WO2010018352A1 - Heterocyclic compounds used in the treatment of diseases where enhanced m3 receptor activation is implicated - Google Patents

Abstract

The invention provides named compounds of formula (I), pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions and their use in in the treatment of diseases where enhanced M3 receptor activation is implicated.

Description

HETEROCYCLIC COMPOUNDS USED IN THE TREATMENT OF DISEASES WHERE ENHANCED M3 RECEPTOR ACTIVATION IS IMPLICATED

This invention relates to heterocycles, pharmaceutical compositions, methods for their preparation and use in the treatment of diseases where enhanced M3 receptor activation is implicated.

BACKGROUND TO THE INVENTION

Anti-cholinergic agents prevent the passage of, or effects resulting from the passage of, impulses through the parasympathetic nerves. This is a consequence of the ability of such compounds to inhibit the action of acetylcholine (Ach) by blocking its binding to the muscarinic cholinergic receptors.

There are five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M1-M5, and each is the product of a distinct gene and each displays unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract,

M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319 - 379).

In the lungs, muscarinic receptors M1 , M2 and M3 have been demonstrated to be important and are localized to the trachea, the bronchi, submucosal glands and parasympathetic ganglia (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) S 154 - 160). M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.

Increased signalling through muscarinic acetylcholine receptors has been noted in a variety of different pathophysiological states including asthma and COPD. In

COPD, vagal tone may either be increased (Gross et al. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross et al. 1984, Am Rev

Respir Dis; 129:856-870). In addition, inflammatory conditions can lead to a loss of inhibitory M2 receptor activity which results in increased levels of acetylcholine release following vagal nerve stimulation (Fryer et al, 1999, Life ScL, 64, (6-7) 449- 455). The resultant increased activation of M3 receptors leads to enhanced airway obstruction. Thus the identification of potent muscarinic receptor antagonists would be useful for the therapeutic treatment of those disease states where enhanced M3 receptor activity is implicated. Indeed, contemporary treatment strategies currently support regular use of M3 antagonist bronchodilators as first-line therapy for COPD patients (Pauwels et al. 2001 , Am Rev Respir Crit Care Med; 163:1256-1276).

Incontinence due to bladder hypercontractility has also been demonstrated to be mediated through increased stimulation of M3 mAChRs. Thus M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.

Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for treatment of airway disease states, relatively few anti-muscarinic compounds are in use in the clinic for pulmonary indications. Thus, there remains a need for novel compounds that are capable of causing blockade at M3 muscarinic receptors, especially those compounds with a long duration of action, enabling a once-daily dosing regimen. Since muscarinic receptors are widely distributed throughout the body, the ability to deliver anticholinergic drugs directly to the respiratory tract is advantageous as it allows lower doses of the drug to be administered. The design and use of topically active drugs with a long duration of action and that are retained on the receptor or in the lung would allow reduction of unwanted side effects that could be seen with systemic administration of the same drugs.

Tiotropium (Spiriva ™) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.

Tiotropium

Additionally ipratropium is a muscarinic antagonist marketed for the treatment of COPD.

Ipratropium

Chem. Pharm. Bull. 27 (12) 3149-3152 (1979) and J. Pharm. Sci 69 (5) 534-537 (1980) describe furyl derivatives as possessing atropine-like activities.

Med. Chem. Res 10 (9), 615-633 (2001 ) describes isoxazoles and Δ²-isoxazolines as muscarinic antagonists.

WO97/30994 describes oxadiazoles and thiadiazoles as muscarinic receptor antagonists. EP0323864 describes oxadiazoles linked to a mono- or bicyclic ring as muscarinic receptor modulators.

Our co-pending application PCT/GB2008/000519 relates to compounds of formula (I):

wherein

R² is a group H, -(Z)_p-R⁷, -Z-Y-R⁷ or -Y-R⁷; p is 0 or 1 ;

R⁴ and R⁵ are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, d-C₆-alkyl, and cycloalkyl;

R⁶ is -OH, CrCe-alkyl, C_rC₆-alkoxy, hydroxy-CrC₆-alkyl, nitrile, a group CONR¹R⁹ or a hydrogen atom; one of W, V and A is N or NR¹¹; another of W, V and A is N, O, S or CR⁸; and the last one of W, V and A is N or CR⁸; X is an C^C^alkylene, C₂-C₄-alkenylene or C₂-C₄-alkynylene group; R⁷ is an CrC₆-alkyl, C₂-C₆-alkenyl, aryl, aryl-fused-cycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl, aryl(C_rC₈-alkyl)-, heteroaryl(CrC₈-alkyl)-, heterocycloalkyl or cycloalkyl 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 CrC₄-alkylene, C₂-C₄-alkenylene or C₂-C₄-alkynylene group; Y is an oxygen atom, a group -OC(O)-, a group -N(H)C(O)- or a group -S(O)_n; n is O, 1 or 2;

R¹, R⁸, R⁹ and R¹¹ are, independently, a hydrogen atom or Ci-C₆-alkyl group; and

D^" is a pharmaceutically acceptable counter-ion;

wherein, unless otherwise specified, 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.

Summary of the Invention

The present invention provides compounds falling within the scope of, but not specifically disclosed in, our co-pending application PCT/GB2008/000519 referred to above.

Thus, in one aspect, the present invention provides a compound which has a quaternary ammonium species selected from the group consisting of:

(R)-3-(3,4-Dichloro-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-

5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1 -[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]- 3-phenylsulfanylmethyl-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzyloxy-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1 - azonia-bicyclo[2.2.2]octane X; (R)-3-(3-Chloro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzylsulfanyl-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-yimethyl]-1- azonia-bicyclo[2.2.2]octane X; (R)-3-(4-Fiuoro-phenoxy)-1-[3-(hydroxy-diphenyi-methyl)-isoxazol-5-ylmethyl]-

1-azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Chloro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(Benzo[1 ,3]dioxol-5-yloxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzylsulfanyl-1-[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)- [1 A^oxadiazol^-ylmethyO-i-azonia-bicyclo^^loctane X;

(R)-3-(3-Chloro-phenoxy)-1-[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)- [1.S^oxadiazol^-ylmethylH-azonia-bicyclo^^octane X; (R)-3-(Benzo[1 ,3]dioxol-5-yloxy)-1 -[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)-

[1 ,3,4]oxadiazol-2-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-4-fIuoro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-yimethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(Benzo[1 ,3]dioxol-5-yloxy)-1 -[5-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-3-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Fluoro-phenoxy)-1-[5-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-3- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenoxy)-1-[5-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-3- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[5-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-3-ylmethyl]-3- phenylsulfanyl-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1 -[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3-hydroxy- phenylsulfanyl)-1 -azonia-bicycio[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(3- hydroxy-phenylsulfany^-i -azonia-bicyclop^^loctane X;

(R)-3-(3,4-Difluoro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol- 5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Chloro-3-fluoro-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1-azonia-bicyclo[2.2.2]octane X; (R)-3-[((E)-But-2-enyl)oxy]-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(4-Fluoro-benzyloxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Fluoro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]- 1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(3-Chloro-phenoxy)-1-[3-((R)-cyclohexyl-hydroxy-phenyl-methyl)-

[1 ,2,4]oxadiazol-5-ylmethyl]-1-azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzylsulfanyl-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-1-[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Bromo-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-m-tolyloxy- 1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3- methoxy-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(2,3-Dihydro-benzofuran-5-yloxy)-1-[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyi]-1-azonia-bk3ycio[2.2.2]octane X;

(R)-3-(3,4-Dimethyl-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzyloxy-1 -[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-1-[3-(hydroxy-diphenyl-methyl)- isoxazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(3-Fluoro-4-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-

[1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3,4-difluoro-phenylsulfanyl)-1 -[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Fluoro-phenylsulfanyl)-1-[3-(hydroxy-diphenyI-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1 -[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-phenylsulfanyl-1 - azonia-bicyclo[2.2.2]octane X; (R)-3-(2,3-Dihydro-benzofuran-5-yloxy)-1-[3-(hydroxy-diphenyl-methyl)- isoxazol-5-yImethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(4-Fluoro-3-methyl-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Chloro-3-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(3-Fluoro-4-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 3-(3,4-dimethyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 3-(2,3-dihydro-benzo[1 ,4]dioxin-6-yloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Chloro~3-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)- [1 ^^joxadiazol-δ-ylmethylj-i -azonia-bicyclol^^octane X;

(R)-3-(4-Fluoro-3-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)- [1 ^^oxadiazol-δ-ylmethylj-i-azonia-bicyclo^^octane X; (R)-1 -[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-

3-(3-fluoro-4-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1 -[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)- [1 ,3,4loxad\azol-2-ylmethy\]-1-azon\a-bicyc\o[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(indan-5- yloxy)-1-azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-hydroxy- phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-methyl-but-2- enyloxy)-1 -azonia-bicyclo[2.2.2]octane X; (R)-1-[3-(Hydroxy-diphenyI-methyl)-isoxazol-5-ylmethyl]-3-m-tolyloxy-1 - azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]- 3-(3-hydroxy-phenylsulf anyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]- 3-(2,3-dihydro-benzo[1 ,4]dioxin-6-yloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]- 3-m-tolyloxy-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-

3-(2,3-dihydro-benzofuran-5-yloxy)-1-azonia-bicyclo[2.2.2]octane X; (R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 3-m-tolyloxy-1 -azonia-bicyclo[2.2.2Joctane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 3-(2,3-dihydro-benzofuran-5-yloxy)-1-azonia-bicyclo[2.2.2]octane X; (R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(2,3- dihydro-benzof uran-5-yloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1-[3-((R)-cyclohexyl-hydroxy-phenyl-methyl)- isoxazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-fluoro-phenylsulfanyl)-1-[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1 -[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 3-(4-fluoro-3-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Ch!oro-phenyisulfanyl)-1-[3-((R)-cyclohexy!-hydroxy-phenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-

3-(3-hydroxy-phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(3- fluoro-4-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(4- fluoro-3-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-m- tolyloxy-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(5-nnethyl- thiophen-2-yloxy)-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-

3-(3-fluoro-4-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3-methyl- but-2-enyloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3-hydroxy- phenoxy)-1-azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 3-(3-hydroxy-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]- 3-(3-hydroxy-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X; (R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(3- hydroxy-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X; (R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxa2ol-5-ylmethyl]-3-(3- fluoro-phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Fluoro-phenylsulfanyl)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]- 3-(3-fluoro-phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]- 3-(3-fluoro-phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-hydroxy- phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

In a further aspect, the present invention provides a compound which has a quaternary ammonium species selected from the group consisting of:

(R)-3-(3-Fluoro-4-methyl-phenoxy)-1-[3-(hydroxy-diphenyi-methyl)-isoxazol-5- yimethyl]-1 -azonia-bicyclo[2.2.2]octane X

(R)-3-(3-Fluoro-phenylsulfanyl)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X

wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid. In a further aspect, the present invention provides (R)-3-(3-Fluoro-4-methyl- phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1-azonia- bicyclo[2.2.2]octane bromide

In a further aspect, the present invention provides (R)-3-(3-Fluoro-phenylsulfanyl)-1-

[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1-azonia-bicyclo[2.2.2]octane bromide

The compounds of formula (I), referred to above, and those of the present invention comprise an anion X associated with the positive charge on the quaternary nitrogen atom. The anion X may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g. bivalent) acid. In an embodiment of the invention X may be an anion of a mineral acid, for example chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, for example acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, methanesulphonate, p-toluenesulphonate, benzenesulphonate, napadisylate (naphthalene-1 ,5-disulfonate) (e.g. a heminapadisylate), 2,5-dichlorobenzenesulphonate, 1-hydroxynaphthalene-2- sulphonate or xinafoate (1-hydroxy-2-naphthoate).

It will be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms. Certain compounds of the present invention may exist as tautomers. Tautomers and mixtures thereof also form an aspect of the present invention. The present invention also comprises the following novel intermediate compounds which have utility in the synthesis of some of the claimed muscarinic antagonists of the present invention: (R)-(5-Bromomethyl-[1 ,3,4]oxadiazol-2-yl)-cyclohexyl-phenyl-methanol; (R)-(5-Chloromethyl-[1 ,3,4]oxadiazol-2-yl)-cyclohexyl-phenyl-methanol; and (RHδ-Chloromethyl-fi ^^Joxadiazol-S-yO-cyclohexyl-phenyl-methanol.

The compounds of the present invention display beneficial pharmaceutical properties. For example, the compounds of the invention display activity as antagonists of muscarinic receptors, particularly muscarinic M₃ receptors. Moreover, the compounds also display desirable plasma protein binding properties. Plasma protein binding may be an advantageous property for compounds administered via inhalation as it can lessen the impact of any systemic effect the compound may have.

The compounds of the invention have activity as pharmaceuticals, in particular as anticholinergic agents including muscarinic receptor (M1 , M2, and M3) antagonists, in particular M3 antagonists. Diseases and conditions which may be treated with the compounds include: 1 . respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; 2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;

3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis);

4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;

5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;

6. gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);

7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8. genitourinary, nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);

9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;

10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11. other auto-immune and allergic disorders including Hashimoto's thyroiditis,

Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-lgE syndrome, antiphospholipid syndrome; 12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes; 13. cardiovascular, atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. oncology, treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,

15. gastrointestinal tract. Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.

Accordingly, the present invention further provides a compound of the present invention, as hereinbefore defined, for use in therapy.

In another aspect, the invention provides the use of a compound of the present invention, as hereinbefore defined, in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

A further aspect of the invention provides a method of treating a disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the present invention, as hereinbefore defined. The present invention also provides a compound of the present invention, as hereinbefore defined, for use in treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).

The present invention also provides a compound of the present invention, as hereinbefore defined, for use in treating asthma.

The present invention also provides the use of a compound of the present invention, as hereinbefore defined, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).

The present invention also provides the use of a compound of the present invention, as hereinbefore defined, in the manufacture of a medicament for use in the treatment of asthma.

The present invention further provides a method of treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD)₁ in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of the present invention, as hereinbefore defined.

The present invention further provides a method of treating asthma in a warmblooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of the present invention, as hereinbefore defined.

In order to use a compound of the invention for the therapeutic treatment of a warmblooded animal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition that comprises a compound of the invention as hereinbefore defined and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition, which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection. Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg^'1 to l OOmgkg^"1 of the compound, for example in the range of 0.1 mgkg^"1 to 20mgkg^"1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day

Another suitable pharmaceutical composition of this invention is one suitable for inhaled administration, inhalation being a particularly useful method for administering the compounds of the invention when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma. When administered by inhalation the compounds of the present invention may be used effectively at doses in the μg range, for example 0.1 to 500 μg, 0.1 to 50 μg, 0.1 to 40 μg, 0.1 to 30 μg, 0.1 to 20 μg, 0.1 to 10 μg, 5 to 10 μg, 5 to 50 μg, 5 to 40 μg, 5 to 30 μg, 5 to 20 μg, 5 to 10 μg, 10 to 50 μg, 10 to 40 μg 10 to 30 μg, or 10 to 20 μg of active ingredient. In an embodiment of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, which is formulated for inhaled administration.

When administered by inhalation, metered dose inhaler devices may be used to administer the active ingredient, dispersed in a suitable propeliant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents. Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants. Preferred propellants are P134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients. Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.

Dry powder inhalers may be used to administer the active ingredient, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture. The dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.

Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.

The invention further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below. Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo- oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention still further relates to the combination of a compound of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.

In addition the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA- alLl6R and T-Lymphocytes, CTLA4-lg, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCR1 , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CRI for the C-X₃-C family. The present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-1 1 ) and MMP-9 and MMP-12, including agents such as doxycycline.

The present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5- lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761 ; fenleuton; tepoxalin; Abbott-79175; Abbott-85761 ; a N-(5-substituted)-thiophene-2- alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 ; a pyridinyl-substituted 2- cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591 , MK-886, and BAY x 1005.

The present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651 ,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, abiukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro- 245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally. The present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The present invention still further relates to the combination of a compound of the invention and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, or indacaterol or a chiral enantiomer thereof.

The present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention further relates to the combination of a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-lgE (for example omalizumab). The present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.

The present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.

The present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an antiparkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate. The present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.

The present invention further relates to the combination of a compound of the invention together with a parenteral^ or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.

A compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.

The present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or lmatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B1. - or B2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK1 or NK3 receptor antagonist such as NKP-608C, SB-233412

(talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or 2D-0892; (xxi) TNF- alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.

A compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin);

(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function);

(iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)quinazolin-4-amine (Cl 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; (v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin); (vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

In a further embodiment the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of the present invention, as hereinbefore described, and at least one further active ingredient selected from:-

• a phosphodiesterase inhibitor,

• a β2. adrenoceptor agonist,

• a modulator of chemokine receptor function,

• an inhibitor of kinase function, • a protease inhibitor,

• a steroidal glucocorticoid receptor agonist, and a • a non-steroidal glucocorticoid receptor agonist.

The pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture. Alternatively, the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.

The pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.

Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor. Examples include the compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile,

N-[9-amino-4-oxo-1 -phenyl-3,4,6,7-tetrahydropyrrolo[3,2, 1 -Jk][1 ,4]benzodiazepin-

3(R)-yl]pyridine-3-carboxamide (CI-1044)

3-(benzyloxy)-1-(4-fluorobenzyl)-N-[3-(methylsulphonyl)phenyl]-1 H-indole-2- carboxamide, (1S-exo)-5-[3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]tetrahydro-2(1H)- pyrimidinone (Atizoram),

N-(3,5,dichloro-4-pyridinyl)-2-[1 -(4-fluorobenzyl)-5-hydroxy-1 H-indol-3-yl]-2- oxoacetamide (AWD-12-281), β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1 ,3-dihydro-1 ,3-dioxo-2H-isoindole-2- propanamide (CDC-801),

N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1 ,4]benzodiazepin-

3(R)-yl]pyridine-4-carboxamide (CI-1018), cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid

(Cilomilast) 8-amino-1 ,3-bis(cyclopropylmethyl)xanthine (Cipamfylline)

N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide (D-4418),

5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-iminothiazolidin-4-one (Darbufelone),

2-methyl-1 -[2-(1 -methylethyl)pyrazolo[1 ,5-a]pyridin-3-yl]-1 -propanone (Ibudilast),

2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl methanesulphonate (Lirimilast),

(-)-(R)-5-(4-methoxy-3-propoxyphenyl)-5-methyloxazolidin-2-one (Mesopram), (-)-cis-9-ethoxy-8-methoxy-2-methyl-1 ,2,3,4,4a,10b-hexahydro-6-(4- diisopropylaminocarbonylphenyl)-benzo[c][1 ,6]naphthyridine (Pumafentrine), 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide (Roflumilast), the N-oxide of Roflumilast,

5,6-diethoxybenzo[b]thiophene-2-carboxylic acid (Tibenelast) 2,3,6,7-tetrahydro-2-(mesitylimino)-9,10-dimethoxy-3-methyl-4H-pyrimido[6,1- a]isoquinolin-4-one (trequinsin) and

3-[[3-(cyclopentyloxy)-4-methoxyphenyl]-methyl]-N-ethyl-8-(1-methylethyl)-3H-purine- 6-amine (V-11294A).

Examples of a β₂-adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol. The β₂-adrenoceptor agonist of this embodiment may be a long-acting β₂-agonists, for example salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically identified as 2(1 H)-Quinolone, 8-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-phenyl)-1 - methylethyl]-amino]ethyl]-monohydrochloride, [R-(R^*, R^*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S. Patent No 4,579,854), indacaterol (CAS no 312753-06-3; QAB-149), formanilide derivatives e.g. 3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2- hydroxyethyl}amino)hexyl]oxy}-butyl)-benzenesulfonamide as disclosed in WO 2002/76933, benzenesulfonamide derivatives e.g. 3-(4-{[6-({(2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxy-methyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamide as disclosed in WO 2002/88167, aryl aniline receptor agonists as disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives as disclosed in WO 2004/032921 and US 2005/222144, and compounds GSK 159797, GSK 159802, GSK 597901 , GSK 642444 and GSK 678007.

Examples of a modulator of chemokine receptor function that may be used in the pharmaceutical product according to this embodiment include a CCR1 receptor antagonist. Examples of an inhibitor of kinase function that may be used in the pharmaceutical product according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.

Examples of a protease inhibitor that may be used in the pharmaceutical product according to this embodiment include an inhibitor of neutrophil elastase or an inhibitor of MMP12.

Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17-propionate or 17,21 -dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, rofleponide, butixocort (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters e.g. 6α,9α- difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4- diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-1 1β-hydroxy-16α- methyl-3-oxo-17α-propionyloxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo- tetrahydro-furan-3S-yl) ester and 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-[(4- methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester, steroid esters according to DE 4129535, steroids according to WO 2002/00679, WO 2005/041980, or steroids GSK 870086, GSK 685698 and GSK 799943.

Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916.

The invention is illustrated by the following Examples. In the Examples the following Figures are presented:

Figure 1 : X-ray powder diffraction pattern of (R)-3-(3-Fluoro-4-methyl-phenoxy)-1 - [3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane bromide (Example 42). Figure 2: DSC trace of (R)-3-(3-Fluoro-4-methy|-phenoxy)-1-[3-(hydroxy-diphenyl- methyl)-isoxazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane bromide (Example 42).

General Experimental Details:

All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5 mm dual frequency probe operating at 300 MHz. Shifts are given in ppm relative to tetramethylsilane. Where products were purified by column chromatography, '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 or use of the semi-automated CombiFlash ® Companion purification system or by manual elution of Biotage ® lsolute Flash Si Il cartridges under reduced pressure. All solvents and commercial reagents were used as received. SCX chromatography was performed on Biotage ® lsolute SCX or SCX-2 pre-packed cartridges.

The Liquid Chromatography Mass Spectroscopy (LCMS) methods referred to are described below:

Method 1 Waters Micromass ZQ2000 with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - - Time flow mL/min %A %B

0.00 1.0 95 5

1.00 1.0 95 5

15.00 1.0 5 95

20.00 1.0 5 95

22.00 1.0 95 5

25.00 1.0 95 5 Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive ion)

Method 2

Waters Platform LC Quadrupole mass spectrometer with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 2.0 95 5

0.50 2.0 95 5

4.50 2.0 5 95

5.50 2.0 5 95

6.00 2.0 95 5 Detection - MS, ELS, UV (200 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive and negative ion).

Method 3

Waters ZMD mass spectrometer with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 2.0 95 5

0.50 2.0 95 5

4.50 2.0 5 95

5.50 2.0 5 95

6.00 2.0 95 5

Detection - MS, ELS, UV (200 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive and negative ion).

X-Ray Powder Diffraction (XRPD) - PANalytical X'Pert machine in 20 - 0 configuration or a PANalytical Cubix machine in 0 - 0 configuration over the scan range 2° to 40° 20 with 100-second exposure per 0.02° increment. The X-rays were generated by a copper long-fine focus tube operated at 45kV and 4OmA. The wavelength of the copper X-rays was 1.5418 Λ . The Data was collected on zero background holders on which ~ 2mg of the compound was placed. The holder was made from a single crystal of silicon, which had been cut along a non-diffracting plane and then polished on an optically flat finish. The X-rays incident upon this surface were negated by Bragg extinction.

Differential Scanning Calorimetry (DSC) thermograms were measured using a TA Q1000 Differential Scanning Calorimeter, with aluminium pans and pierced lids. The sample weights varied between 0.5 to 5mg. The procedure was carried out under a flow of nitrogen gas (50ml/min) and the temperature studied from 25 to 300⁰C at a constant rate of temperature increase of 10⁰C per minute.

Thermogravimetric Vapour Sorption (TGA) thermograms were measured using a TA Q500 Thermogravimetric Analyser, with platinum pans. The sample weights varied between 1 and 5mg. The procedure was carried out under a flow of nitrogen gas (60ml/min) and the temperature studied from Room Temperature to 300°C at a constant rate of temperature increase of 10°C per minute.

Gravimetric Vapour Sorption (GVS) profiles were measured using a Surface Measurements Systems Dynamic Vapour Sorption DVS-1 or a DVS Advantage instrument. The solid sample ca. 1 -5mg was placed into a glass vessel and the weight of the sample was recorded during a dual cycle step method (40 to 90 to 0 to 90 to 0% relative humidity (RH), in steps of 10% RH).

Abbreviations used in the experimental section: AIBN = 2,2'-azobis(2- methylpropionitrile); DCM = dichloromethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; IMS = industrial methylated spirit; LCMS = Liquid Chromatography-Mass Spectrometry; NBS = N-bromosuccinimide; RT = room temperature; Rt = retention time; TFA = trifluoroacetic acid; THF = tetrahydrofuran; SCX = strong cation exchange chromatography.

Intermediate 1 - (RJ-S-β-Fluoro-phenoxyJ-i-aza-bicycioβ^^octane

A solution of (R)-1 -aza-bicyclo[2.2.2]octan-3-ol (1.25 g), CuI (93.1 mg), 1 ,10- phenanthroline (176 mg), Cs₂CO₃ (3.19 g) and 3-f!uoro-iodo-benzene (1.1 1 g) in toluene (2.5 mL) was heated at 100⁰C 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 5% copper sulphate solution, water, dried (MgSO₄), filtered and evaporated in vacuo. Purification by SCX gave (R)-3-(3^:fluoro-phenoxy)-1-aza-bicyclo[2.2.2]octane (490 mg, 45 %) as a brown oil. LCMS (Method 2, Rt 2.09 min). MH⁺ = 222.

Intermediates 2-19 were prepared from (R)-1-aza-bicyclo[2.2.2]octan-3-ol and the appropriate aryl iodide by analogy with the procedure described for Intermediate 1. Data for Intermediates 2-19:

Intermediate 20 - (R)-3-(lndan-5-yloxy)-1-aza-bicyclo[2.2.2]octane

A solution of (S)-1-aza-bicyclo[2.2.2]octan-3-ol (1.5 g) in THF (55 ml_) was stirred with 5-indanol (0.78 g), diisopropyl azodicarboxylate (2.3 mL) and triphenylphosphine (3.1 g) at room temperature for 48 hours. The solvent was evaporated and the crude mixture was purified by silica gel chromatography (eluting with DCM/methanol [10:0 to 9.3:0.7]) to give (R)-3-(indan-5-yloxy)-1-aza- bicyclo[2.2.2]octane (0.98 g, 70%). ¹H NMR (300 MHz, CDCI₃): δ 7.12-7.09 (1 H, d, J = 7.94), 6.75 (1 H, s), 6.67-6.63 (1 H, d, J = 7.94), 4.34-4.29 (1 H, m), 3.30-3.22 (1 H, m), 3.04-2.70 (8H, m), 2.15-1.94 (4H, m), 1.77-1.67 (1 H, m), 1.58-1.48 (1 H, m), 1.41 - 1.22 (2H₁ m).

Intermediate 21 - 3-[(R)-(1-Aza-bicyclo[2.2.2]oct-3-yl)oxy]-phenol

A stirred solution of (S)-1-aza-bicyclo[2.2.2]octan-3-ol (1.27 g) in THF (50 ml_) at room temperature was treated with 1 ,3-benzenediol (1.1 g), diisopropyl azodicarboxylate (2.02 g), and triphenylphosphine (2.62 g). The dark reaction mixture was stirred for 2 days and then evaporated in vacuo. The residue was dissolved in methanol and purified using an isolute SCX-2 cartridge eluting with MeOH and then MeOH:2 M NH₃ in MeOH (4:1 then 2:1). The resultant material was triturated with acetonitrile to give a brown solid which was further purified by chromatography (isolute silica gel cartridge) eluting with DCM containing 0.5-10% 2M NH₃ in MeOH. The title compound was obtained as a cream solid (0.275 g, 12.5%). Data for 3-[(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)oxy]-phenol: LCMS (Method 2, Rt 1.73 min). MH⁺ = 220.

Intermediate 22 - (R^-^^-Difluoro^henylsulfanyO-i-aza-bicyclol^^octane

3,4-Difluorothiophenol (0.33 mL) was added slowly to a suspension of NaH (234 mg of 60% dispersion in mineral oil) in DMF (1 mL) at 0°C. After 30 min, a solution of methanesulfonic acid (S)-(I -aza-bicyclo[2.2.2]oct-3-yl) ester (0.5 g) (J. Med. Chem., 1992, 35, 2392-2406) in DMF (4 mL) was added to the mixture dropwise and the reaction mixture was heated at 100⁰C overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 2 N NaOH, dried (MgSO₄), filtered and evaporated in vacuo. Purification by silica gel chromatography (eluting with DCM/methanol [10:0 to 8:2]) gave (R)-3-(3,4-difluoro- phenylsulfanyl)-1-aza-bicyclo[2.2.2]octane (385 mg, 63%). Data for Intermediate 22: ¹H NMR (300 MHz, CDCI₃): 7.28-7.06 (3 H, m), 3.57-3.40 (1 H, m), 3.18-2.73 (8 H, m), 2.26-2.13 (1 H, m), 1.99-1.82 (2 H, m).

Intermediate 23 - (R)-3-Phenylsulfanyl-1-aza-bicyclo[2.2.2]octane

-aza-bicyclo[2.2.2]octane was prepared from thiophenol according to the procedure described for Intermediate 22. Data for Intermediate 23: NMR (300 MHz, CDCI₃): 7.38-7.34 (2 H, m), 7.30-7.17 (3 H, m), 3.47-3.32 (1 H, m), 2.99-2.87 (2 H, m), 2.88-2.67 (4 H, m), 2.19-2.01 (1 H, m), 1.89-1.84 (1 H, m), 1.79- 1.69 (1 H, m), 1.61-1.51 (1 H, m), 1.45-1.35 (1 H, m).

Intermediate 24 - (RJ-S-fS-Fluoro-phenylsulfanyO-i-aza-bicycloJ^^Joctane

(R)-3-(3-Fluoro-phenylsulfanyl)-1-aza-bicyclo[2.2.2]octane was prepared from 3- fluorothiophenol according to the procedure described for Intermediate 22. Data for Intermediate 24: NMR (300 MHz, MeOD): 7.33 (1 H, td, J = 8.04, 6.01 Hz), 7.22-7.13 (2 H, m), 7.01 -6.93 (1 H, m), 3.81-3.70 (1 H, m), 3.58-3.48 (1 H, m), 3.14-2.91 (2H, m), 2.92-2.77 (2 H, m), 2.26-2.15 (1 H, in), 2.01 -1.77 (4 H, m), 1.70-1.58 (1 H, m).

Intermediate 25 - (R)-3-(3-Chloro-phenylsulfanyl)-1-aza-bicycJo[2.2.2Joctane

(R)-3-(3-Chloro-phenylsulfanyl)-1-aza-bicyclo[2.2.2]octane was prepared from 3- chlorothiophenol according to the procedure described for Intermediate 22. Data for Intermediate 25: ¹H NMR (300 MHz, CDC\₃): 7.32-7.12 (4 H, m), 3.49-3.32 (2 H, m), 3.00-2.76 (4 H, m), 2.69 (1 H, ddd, J = 13.17, 4.91 , 2.01 Hz), 2.12-1.98 (1 H, m), 1.91-1.84 (1 H, m), 1.83-1.70 (1 H₁ m), 1.65-1.52 (1 H, m), 1.48-1.36 (1 H, m). Intermediate 26 - S-KRHI-Aza-bicyclo^^oct-S-yOsulfanyll-phenol

3-[(R)-(1-Aza-bicyclo[2.2.2]oct-3-yl)sulfanyl]-phenol was prepared from 3- hydroxythiophenol as follows:

A solution of 3-mercaptophenol (3.69 g) in DMF (10 ml_) was added slowly to a suspension of NaH (2.92 g of 60% dispersion in mineral oil) in DMF (30 rnl_) at 0⁰C. After 30 mins, the reaction mixture was treated with a solution of methanesulfonic acid (S)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (3.0 g) in DMF (7 ml_) (J. Med. Chem., 1992, 35, 2392-2406) and the reaction mixture was heated at 70⁰C for 18 h. The reaction mixture was diluted with 2 M NaOH solution and extracted with ethyl acetate. The organic layer was dried (MgSO₄), filtered and evaporated in vacuo. The residue was triturated with methanol and the resulting white solid was collected by filtration to give 3-[(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)sulfanyl]-phenol (1.11 g, 32%). LCMS (Method 3, Rt 0.35 min). MH⁺ = 236.

Intermediate 27 - (R)-3-Benzyloxy-1-aza-bicyclo[2.2.2]octane

Step 1. A solution of borane-THF (1.0 M in THF, 24.8 mL) was added dropwise to a solution of (R)-1-aza-bicyclo[2.2.2]octan-3-ol (3 g) in THF (20 mL) at 0⁰C. 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 (MgSO₄), filtered and evaporated in vacuo. The resulting residue was dissolved in ether and treated with 0-50% DCM/petroleum spirit (bp 40-60⁰C). The resulting fine precipitate was collected by filtration to afford (R)-1-boranyl-1 -aza- bicyclo[2.2.2]octan-3-ol (2.1 g, 63%). ¹H NMR (400 MHz, CDCI₃): δ 4.02-3.97 (1 H, m), 3.19-3.12 (1 H, m), 2.98-2.67 (6H, m), 2.11-2.01 (1 H, m), 1.83-1.75 (1 H, m), 1.66- 1.27 (3H, m). 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 room temperature, evaporated in vacuo and purified by silica gel chromatography (eluting with petroleum spirit 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%). ¹H NMR (400 MHz, CDCI₃): δ 7.37-7.24 (5H, m), 4.52 (1 H, d, J = 11.6), 4.44 (1 H, d, J = 11.6), 3.74-3.67 (1 H, m), 3.23-2.78 (7H, m), 2.26-2.20 (1 H, m), 2.13-2.01 (1 H, m), 1.87-1.76 (1 H, m), 1.64-1.49 (1 H, m). Step 3. A solution of the foregoing compound (433 mg) in acetone (5 mL) at 0°C was treated with 1.25 M HCI-MeOH (10.45 mL), stirred at 0⁰C for 0.5 h, and then stirred at room 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. LCMS (Method 2, Rt 0.35 min). MH⁺ = 218.

Intermediate 28 - (RJ-S-^-Fluoro-benzyloxyH-aza-bicyclo^^^Joctane

(R)-3-(4-fluoro-benzyloxy)-1 -aza-bicyclo[2.2.2]octane was prepared from 4- fluorobenzyl bromide and (R)-1 -aza-bicyclo[2.2.2]octan-3-ol by the procedure described for Intermediate 27. Data for (R)-3-(4-fluoro-benzyloxy)-1-aza- bicyclo[2.2.2]octane: LCMS (Method 2, Rt 2.10 min). MH⁺ = 236.

Intermediate 29 - (R)-3-[((E)-But-2-enyl)oxy]-1 -aza-bicyclo[2.2.2]octane

(R)-3-Allyloxy-1-aza-bicyclo[2.2.2]octane was prepared from ally) bromide and (R)-1- aza-bicyclo[2.2.2]octan-3-ol by the procedure described for Intermediate 27. Data for (R)-3-allyloxy-1-aza-bicyclo[2.2.2]octane: LCMS (Method 2, Rt 1.94 min). MH⁺ = 168. Intermediate 30 - (R)-3-(3-I\/Iethyl-but-2-enyloxy)-1-aza-bicyclo[2.2.2]octane

SK,

(R)-3-(3-Methyl-but-2-enyloxy)-1-aza-bicyclo[2.2.2]octane was prepared from prenyl bromide and (R)-1-aza-bicyclo[2.2.2]octan-3-ol by the procedure described for Intermediate 27, except that HCI-MeOH was replaced by TFA-MeOH in Step 3. Data for (R)-3-(3-methyl-but-2-enyloxy)-1-aza-bicycIo[2.2.2]octane: LCMS (Method 2, 0.37 min). MH⁺ = 196.

Intermediate 31 - (R)-3-Benzylsulfanyl-1-aza-bicyclo[2.2.2]octane

(R)-3-Benzylsulfanyl-1 -aza-bicyclo[2.2.2]octane was prepared from benzyl mercaptan according to the procedure described for Intermediate 22. Data for Intermediate 31 : ¹H NMR (300 MHz₁ CDCI₃): δ 7.33-7.20 (5 H, m), 3.69 (2 H, s), 3.18 (1 H, ddd, J = 13.86, 9.60, 2.37 Hz), 2.96-2.66 (5 H, m), 2.55 (1 H, ddd, J = 13.87, 6.00, 2.20 Hz), 2.09-1.95 (1 H, m), 1.85-1.78 (2 H, m), 1.52-1.30 (2 H, m).

Intermediate 32 - (R)-3-Phenylsulfanylmethyl-1-aza-bicyclo[2.2.2]octane

Thiophenol (1.25 g) was added to a stirred suspension of NaH (455 mg of 60% dispersion in mineral oil) in DMF (6 ml_). After 10 min, methanesulfonic acid (R)-1- (1-aza-bicyclo[2.2.2]oct-3-yl)methyl ester (D)-tartrate salt (0.6 g) (Y. Guminski et al., Org. Prep. Proc. Int., 1999, 31 , 399) was added and the reaction mixture was heated at 100⁰C for 1 h. The reaction mixture was cooled, and diluted with water and ethyl acetate. The organic phase was separated and washed with 2 M NaOH and brine; dried (MgSO₄), filtered and evaporated in vacuo. Purification by SCX and silica gel chromatography (eluting with 0-10% [2M NH₃ in MeOH] - DCM) gave (R)-3- phenylsulfanylmethyl-1-aza-bicyclo[2.2.2]octane (250 mg, 66%) as a colourless oil. 1H NMR (300 MHz, CDCI₃) 7.36-7.27 (4H, m), 7.21-7.15 (1 H₁ m), 3.16-2.73 (7H, m), 2.51 -2.43 (1 H, m), 1.89-1.35 (6H, m).

Intermediate A - (5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-diphenyl-methanol

The title compound was obtained from ethyl 2-oximinooxamate as follows: Step 1. Diisopropylamine (21.6 ml_) was added dropwise to a stirred suspension of ethyl 2-oximinooxamate (15 g) in dry DCM (300 mL) cooled to -10°C. After stirring for 10 minutes a solution of chloroacetyl chloride (9.96 mL) in dry DCM (30 mL) was added dropwise over 20 minutes to the cooled mixture. After stirring at room temperature overnight, the reaction was poured into ice/water mixture (1 L) to obtain two layers. Filtration of the bottom layer gave a brown precipitate which was washed with ethyl acetate (50 mL) and dried in vacuo to give the chloroacetylated oximinooxamate (21.54 g, 91 %) as a cream solid. LCMS (Method 2): Rt 2.41 min, m/z 209 [MH]⁺.

Step 2. A thick suspension of the foregoing compound (11.43 g) in toluene (200 mL) was allowed to reflux in a Dean-Stark apparatus for 12 h. The reaction mixture was allowed to cool down to room temperature and dried with MgSO₄. Filtration of the solid residue and evaporation of the solvent in vacuo gave 5-chioromethyl-

[1 ,2,4]oxadiazole-3-carboxylic acid ethyl ester (10.2 g, 97%) as an oil. LCMS

(Method 2): Rt 2.97 min, m/z 190 [no MH]+. ¹H NMR (400 MHz, DMSO-d₆): δ 5.17 (s, 2 H), 4.45 (q, 2 H), 1.28 (t, 3 H).

Step 3. Phenylmagnesium chloride (2 M solution in THF; 91.2 mL) was added drop wise to a stirred solution of 5-chloromethyl-[1 ,2,4]oxadiazole-3-carboxylic acid ethyl ester (15.8 g) in anhydrous THF (300 mL) at -30°C . The reaction mixture was stirred at -30⁰C for 5 mins, warmed to 12°C, recooled to 0⁰C, quenched with ammonium chloride solution (90 mL) and warmed to room temperature. Water (60 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with NaHCO₃, water, and brine, dried (MgSO₄), filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 0- 20% EtOAc/cyclohexane followed by further purification with silica gel chromatography eluting with 0-15% EtOAc/cyclohexane gave the title compound (8.65 g, 35%) as a white solid. LCMS (Method 2): R_t 3.64 min (no [MH]⁺). ¹H NMR (400 MHz₁ DMSO-d₆): δ 7.34-7.24 (m, 10 H), 7.09 (s, 1 H), 5.10 (s, 2 H).

Intermediate B - (5-Bromomethyl-isoxazol-3-yl)-diphenyl-methanol

The title compound was obtained from methyl 5-methylisoxazole-3-carboxylate as follows: Step 1. Phenylmagnesium Bromide (3 M solution in ether; 100 ml_) was added drop wise to a solution of methyl 5-methylisoxazole-3-carboxylate (20.2 g) in anhydrous THF (300 mL) at -10⁰C under a nitrogen atmosphere. The reaction mixture was stirred at -10⁰C for 5 mins, then allowed to warm up to RT and left to stand for 18 hours. The reaction mixture was poured into cold 1 M HCI (300 mL) and extracted with ether. The combined organic extracts were washed with NaHCO₃, water, and brine, dried (MgSO₄), filtered and evaporated in vacuo to give (5-methyl-isoxazo!-3- yl)-diphenyl-methanol (37.21 g, 98%) as a waxy solid. ¹H NMR (400 MHz, CDCI₃): δ 7.39-7.25 (m, 10 H), 5.84 (s, 1 H), 3.69 (s, 1 H), 2.38 (s, 3 H).

Step 2. Dry 1 ,2-DCE (500 mL) was purged with argon for 15 mins. (5-Methyl- isoxazol-3-yl)-diphenyl-methanol (37.9 g) was added under nitrogen with stirring followed by NBS (28.0 g) and AIBN (4.7 g). The reaction mixture was stirred at 80⁰C for 1 hour. Further NBS (28.Og) and AIBN (4.7 g) was added to the reaction mixture and stirring continued at 80⁰C for 3 hours. The reaction mixture was allowed to cool to RT, poured into 1 M HCI (500 mL) and extracted "with ether. The combined organic extracts were washed with NaHCO₃, water, and brine, dried (MgSO₄), filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 10-100% cyclohexane-DCM gave the title compound (26.0 g, 52%) as a pale yellow solid containing minor amounts of unchanged starting material, and dibrominated- and tribrominated impurities. Data for the title compound: ¹H NMR (400 MHz, CDCI3); δ 7.38-7.23 (m, 10 H), 6.18 (s, 1 H), 4.35 (s, 2 H), 3.63 (s, 1 H).

The title compound may also be obtained from ethyl 2-chloro-2- (hydroxyimino)acetate as follows:

Step A - (5-Hydroxymethyl-isoxazol-3-yl)-diphenyl-methanol

A solution of triethylamine (69 ml_) in ether (31 mL) was added slowly over 4 h with the aid of a syringe pump to a briskly stirred solution of propargyl alcohol (37.5 mL) and ethyl 2-chloro-2-(hydroxyimino)acetate (75 g) in ether (500 mL) at room temperature. The reaction mixture was then allowed to stir overnight, filtered and the filtrate washed with water (twice). The aqueous phases were combined, saturated with sodium chloride and re-extracted with ethyl acetate (twice). The combined organic phases were dried (MgSO₄), filtered and evaporated in vacuo to give a thick oil (82 g) comprised mainly of δ-hydroxymethyl-isoxazole-S-carboxylic acid ethyl ester. This was dissolved in THF (700 mL), cooled to -10^DC and treated with a solution of phenylmagnesium chloride (750 mL, 2.0 M in THF) keeping the temperature below -2°C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was poured carefully into ice-cold concentrated hydrochloric acid (200 mL) and ice (500 mL) and the layers separated. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried, filtered and evaporated in vacuo. Trituration with ether gave (5- hydroxymethyl-isoxazol-3-yl)-diphenyl-methanol (82.3 g, 59% (2 steps)) as a white solid. ¹H NMR (300 MHz, DMSO): δ 7.39-7.25 (m, 10 H), 6.82 (s, 1 H), 6.34 (s, 1 H), 5.62 (t, J = 6.0 Hz, 1 H), 4.54 (d, J = 6.0 Hz, 2 H).

Step B - (5-Bromomethyl-isoxazol-3-yl)-diphenyl-methanol

A solution of the foregoing compound (40 g) and tetrabromomethane (70.8 g) in DCM (350 mL) was cooled to -15 ⁰C and treated portionwise with triphenylphosphine (48.5 g), keeping the temperature below -8 ⁰C. The reaction was allowed to warm to 10⁰C, then poured directly onto a silica gel pad and eluted with DCM (2500 mL). The eluent was evaporated and purified by column chromatography (0-25% ethyl acetate in cyclohexane) to give the title compound (43 g, 88%) as a thick, straw-coloured oil. ¹H NMR (400 MHz, CDCI₃): δ 7.38-7.23 (m, 10 H), 6.18 (s, 1 H), 4.35 (s, 2 H), 3.63 (S, 1 H).

Intermediate C - (3-Chloromethyl-[1 ,2,4]oxadiazol-5-yl)-diphenyi-methanol

Phenylmagnesium bromide (3 M solution in diethyl ether; 3.8 mL) was added dropwise to a solution of 3-chloromethyl-[1 ,2,4]oxadiazole-5-carboxylic acid ethyl ester (0.969 g) (prepared as described in DE1915495) in anhydrous THF (85 mL) at -78°C under N₂. The reaction mixture was stirred at -78°C for 45 mins, then was allowed to warm to -20⁰C and stirred for a further 30 mins. It was then allowed to warm to room temperature. The mixture was then cooled to -78°C and quenched by slow addition of a chilled solution of 1 M HCI (10 mL), allowed to warm to room temperature and extracted three times with ethyl acetate. The combined organic extracts were washed with water, NaHCO₃ and brine, dried (MgSO₄), filtered and evaporated in vacuo. Purification by silica gel chromatography (isolute cartridge) eluting with 0-100% DCM in cyclohexane followed by 0-15% EtOAc in DCM gave the title compound (0.2 g, 13%) as a cream-coloured solid. LCMS (Method 2): R, 3.63 min (no [MH]⁺). ¹H NMR (400 MHz₁ DMSO-d₆): δ 7.59 (s, 1 H), 7.39-7.28 (m, 10H)₁ 4.91 (s, 2H).

Intermediate D-Br - (R)-(5-Bromomethyl-[1,3,4]oxadiazol-2-yl)-cyclohexyl- phenyl-methanol

The title compound was obtained from (R)-cyclohexyl-hydroxy-phenyl-acetic acid as follows:

Step 1 : Dimethylamino-acetic acid N'-((R)-2-cyclohexyl-2-hydroxy-2-phenyl-acetyl)- hydrazide

1 ,1 '-Carbonyldiimidazole (6 g) was added to a stirred suspension of (R)-cyclohexyl- hydroxy-phenyl-acetic acid (8 g) in dry DCM (280 mL) at room temperature. After stirring for 2 h a solution of dimethylamino-acetic acid hydrazide (4 g) in dry DCM (40 mL) was added rapidly dropwise. After stirring at room temperature for three days, the reaction mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was dried (MgSO₄), filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 20-100% ethyl acetate in DCM gave (R)-cyclohexyl-hydroxy-phenyl-acetic acid N'-(2-dimethylaminoacetyI)- hydrazide (5.13 g, 45%) as a white foam. ¹H NMR (400 MHz, DMSO-d_B): δ 9.51 (2 H, brs), 7.55-7.6 (2 H, m), 7.28-7.36 (2 H, m), 7.18-7.25 (1 H, m), 5.53 (1 H, s), 2.88 (2 H, s), 2.2-2.8 (1 H, m), 2.2 (6 H, s), 1.68-1.79 (2 H, m), 1.56-1.63 (2 H, m), 1.0-1.38 (6 H, m).

Step 2. A solution of the foregoing compound (5.13 g) in acetic anhydride (65 mL) was heated at 90°C for 1 h. The reaction mixture was cooled and poured into an ice- water-NaHCO₃ mixture. More NaHCO₃ solution was added until the mixture was basic. The mixture was extracted with DCM and the organic phase was washed with brine, dried (Na₂SO₄), filtered and evaporated in vacuo to give a crude solid. Purification by silica gel chromatography (eluting with 20-100% ethyl acetate in DCM and 0-20% methanol in DCM) gave (R)-cyclohexyl-(5-dimethylaminomethyl- [1 ,3,4]oxadiazol-2-yl)-phenyl-methanol (3.29 g, 69%) as a yellow foam. LCMS (Method 2, 2.37 min). MH⁺ = 316.

Step 3: (R)-(5-Bromomethyl-[1 ,3,4]oxadiazol-2-yl)-cyclohexyl-phenyl-methanol A solution of the foregoing compound (0.25 g) in DCM (6 mL) was added dropwise over 10 min to a solution of cyanogen bromide (3.0 M in DCM; 1.05 mL). The reaction mixture was left to stand for four days at room temperature, evaporated under a stream of nitrogen and purified by column chromatography (silica, cyclohexane to 20% EtOAc in DCM) to give the desired compound (93.7 mg, 34%) as a thick syrup. Data for the title compound: LCMS (Method 2, 3.90 min). MH⁺ = 353.

Intermediate D-Cl - (RHS-ChloromethyKi^^oxadiazol-^-yO-cyclohexyl- phenyl-methanol

Step 1 : (R)-Cyclohexyl-hydroxy-phenyl-acetic acid hydrazide

A solution of (R)-cyclohexylmandelic acid (2.34 g) was dissolved in DCM (20 ml_), treated with 1 ,1'-carbonyldiimidazole (1.95 g) and stirred at room temperature for 1 h. The reaction mixture was treated with hydrazine monohydrate (1.0 ml_) and stirred for a further 30 minutes. The reaction mixture was diluted with DCM, washed with 1 N NaOH solution and brine, dried (MgSO₄), filtered and evaporated in vacuo to give the title compound as a white solid (2.Og, 81 %). LCMS (Method 2, 2.73 min). MH⁺ = 249.

Step 2: Chloro-acetic acid N'-((R)-2-cyclohexyl-2-hydroxy-2-phenyl-acetyl)-hydrazide A solution of the foregoing compound (1.0 g) was dissolved in DCM (20 mL) and treated at 0 ⁰C with diisopropylethylamine (0.83 mL) and chloroacetyl chloride (0.39 ml). After warming to room temperature and stirring for 10 minutes, the reaction mixture was diluted with DCM, washed with water and brine, dried (MgSO₄), filtered and evaporated in vacuo to give the desired compound (1.1 g, 73%) as a white solid. LCMS (Method 2, 3.20 min). MH⁺ = 325.

Step 3: (R)-(5-Chloromethyl-[1 ,3,4]oxadiazol-2-yl)-cyclohexyl-phenyl-methanol

A solution of the foregoing compound (170 mg), tosyl chloride (96 mg) and 1 ,2,2,6,6- pentamethylpiperidine (175 mg) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with NaHCO₃ solution (twice), brine, dried (MgSO₄), filtered and evaporated in vacuo. Purification by column chromatography (silica, 0-100% cyclohexane/ethyl acetate) gave the title compound as a white solid (105 mg, 63%). Data for the title compound: LCMS (Method 2, 3.79 min). MH⁺ = 307. Intermediate E - (R)-(5-Chloromethyl-isoxazol-3-yl)-cyclohexyl-phenyl-methanol

The title compound was obtained from (R)-cyclohexyl-hydroxy-phenyl-acetic acid as follows:

Step 1 : 1 ,1 '-Carbonyl diimidazole (25.0 g, 154 mmol) was added to a stirred suspension of (R)-cyclohexyl-hydroxy-phenyl-acetic acid (30.0 g, 128 mmol) in dry THF (600 ml_). After stirring for 90 mins at room temperature, sodium borohydride (1 1.6 g, 307 mmol) was added portionwise over a period of 1 hour. The reaction mixture was then left to stir at room temperature overnight. The reaction was quenched by the addition of water (100 ml_) then extracted with DCM. The combined organic phases were dried (MgSO₄), filtered and evaporated in vacuo to give a crude solid. Purification by silica gel chromatography (eluting with 0-5% methanol in DCM) gave (R)-1-cyclohexyl-1-phenyl-ethane-1 ,2-diol (20.7 g, 73 %). ¹H NMR (400 MHz, CDCI₃): δ 7.41-7.33 (4 H, m), 7.28-7.24 (1 H, m), 3.99 (1 H, d), 3.83 (1 H, d), 2.68 (1 H, br s), 1.86-1.80 (1 H, m), 1.78-1.64 (3 H, m), 1.63-1.57 (1 H, m), 1.47-1.41 (1 H, m), 1.27-0.94 (5 H, m).

Step 2: A solution of oxalyl chloride (15.5 ml_, 201 mmol) in dry DCM (900 ml_) was cooled to -78 ⁰C under a nitrogen atmosphere. A solution of DMSO (28.5 mL, 401 mmol) in DCM (25 mL) was added drop wise then the mixture stirred at -78 ⁰C for 10 mins. A solution of (R)-1-cyclohexyl-1 -phenyl-ethane-1 ,2-diol (29.5 g, 134 mmol) in DCM (250 mL) was added dropwise over the course of 1 hour giving a thick slurry. The internal temperature was allowed to reach -45 ⁰C. Triethylamine (92.8 mL, 669 mmol) was added dropwise and after complete addition the mixture was allowed to warm to room temperature. The mixture was washed with 1 N hydrochloric acid (500 mL x 2), water (500 mL) and brine (500 mL) then dried (MgSO₄), filtered and evaporated to give an orange oil. This was dissolved in IMS (320 mL) and added portionwise to a preformed solution of hydroxylamine hydrochloride (14.0 g, 201 mmol) and sodium carbonate (21.3 g, 201 mmol) in water (210 mL). The resulting emulsion was stirred at room temperature overnight then partitioned between DCM and water. The organic layer was washed with water and brine, then dried (MgSO₄), filtered and evaporated in vacuo. Purification by silica gel chromatography (eluting with 0-15% EtOAc in cyclohexane) gave (R)-cyclohexyl-hydroxy-phenyl- acetaldehyde oxime (25.9 g, 83 %). ¹H NMR (400 MHz, CDCI₃): δ 7.76 (1 H, s), 7.44- 7.41 (2 H, m), 7.37-7.33 (2 H, m), 7.27-7.23 (1 H, m), 7.22 (1 H, br s), 3.34 (1 H, s), 1.90-1.60 (5 H, m), 1.37-1.05 (6 H, m).

Step 3: A solution of (R)-cyclohexyl-hydroxy-phenyl-acetaldehyde oxime (8 g, 34 mmol) and 2,6-lutidine (10 ml_, 86 mmol) in DCM (150 ml_) was cooled in an ice-bath.

Trimethylsilyl trifluoromethanesulfonate (15.6 mL, 86 mmol) was added dropwise.

The mixture was stirred for 10 minutes at 0 ⁰C then allowed to warm to room temperature for 30 mins. The reaction was quenched by addition of water (50 mL).

The organic phase was isolated by passage though a phase separation cartridge and evaporated in vacuo. Purification by silica gel chromatography (eluting with 10-20%

EtOAc in cyclohexane) gave a mixture of mono and bis TMS-protected compounds.

This was dissolved in methanol and left at room temperature overnight and evaporated in vacuo to give (R)-cyclohexyl-phenyl-trimethylsilanyloxy-acetaldehyde oxime (10 g, 96 %).¹H NMR (400 MHz, CDCI₃): δ 7.62 (1 H, s), 7.32-7.28 (4 H, m), 7.26-7.21 (1 H, m), 7.11 (1 H₁ s), 1.93-1.85 (2 H, m), 1.76-1.71 (1 H, m), 1.68-1.56 (2

H₁ m), 1.49-1.42 (1 H₁ m), 1.27-0.78 (5 H, m), 0.11 (9 H, m).

Step 4: A solution of (R)-cyclohexyl-phenyl-trimethylsilanyloxy-acetaldehyde oxime (6 g, 19.6 mmol) was formed in dry DCM (400 mL) and cooled to -78 ⁰C. Under reduced lighting, a solution of tert-butylhypochlorite (4.3 g, 39.3 mmol) in DCM (10 mL) was added dropwise. After 2 hours at -78 °C a solution of triethylamine (4.1 mL, 29.4 mmol) in DCM (10 mL) was added dropwise. After a further 10 mins at -78 ⁰C the mixture was allowed to warm to 0 ⁰C. At this point, propargyl chloride (14.4 mL, 196 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was washed with brine (200 mL), dried (Na₂SO₄), filtered and evaporated. Purification by silica gel chromatography (eluting with 0-10% EtOAc in cyclohexane) gave crude 5-chloromethyl-3-((R)-cyclohexyl-phenyl- trimethylsilanyloxy-methyl)-isoxazole. This was re-dissolved in THF (100 mL), cooled in an ice-bath and a solution of tetrabutylammonium fluoride (19.6 mL of 1 M in THF) was added drop wise. This mixture was stirred for 30 mins at 0 ⁰C then partitioned between ethyl acetate and water. The organic phase was dried (Na₂SO₄), filtered and evaporated in vacuo. Purification by silica gel chromatography (eluting with 0-20% EtOAc in cyclohexane) gave the title compound as a white solid (3.5 g, 58 %). ¹H NMR (400 MHz, CDCI₃): δ 7.51 (2 H, m), 7.32 (2 H, m), 7.25-7.21 (1 H, m), 6.29 (1 H, s), 4.52 (2 H, s), 2.80 (1 H, s), 2.34-2.28 (1 H, m), 1.81-1.76 (1 H, m), 1.72-1.62 (3 H, m), 1.36-1.02 (6 H, m).

Intermediate F - (R)-(5-Chloromethyl-[1 ,2,4]oxadiazol-3-yl)-cyclohexyl-phenyl- methanol

A solution of (RJ-cyclohexyl-phenyl-trimethylsilanyloxy-acetaldehyde oxime (Intermediate E - step 3, 2.25 g, 7.36 mmol) was formed in dry DCM (120 ml_) and cooled to -78 ⁰C. Under reduced lighting, a solution of tert-butylhypochlorite (1.6 g, 14.7 mmol) in DCM (2 ml_) was added dropwise. After 2 hours at -78 ⁰C a solution of triethylamine (1.5 ml_, 1 1.0 mmol) in DCM (2 mL) was added drop wise. After a further 30 mins at -78 ⁰C the mixture was allowed to warm to 0 ⁰C. At this temperature, chloroacetonitrile (9 mL, 147 mmol) was added followed by dry toluene (300 mL). The mixture was allowed to warm to room temperature then heated at reflux for 5 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was dried (Na₂SO₄), filtered and evaporated. Purification by silica gel chromatography (eluting with 0-20% EtOAc in cyclohexane) gave crude 5-chloromethyl-3-((R)-cyclohexyl-phenyl- trimethylsilanyloxy-methyl)-[1 ,2,4]oxadiazole (2 g). This was re-dissolved in THF (50 mL), cooled in an ice-bath and a solution of tetrabutylammonium fluoride (5 mL of 1 M in THF) was added drop wise. This mixture was stirred for 30 mins at 0 ⁰C then partitioned between ethyl acetate and water. The organic phase was dried (Na₂SO₄), filtered and evaporated. Purification by silica gel chromatography (first column eluted with 0-20% EtOAc in cyclohexane then a second column eluted with DCM) gave the title compound as a white solid (800 mg, 35 %). ¹H NMR (400 MHz, CDCI₃): δ 7.61 (2 H, m), 7.34 (2 H₁ m), 7.26 (1 H, m), 4.64 (2 H, s), 3.12 (1 H, s), 2.35-2.28 (1 H, m), 1.80-1.73 (1 H, m), 1.71-1.63 (2 H, m), 1.52-1.49 (1 H, m), 1.45-1.25 (3 H, m), 1.20- 1.11 (3 H, m).

General Procedure A - Formation of quaternary ammonium salts from quinuclidines and alkyl halides

A solution of a quinuclidine (Intermediate 1-32) (1.0 equivalent) and alkylating agent (Intermediate A-F) (1.0-1.2 equivalents) was heated at 50⁰C in acetonitrile. If the resulting product precipitated, it was collected by filtration, washed with ethyl acetate and ether and dried in vacuo; or if it did not precipitate, the reaction mixture was evaporated and the product isolated by silica gel chromatography and/or HPLC.

Example 1 - (R)-3-(3,4-Dichloro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)- [I^^oxadiazol-δ-ylmethylj-i-azonia-bicyclol^^loctane; chloride

The title compound was prepared by application of General Procedure A: Intermediate A (55.3 mg, 0.184 mmol) and Intermediate 2 (45.5 mg, 0.167 mmol) were mixed in acetonitrile (1.0 mL) and heated at 50⁰C for 1 h. The resulting white solid was collected by filtration, washed with ether and dried in vacuo to yield the title compound (80.8 mg, 84%). Data for Example 1 : ¹H NMR δ (ppm)(DMSO-dr, ): 7.58 (1 H, d, J = 8.92 Hz), 7.39-7.35 (4 H, m), 7.34-7.25 (7 H, m), 7.14 (1 H, s), 7.01 (1 H, dd, J = 8.93, 2.91 Hz), 5.07-4.98 (3 H, m), 4.14-4.06 (1 H, m), 3.71-3.50 (5 H, m), 2.46 (1 H, s), 2.18-1.99 (2 H, m), 1.99-1.81 (2 H, m). LCMS (Method 1 , 8.50 min). M⁺ = 536.16. Examples 2-80

These were made from combination of Reactant 1 (Intermediate A-F) and Reactant 2 (Intermediate 1-32) as described in Table 1 , according to General Procedure A. Data for Examples 2-80 are listed in Table 1. The chemical names of Examples 2-80 are provided in Table 2.

;

min min min

OO

min

Table 1

August 8, 20Q8

CARPMAELS & RANSFORD (MDN)

Table 2

An XRPD spectrum of (R)-3-(3-Fluoro-4-methyl-phenoxy)-1 -[3-(hydroxy-diphenyi-methyi)- isoxazol-δ-ylmethyπ-i-azonia-bicycloβ^^loctane bromide prepared as described herein above is presented in Figure 1. Characteristic peaks from the spectrum are listed in Table 3 below.

Table 3

The melting temperature of this solid form was determined by DSC (Figure 2) and was found to be 241.6⁰C (onset). GVS determination showed a mass increase of approximately 0.1% was measured at 80%RH.

BIOLOGICAL EXAMPLES

The inhibitory effects of compounds of the present invention at the M3 muscarinic receptor were determined by the following binding assays:

Muscarinic Receptor Radioligand Binding Assays

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 μM 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 μM 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. All compounds tested exhibited potencies (as Ki values) in the M3 binding assay of less than 1 nM. In particular, Example 24 exhibited a Ki value of 0.52nM, Example 42 exhibited a Ki value of 0.4OnM and Example 45 exhibited a Ki value of 0.31 nM 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:

Evaluation of potency and duration of action in Isolated Guinea Pig Tracheae Experiments are carried out at 37⁰C in modified Krebs-Henseleit solution, (114mM NaCI, 15mM NaHCO₃, 1 mM MgSO₄, 1.3mM CaCI₂, 4.7mM KCi, 1 1.5mM glucose and 1.2mM KH₂PO₄ , pH 7.4) gassed with 95% O₂/5% CO₂. lndomethacin is added to a final concentration of 3μM. 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 1OmL 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 MPI OOW/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 0.1 ms, 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 IC₅₀ calculated for each compound. By means of illustration, Example 42 and Example 45 both showed an IC₅₀ <4nM in this assay.

Onset time and duration of action studies may be performed by adding the previously determined EC₅₀ concentration of compound to EFS contracted tissues and the response allowed to plateau. The time taken to reach 50% of this response is determined to be the onset time. Tissues are then washed free of compound by flushing the tissue bath with fresh Krebs solution and the time taken for the contraction in response to EFS to return to 50% of the response in the presence of compound is measured. This is termed the duration of action.

Methacholine Induced Bronchoconstriction in vivo

Male Guinea pigs (Dunkin Hartley), weighing 500-60Og 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 mLVkg) 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 (250μg/mL, 2mL7kg). At the point of surgical anaesthesia, 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. 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 0.2cm H20/mL/s. A 2 minute baseline reading is recorded before i.v. administration of methacholine (up to 30μg/kg, 0.5mL_/kg). 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. In this assay Example 42 showed a reduction in peak resistance of 79% when dosed at 1 μg/kg (i.n.) 48 hrs prior to 10μg/kg (i.v) methacholine challenge.

Inhibition of pilocarpine induced salivation bv i.n. administered 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.δmLΛg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs are terminally anaesthetised with urethane (25% solution in H₂O, 1.5g/kg). Once sufficient anaesthesia has developed (absence of toe pinch reflex) 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.

In this assay, Example 42 showed no reduction in salivation when dosed at 10μg/kg 4hrs prior to pilocarpine (0.6mg/kg s.c.) challenge.

Claims

1. A compound selected from the group consisting of:

(R)-3-(3,4-Dichloro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-3- pheny!sulfanylmethyl-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzyloxy-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1-azonia- bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1- azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzylsulfanyl-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1-azonia- bicyclo[2.2.2]octane X; (R)-3-(4-Fluoro-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1 - azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Chloro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1- azonia-bicyclo[2.2.2]octane X;

(R)-3-(Benzo[1 ,3]dioxol-5-yloxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1-azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzylsulfanyl-1 -[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol- 2-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenoxy)-1-[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)- [1 ,3,4]oxadiazol-2-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(Benzo[1 ,3]dioxol-5-yloxy)-1 -[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)-

[1 ,3,4]oxadiazol-2-ylmethyl]-1-azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-4-fluoro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol- 5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(Benzo[1 ,3]dioxol-5-yloxy)-1 -[5-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-3- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Fluoro-phenoxy)-1 -[5-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-3- ylmethyl]-1 -azonia-bicyc!o[2.2.2]octane X;

(R)-3-(3-Chloro-phenoxy)-1 -[5-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-3- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-1-[5-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-3-ylmethyl]-3-phenylsulfanyl- 1-azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3-hydroxy- phenylsulfany!)-1 -azonia-bicyclo[2.2.2]octane X; " (R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(3- hydroxy-phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3,4-Difluoro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Chloro-3-fluoro-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol- 5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-[((E)-But-2-enyl)oxy]-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1- azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Fluoro-benzyloxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1 - azonia-bicyclo[2.2.2]octane X; (R)-3-(3-Fluoro-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1 - azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenoxy)-1-[3-((R)-cyclohexyl-hydroxy-phenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1-azonia-bicyclo[2.2.2]octane X;

(R)-3-Benzylsulfanyl-1 -[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-1 - azonia-bicyclo[2.2.2]octane X;

(R)-3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-1-[3-(hydroxy-diphenyl-methyl)- [1 ^^Joxadiazol-δ-ylmethylH-azonia-bicyclo^^joctane X;

(R)-3-(3-Bromo-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-m-tolyloxy-1 - azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyi-methyl)-[1 ,2,4]oxadiazo)-5-ylmethyl]-3-(3-methoxy- phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(2,3-Dihydro-benzofuran-5-yloxy)-1 -[3-(hydroxy-diphenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3,4-Dimethyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyi)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicycio[2.2.2]octane X;

(R)-3-Benzyloxy-1 -[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-1 - azonia-bicyclo[2.2.2]octane X; (R)-3-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-1-[3-(hyclroxy-ciiphenyl-methyl)- isoxazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Fluoro-4-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)- [1 ^.^oxadiazol-δ-ylmethyll-i-azonia-bicycloβ^^loctane X; (R)-3-(3,4-dif luoro-phenylsulf anyl)-1 -[3-(hydroxy-dipheny!-methyl)-[1 ,2,4]oxadiazol-

5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Fluoro-phenylsulfanyl)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1-[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1-azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-phenylsulfanyl-1-azonia- bicyclo[2.2.2]octane X;

(R)-3-(2,3-Dihydro-benzofuran-5-yloxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(4-Fluoro-3-methyl-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Chloro-3-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Fluoro-4-methyl-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1-azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3- (3,4-dimethyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-yloxy)-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(4-Chloro-3-methyl-phenoxy)-1 -[3-(hydroxy-diphenyl-methyl)-

[1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(4-Fluoro-3-methyl-phenoxy)-1 -[3-(hydroxy-dipheny)-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-3-(3- fluoro-4-methyl-phenoxy)-1-azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1-[5-((R)-cyclohexyl-hydroxy-phenyl-methyl)- [1 ,3,4]oxadiazo⁾-2-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(indan-5-yloxy)- 1 -azonia-bicyclo[2.2.2]octane X; (R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-hydroxy- phenylsulfanyl)-1 -azonia-bicyc!o[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-methyl-but-2- enyloxy)-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-m-tolyloxy-1 -azonia- bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1 -[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-3-(3- hydroxy-phenylsulfanyl)-1-azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-3- (2,3-dihydro-benzo[1 ,4]dioxin-6-yloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-3-m- tolyloxy-1 -azonia-bicyclo[2.2.2]octane X; (R)-1-[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-3-

(2,3-dihydro-benzofuran-5-yloxy)-1-azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-m- tolyloxy-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3- (2,3-dihydro-benzofuran-5-yloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(2_J3- dihydro-benzofuran-5-yloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsulfanyl)-1-[3-((R)-cyclohexyl-hydroxy-phenyl-methyl)- isoxazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X; (R)-3-(3-fluoro-phenylsulfanyl)-1 -[3-(hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-CycIohexyl-hydroxy-phenyl-methy))-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(4- f luoro-3-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Chloro-phenylsu!fanyl)-1-[3-((R)-cyclohexyl-hydroxy-phenyl-methyl)- [1 ,2,4]oxadiazol-5-ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3- hydroxy-phenylsulf anyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-fluoro- 4-methyl-phenoxy)-i -azonia-bicyc!o[2.2.2]octane X; (R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(4-fluoro- 3-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(^-^^-((RJ-Cyclohexyl-hydroxy-phenyl-methyO-isoxazol-δ-ylmethyO-S-m-tolyloxy- 1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(5-methyl- thiophen-2-yloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3- fluoro-4-methyl-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1 -[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3-methyl-but-2- enyloxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3-hydroxy- phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3- hydroxy-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazoI-2-ylmethyl]-3-(3- hydroxy-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(3- hydroxy-phenoxy)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-fluoro- phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-3-(3-Fluoro-phenylsulfanyl)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,2,4]oxadiazol-5-ylmethyl]-3-(3- fluoro-phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X; (R)-1 -[5-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-[1 ,3,4]oxadiazol-2-ylmethyl]-3-(3- fluoro-phenylsulfanyl)-1 -azonia-bicyclo[2.2.2]octane X;

(R)-1-[3-(Hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-3-(3-hydroxy-phenoxy)-1- azonia-bicyclo[2.2.2]octane X;

wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

2. A compound according to claim 1 , selected from:

(R)-3-(3-Fluoro-4-methyl-phenoxy)-1-[3-(hydroxy-diphenyl-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X

(R)-3~(3-Fluoro-phenylsulfanyl)-1-[3-(hydroxy-diphenyI-methyl)-isoxazol-5- ylmethyl]-1 -azonia-bicyclo[2.2.2]octane X

wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

3. A compound according to claim 2, which is (R)-3-(3-Fluoro-4-methyl-phenoxy)-1- ^-(hydroxy-diphenyl-methyO-isoxazol-δ-ylmethylj-i -azonia-bicyclo^^^joctane bromide

4. A compound according to claim 2, which is (R)-3-(3-Fluoro-phenylsulfanyl)-1-[3- (hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-1-azonia-bicyclo[2.2.2]octane bromide

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

6. A process for the preparation of a pharmaceutical composition as claimed in claim 5, which comprises mixing a compound of according to any one of claims 1 to 4 with a pharmaceutically acceptable adjuvant, diluent or carrier.

7. A compound according to any one of claims 1 to 4 for use in therapy.

8. Use of compound according to any one of claims 1 to 4 in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease.

9. A method of treating chronic obstructive pulmonary disease in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound according to any one of claims 1 to 4.

10. A pharmaceutical product comprising, in combination, a first active ingredient which is a compound according to any one of claims 1 to 4 and at least one further active ingredient selected from:-

• a phosphodiesterase inhibitor,

• a β2. adrenoceptor agonist, • a modulator of chemokine receptor function,

• an inhibitor of kinase function,

• a protease inhibitor,

• a steroidal glucocorticoid receptor agonist, and a

• a non-steroidal glucocorticoid receptor agonist.

1 1. A compound selected from:

(R)-(5-Bromomethyl-[1 ,3,4]oxadiazol-2-y|)-cyclohexyl-phenyl-methanol; (RHδ-Chloromethyl-fi .S^Joxadiazol^-y^-cyclohexyl-phenyl-methanol; and (R)-(5-Chloromethyl-[1 ,2,4]oxadiazol-3-y|)-cyclohexyl-phenyl-methanol.