 94.46 mmol was added drop wise and after complete addition the mixture was allowed to warm to room temperature. The mixture was washed with 1 N hydrochloric acid, water and brine then dried (MgSO 4 ), filtered and evaporated to give an oil. This was dissolved in IMS (45 mL) and added portionwise to a preformed solution of hydroxylamine hydrochloride (1.83 g, 28.34 mmol) and sodium carbonate (3.00 g, 28.34 mmol) in water (30 mL). The resulting emulsion was stirred at room temperature overnight then partitioned between DCM and water.
• Step 3 A solution of ⁇ -hydroxy- ⁇ H-fluorene- ⁇ -carbaldehyde oxime (2.60 g, 11.54 mmol) and 2,6-lutidine (3.36 ml_, 28.86 mmol) in DCM (60 mL) was cooled in an ice-bath. Trimethylsilyl trifluoromethanesulfonate (5.24 mL, 28.86 mmol) was added drop wise.
• Step 4 A solution of 9-trimethylsilanyloxy-9H-fluorene-9-carbaldehyde oxime (3.06 g, 10.29 mmol) was formed in dry DCM (200 mL) and cooled to -78 0 C. Under reduced lighting, a solution of tert-butylhypochlorite (2.23 g, 20.58 mmol) in DCM (15 mL) was added drop wise. After 2 hours at -78 0 C triethylamine (2.14 mL, 15.44 mmol) was added drop wise. After a further 10 mins at -78 0 C the mixture was allowed to warm to 0 0 C.
• Step 1
• Step 1 A solution of R-3-quinuclidinol (1.25 g), CuI (93.1 mg), 1 , 10-phenanthroline (176 mg), Cs 2 CO 3 (3.19 g) and 3-fluoro-iodo-benzene (1.11 g) in toluene (2.5 ml.) was heated at 100 0 C for 20 h. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite. The insoluble material was washed several times with ethyl acetate. The filtrate was washed with water, dried (MgSO 4 ), filtered and evaporated in vacuo.
• Step 1 Benzyl mercaptan (0.34 ml_) was added slowly to a suspension of NaH (117 mg of 60% dispersion in mineral oil) in DMF (10 ml.) at 0 0 C. After 10 mins, the reaction mixture was treated with methanesulfonic acid (R)-(I -aza-bicyclo[2.2.2]oct-3-yl) ester (0.5 g) (J. Med. Chem., 1992, 35, 2392-2406) and the reaction mixture was heated at 100 0 C for 2 h. The reaction mixture was diluted with NaHCO 3 solution and extracted with ethyl acetate.
• R methanesulfonic acid
• Step 1 Thiophenol (1 g) was added to a stirred suspension of sodium hydride (379 mg of 60% dispersion in mineral oil) in DMF (5 ml_). After 10 min, methanesulfonic acid (S)- 1-(1-aza-bicyclo[2.2.2]oct-3-yl)methyl ester (L)-tartrate salt (0.5 g) (Y. Guminski et al., Org. Prep. Proc. Int., 1999, 31 , 399) was added and the reaction mixture was heated at 100 0 C for 1 h. The reaction mixture was cooled, and diluted with water and ethyl acetate.
• Step 1 (R)-3-Fluorophenylsulfanyl-1-aza-bicyclo[2.2.2]octane (410 mg, 72%) was prepared from methanesulfonic acid (R)-(I -aza-bicyclo[2.2.2]oct-3-yl) ester and 3-fluoro- thiophenol by analogy to the procedure described in Example 2, Step 1.
• Step 1 A solution of borane-THF (1.0 M in THF, 24.8 ml_) was added dropwise to a solution of R-3-quinuclidinol (3 g) in THF (20 mL) at 0 0 C. The reaction mixture was allowed to warm to ambient temperature, stirred for 24 h, and evaporated in vacuo. The resulting residue was diluted with chloroform, washed with water, brine, dried (MgSO 4 ), filtered and evaporated in vacuo. The resulting residue was dissolved in ether and triturated with 50% DCM/petroleum spirit (bp 40-60 0 C).
• Step 2 A solution of the foregoing compound (360 mg) in DMF (5 ml_) was treated with NaH (101 mg of 60% dispersion in mineral oil), stirred for 5 mins and then treated with benzyl bromide (0.302 ml_). The reaction mixture was stirred overnight at ambient temperature, evaporated in vacuo and purified by silica gel chromatography (eluting with petroleum spirit (bp 40-60°C)/DCM [1 :0 to 1 :1]) to give (R)-3-benzyloxy-1-boranyl-1-aza- bicyclo[2.2.2]octane as a clear oil (433 mg, 74%).
• Step 3 A solution of the foregoing compound (433 mg) in acetone (5 mL) at 0 0 C was treated with 1.25 M HCI-MeOH (10.45 mL), stirred at 0 0 C for 0.5 h, and then stirred at ambient temperature for 0.5 h. The reaction mixture was evaporated in vacuo and purified by silica gel chromatography (eluting with 0-50% DCM/methanol) to afford the title compound (399 mg, 69%) as a white solid.
• Step 4 The title compound was prepared from the foregoing compound and Intermediate 10 by application of General Procedure A.
• Step 1 A solution of 3-quinuclidinone hydrochloride (16 g) was treated with saturated aqueous NaHCO 3 solution. The reaction mixture was extracted twice with ether and twice with DCM. The combined organic extracts were dried (MgSO 4 ), filtered and evaporated in vacuo to give the free base as a white solid. This was dissolved in ether (20 ml_) and added slowly at 0 0 C to a solution of phenethylmagnesium bromide (1.0 M in THF, 100 ml_) in ether (100 ml_). The reaction mixture was stirred at ambient temperature for 4 h, cooled to 0 0 C and quenched carefully by the addition of water.
• Step 2 A solution of the foregoing compound (1 g) was treated with SOCI 2 (5 ml.) causing dissolution and evolution of gas. The reaction mixture was evaporated in vacuo and triturated with ether to give a mixture of 3-[2-phenyl-eth-(E)-ylidene]-1-aza- bicyclo[2.2.2]octane, 3-[2-phenyl-eth-(Z)-ylidene]-1-aza-bicyclo[2.2.2]octane and 3- phenethyl-1-aza-bicyclo[2.2.2]oct-2-ene (1 g, 93%) as a white solid.
• Step 3 A solution of the foregoing mixture (1 g) and Pd-C (10%, 0.3 g) in ethanol (15 ml_) was stirred under an atmosphere of hydrogen at ambient temperature for 5 h. The reaction mixture was filtered and purified by SCX and column chromatography (eluting with 2-6% [2 M NH 3 in methanol]-DCM) to give the title compound (0.44 g, 51%) as a colourless oil.
• Step 4 The title compound was prepared from the foregoing compound and Intermediate 10 by application of General Procedure A.
• Step 1 A suspension of sodium hydride (380 mg, 60% dispersion in mineral oil) in DMF (5 mL) was treated carefully with phenol (0.9 g). After 10 min, the reaction was treated with methanesulfonic acid (S)-1-(1-aza-bicyclo[2.2.2]oct-3-yl)methyl ester (L)-tartrate salt (0.5 g) (Y. Guminski et al., Org. Prep. Proc. Int., 1999, 31 , 399) and the reaction mixture was heated at 100 c C for 1 h. The reaction mixture was cooled, and diluted with water and ethyl acetate.
• Muscarinic Receptor Radioligand Binding Assays 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). The incubation time was 16 hours at ambient 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.
• SPA WGA Wi-heat germ agglutinin
• 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. Binding data for Examples of the invention, where tested, are shown in the table below.
• Example 1 exhibited a plC50 value of 9.4 and Example 4 exhibited a plC50 value of 8.9 in the M3 binding assay.
• the compounds of the invention may also be tested for appropriate pharmaceutical activity using assays know in the art, such as for example:
• Tracheae are 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 are cut and suspended using cotton thread in 10mL water-jacketed organ baths and attached to a force transducer ensuring that the tissue is located between two platinum electrodes. Responses are recorded via a MPIOOW/Ackowledge data acquisition system connected to a PC. Tissues are equilibrated for one hour under a resting tone of 1 g and were then subjected to electrical field stimulation at a frequency of 80Hz with a pulse width of 0.1ms, a unipolar pulse, triggered every 2 minutes.
• a "voltage-response" curve is generated for each tissue and a submaximal voltage then applied to every piece of tissue according to its own response to voltage. Tissues are washed with Krebs solution and allowed to stabilize under stimulation prior to addition of test compound. Concentration response curves are 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 is made. Percentage inhibition of EFS-stimulated contraction is calculated for each concentration of each compound added and dose response curves constructed using Graphpad Prism software and the EC 50 calculated for each compound.
• Guinea pigs Male Guinea pigs (Dunkin Hartley), weighing 500-60Og housed in groups of 5 are individually identified. Animals are allowed to acclimatize to their local surroundings for at least 5 days. Throughout this time and study time animals are allowed access to water and food ad libitum. Guinea pigs are anaesthetized with the inhaled anaesthetic Halothane (5%). Test compound or vehicle (0.25 - 0.50 mUkg) is administered intranasally. Animals are placed on a heated pad and allowed to recover before being returned to their home cages. Up to 72hrs post dosing guinea pigs are terminally anaesthetized with Urethane (250 ⁇ g/ml_, 2mL/kg).
• the jugular vein is cannulated with a portex i.v. cannula filled with heparinised phosphate buffered saline (hPBS) (10U/mL) for i.v. administration of methacholine.
• hPBS heparinised phosphate buffered saline
• the trachea is exposed and cannulated with a rigid portex cannula and the oesophagus cannulated transorally with a flexible portex infant feeding tube.
• the spontaneously breathing animal is then connected to a pulmonary measurement system (EMMS, Hants, UK) consisting of a flow pneumotach and a pressure transducer.
• the tracheal cannula is attached to a pneumotach and the oesophageal cannula attached to a pressure transducer.
• the oesophageal cannula is positioned to give a baseline resistance of between 0.1 and 0.2cmH20/mL/s.
• a 2 minute baseline reading is recorded before i.v. administration of methacholine (up to 30 ⁇ g/kg, O. ⁇ mLAg).
• a 2 minute recording of the induced constriction is taken from the point of i.v. administration.
• the software calculates a peak resistance and a resistance area under the curve (AUC) during each 2 minute recording period which are used to analyse the bronchoprotective effects of test compounds.
• Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK are acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs are randomly assigned into treatment groups and weighed. Each animal is lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally (O. ⁇ mUkg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs are terminally anaesthetised with urethane (25% solution in H 2 O, 1.5g/kg).
• each animal has an absorbent pad placed in the mouth for 5 minutes to dry residual saliva, this pad is removed and replaced with a new pre-weighed pad for 5 minutes to establish a reading of baseline saliva production. At the end of this 5 minute period the pad is removed and weighed. A new pre-weighed pad is inserted into the mouth before each animal receives s. c. pilocarpine administered under the skin at the back of the neck (0.6mg/kg @ 2mL/kg). The pad is removed, weighed and replaced with a new pre-weighed pad every 5 minutes up to 15 minutes.
• Saliva production is calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period could be analysed in addition to the whole 15 minute recording period. Baseline production of saliva is assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes. Inhibition of saliva produced by the compound could be calculated by using the following equation: (1 -(Test-baseline)/(Veh-baseline))*100.

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