WO2008017824A1

WO2008017824A1 - Bicyclo [2. 2. 1] hept-7-ylamine derivatives and their use

Info

Publication number: WO2008017824A1
Application number: PCT/GB2007/002985
Authority: WO
Inventors: Harry Finch; Richard James Bull
Original assignee: Argenta Discovery Limited
Priority date: 2006-08-08
Filing date: 2007-08-07
Publication date: 2008-02-14
Also published as: GB0702384D0

Abstract

According to the invention, there is provided a compound of formula (Ia): wherein A and R1-R4 are as defined herein, such compounds having utility in the treatment of diseases where M3 and beta2 receptors are implicated, such as respiritory tract diseases; compositions comprising such compounds; uses of such compounds in therapy (such as asthma or COPD); and methods of treating a patient with such compounds.

Description

BICYCLO [2.2. I]HEPT-7-YLAMIWE DERIVATIVES AND THEIR USE

Field of the Invention

This invention relates to bicyclo[2.2.1]hept-7-ylamine derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of M3 muscarinic receptor mediated diseases, for example respiratory diseases.

Background to the invention

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

There are five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M1-M5, and each is the product of a distinct gene and each displays unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract, M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319 - 379).

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

Increased signalling through muscarinic acetylcholine receptors has been noted in a variety of different pathophysiological states including asthma and COPD. In COPD, vagal tone may either be increased (Gross et al. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross etal. 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

Other muscarinic receptor modulators have been referred to. For example: US4353922 describes muscarinic modulators based upon a [2.2.1]azabicycloheptane ring system. EP418716 and US005610163 describe various [3.2.1]azabicyclooctane ring systems. WO06/017768 describes [3.3.1]azabicyclononane ring systems. [2.2.2]azabicyclooctane systems (quinuclidines) have been previously described, for example in US2005/0209272 and WO06/048225. [3.1.0]azabicyclohexane systems have been described in, for example in WO06/035282. [3.2.1]azabicyclooctane systems have been described in for example WO06/035303.

The class of β2 adrenergic receptor agonists is well known. Many known β2-agonists, in particular, long-acting β2-agonists such as salmeterol and formoterol, have a role in the treatment of asthma and COPD. These compounds are also generally administered by inhalation. Compounds currently under evaluation as once-daily β2 agonists are described in Expert Opin. Investig. Drugs 14 (7), 775-783 (2005). A well known β2-agonist pharmacophore is the moiety:

Also known in the art are pharmaceutical compositions that contain both a muscarinic antagonist and a β2-agonist for use in the treatment of respiratory disorders. For example, US2005/0025718 describes a β2-agonist in combination with tiotropium, oxotropium, ipratropium and other muscarinic antagonists; WO02/060532 describes the combination of ipratropium with β2-agonists and WO02/060533 describes the combination of oxotropium with β2-agonists. Other M3 antagonist / β2-agonist combinations are described in WO04/105759 and WO03/087097.

Also known in the art are compounds possessing both muscarinic receptor antagonist and β2-agonist activity present in the same molecule. Such bifunctional molecules provide bronchodilation through two separate modes of action whilst possessing single molecule pharmacokinetics. Such a molecule might be easier to formulate for therapeutic use as compared to two separate compounds and could be more easily co-formulated with a third active ingredient, for example a steroid. Such molecules are described in for example, WO04/074246, WO04/089892, WO05/111004, WO06/023457 and WO06/023460, all of which use different linker radicals for covalently linking the M3 antagonist to the β2-agonist.

Summary of the Invention

According to the invention, there is provided the use of a compound of formula (I):

wherein A is an oxygen atom or group -N(R¹²)-;

(i) R¹ is C_rC₆-alkyl or a hydrogen atom; and R² is a hydrogen atom or a group -R⁵, or a group, -Z-Y-R⁵, or a group -Z-NR⁹R¹⁰; or a group -Z-CO-NR⁹R¹⁰; or a group -Z- NR⁹-CO-R⁵; or a group -Z-CO₂-R⁵; or a group -Z-CO₂H; and R³ is a lone pair, or R³ is Ci-C₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or

(ii) R¹ and R³ together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R² is a hydrogen atom; or R² is a group -R⁵, or a group, - Z-Y-R⁵, or a group -Z-NR⁹R¹⁰, or a group -Z-CO-NR⁹R¹⁰, or a group -Z-NR⁹-CO-R⁵, or a group -Z-CO₂-R⁵, or a group -Z-CO₂H, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or

(iii) R¹ and R² together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group -Y-R⁵, or a group -Z-Y- R⁵, or a group -Z-NR⁹R¹⁰; or a group -Z-CO-NR⁹R¹⁰; or a group -Z-NR⁹-CO-R⁵; or a group -Z-CO₂-R⁵; or a group -Z-CO₂H and R³ is a lone pair, or R³ is C_rC₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;

R⁴ is selected from one of the groups of formula (a), (b), (c) or (d);

(a) (b) (C) (d)

Z is a Ci-C₁₆-alkylene, C₂-C₁₆-alkenylene or C₂-C₁₆-alkynylene group;

Y is a bond or oxygen atom;

R⁵ is an C_rC₆-alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(CrC₈-alkyl)-, heteroary^CrCs-alkyl)-, cycloalkyl or heterocycloalkyl group;

R⁶ is CrC₆-alkyl or a hydrogen atom;

R^7a and R^7b are a CrC₆-alkyl group or halogen;

n and m are independently 0, 1 , 2 or 3;

R^8a and R^8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, Ci-C₆-alkyl, cycloalkyl;

R^8c is -OH, C_rC₆-alkyl, hydroxy-C_rC₆-alkyl, nitrile, a group CONR^8d ₂ or a hydrogen atom;

R^8d is C_rC₆-alkyl or a hydrogen atom;

R⁹ and R¹⁰ are independently a hydrogen atom, C_rC₆-alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C_rC₆-alkyl)-, or heteroaryl(C_r C₆-alkyl)- group; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;

R is CrC₆-alkyl or a hydrogen atom;

Ar¹ is aryl, heteroaryl or cycloalkyl;

Ar² are independently aryl, heteroaryl or cycloalkyl; and

Q is an oxygen atom, -CH₂-, -CH₂CH₂- or a bond;

wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted;

or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof;

in the manufacture of a medicament for the treatment of prevention of a disease or condition in which M3 muscarinic receptor activity and β-adrenergic receptor activity is implicated.

Conveniently, R¹ is Ci-C₆-alkyl; R² is a group -Z-NR⁹R¹⁰; and R³ is a lone pair.

Convenient R¹⁰ groups of the present invention include:

More conveniently, R is

Conveniently, unless otherwise specified, each alkyl, heterocycloalkyl, aryl, aryl- fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl group of the compounds of fomula (I) is unsubstituted.

Conveniently, each alkenylene chain may contain 1 , 2 or 3 carbon-carbon double bonds and each alkynylene chain may contain up to 1 , 2 or 3 carbon-carbon triple bonds.

According to a futher aspect of the invention, there is provided a compound of formula (Ia):

wherein

A is an oxygen atom or group -N(R¹²)-;

(i) R¹ is CrC₆-alkyl or hydrogen; and R² is a group-Z-NR⁹R¹⁰; and R³ is a lone pair, or R³ is Ci-C₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or

(ii) R¹ and R³ together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R² is a group -Z-NR⁹R¹⁰, in which case the nitrogen atom to which they are attached is a quaternary nitrogen and carries a positive charge; or

(iii) R¹ and R² together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR⁹R¹⁰; and R³ is a lone pair, or R³ is Ci-C₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;

R⁴ is selected from one of the groups of formula (a), (b), (c) or (d);

(a) (b) (C) (d)

Z is a C₉-C₁₅-alkylene, C₉-Ci₅-alkenylene or C₈-C₁₅-alkynylene group; or alternatively Z is an C₈-alkylene, C₈-alkenylene or C₈-alkynylene group;

or Z is a divalent linker radical of formula (A):

wherein L represents a linker comprising a hydrocarbyl chain of 8 or 9 to 15 carbon atoms, wherein the chain may additionally comprise up to three carbon-carbon double bonds, and, wherein the chain may additionally comprise up to three carbon-carbon triple bonds;

L¹ and L² each independently represent hydrogen, Ci_-6 alkyl or C₃.₆ cycloalkyl;

L³ and L⁴ each independently represent hydrogen, C_1-6 alkyl or C₃.₆ cycloalkyl, wherein Ci.₆ alkyl and C₃.₆ cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and ^* denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R¹ and R³, and ^** denotes the point of attachment to the group NR⁹R¹⁰;

R⁶ is C_rC₆-alkyl or a hydrogen atom;

R^7a and R^7b are a C_rC₆-alkyl group or halogen;

n and m are independently 0, 1 , 2 or 3; R^8a and R^8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, C_rC₆-alkyl, cycloalkyl;

R^8d is C_rC₆-alkyl or a hydrogen atom;

R⁹ is a hydrogen atom or CrCValkyl;

R¹⁰ is an aryl (C₁ -C₆-alkyl)-, or heteroaryl(C_rC₆-alkyl) group, in which the C_rC₆-alkyl group is optionally substituted by hydroxy;

R¹² is C_rC₆-alkyl or a hydrogen atom;

Ar¹ is aryl, heteroaryl or cycloalkyl;

Ar² are independently aryl, heteroaryl or cycloalkyl; and

Q is an oxygen atom, -CH₂-, -CH₂CH₂- or a bond;

wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkylene, alkenylene and alkynylene may be optionally substituted;

or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a prodrug of a compound of formula (Ia) as herein defined, or a pharmaceutically acceptable salt thereof.

In yet another aspect the present invention provides an N-oxide of a compound of formula (Ia) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.

In a further aspect the present invention provides a solvate (such as a hydrate) of a compound of formula (Ia) as herein defined, or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.

In one subset of the compounds of the invention:

A is an oxygen atom;

R¹ is C_rC₆-alkyl ; R² is a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is C_rC₆-alkyl, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or:

R¹ and R² together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is C_rC₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or:

R¹ and R³ together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R² is a group -Z-NR⁹R¹⁰ in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;

R⁴ is selected from one of the groups of formula (a), (b) or (c):

(a) (b) (C) Z is a divalent linker radical of formula (A):

L³ L¹

L⁴ L²

(A)

L¹ and L² each independently represent hydrogen, Ci-₆ alkyl or C₃.₆ cycloalkyl; L³ and L⁴ each independently represent hydrogen, C_1-6 alkyl or C_3-6 cycloalkyl, wherein C_1-6 alkyl and C_3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and ^* denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R¹ and R³, and ^** denotes the point of attachment to the group NR⁹R¹⁰;

R⁶ is a hydrogen atom;

R^7a and R^7b are independently a C_rC₆-alkyl group or halogen;

n and m are independently 0, 1 , 2 or 3;

R^8a and R^8b are independently selected from the group consisting of aryl, heteroaryl, C_rC₆-alkyl, cycloalkyl;

R^8c is -OH, C_rC₆-alkyl, hydroxy-C_rC₆-alkyl, or a hydrogen atom;

R⁹ is a hydrogen atom or CrC₆-alkyl;

R¹⁰ is an aryl(C_rC₆-alkyl)-, or heteroaryl(CrC₆-alkyl) group, in which the CrCe-alkyl group is optionally substituted by hydroxy.

In a further subset of compounds of the invention:

A is an oxygen atom;

R¹ is C_rC₆-alkyl; R² is a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is C-|-C₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or:

R¹ and R² together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is C_rC₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or: R¹ and R³ together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R² is a group -Z-NR⁹R¹⁰, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; R⁴ is selected from one of the groups of formula (a), (b) or (c):

(a) (b) (C) Z is a divalent linker radical of formula (A):

L³ L¹

(A)

wherein L represents a linker comprising a hydrocarbyl chain of 8 to 1 1 carbon atoms, wherein the chain may additionally comprise up to three carbon-carbon double bonds, and, wherein the chain may additionally comprise up to three carbon-carbon triple bonds;

L¹ and L² each independently represent hydrogen, Ci_-6 alkyl or C_3-6 cycloalkyl;

L³ and L⁴ each independently represent hydrogen, C_1-6 alkyl or C₃-₆ cycloalkyl, wherein C_1-6 alkyl and C_3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and ^* denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R¹ and R³, and ^** denotes the point of attachment to the group NR⁹R¹⁰;

In the group (a):

Ar¹ is a phenyl group; R⁶ is a hydrogen atom; n and m are 0;

In the group (b):

R^8a and R^8b are both a phenyl group; or, R^8a and R^8b are both a thienyl group, or R¹ is a phenyl group and R is a cycloalkyl group, such as cyclopentyl or cyclohexyl; R is -OH or CrCβ-alkyI (especially methyl or ethyl); In a further embodiment, R is -OH;

In the group (c):

Ar² is a phenyl ring Q is an oxygen atom

R^8c is hydrogen, C_1-6 alkyl (especially methyl) or -OH; R⁹ is a hydrogen atom or CrC₆-alkyl;

R¹⁰ is an aryKCVCe-alkyl)-, or heteroaryl(Ci-C₆-alkyl) group, selected from the group

Conveniently, the present invention provides compounds of formula (Ia) wherein R¹ is Ci-C₆-alkyl; R² is a group -Z-NR⁹R¹⁰; and R³ is a lone pair.

Conveniently, the present invention provides compoinds of formula (Ia) wherein R³ is methyl, so that the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge.

More conveniently, the present invention provides compoinds of formula (Ia) wherein R¹ and R³ are each methyl, so that the nitrogen atom to which they attached is a quaternary nitrogen and carries a positive charge.

Conveniently, the present invention provides compounds of formula (Ia) wherein R¹⁰ is a group selected from:

More conveniently, the present invention provides compounds of formula (Ia) wherein R¹⁰ is:

Compounds of the invention exist in either the syn- or anti- forms;

s^~ anti-

Compounds of the invention also exist with the group -AR⁴ in either the exo or endo orientation;

endo- exo-

Currently it is preferred that the compounds of the invention be predominantly in the anti-endo configuration.

anti-, endo-

Compounds of the invention can also exist as optical isomers since substituted bicyclic ring systems can lack a plane of symmetry. The absolute configuration of the molecule can be defined using Cahn-lngold-Prelog rules to assign the R or S designation to each position. To avoid confusion the ring numbering used below is employed.

However, compounds of the invention include racemates, single enantiomers and mixtures of the enantiomers in any ratio, since all such forms have muscarinic M3 receptor modulating activity to varying extents.

A preferred class of compounds of the invention consists of compounds of formula (Ia) wherein the non-aromatic nitrogen shown in formula (Ia) is a tertiary nitrogen.

Another preferred class of compounds of the invention consists of quaternary ammonium salts of formula (Ia) wherein the non-aromatic nitrogen shown in formula (Ia) is quaternary nitrogen, carrying a positive charge. Compounds of the invention may be useful in the treatment or prevention of diseases in which activation of muscarinic receptors are implicated, for example the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'wheezy-infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy, pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis); gastrointestinal-tract disorders such as irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders including neurogenic pollakisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria; motion sickness; and cardiovascular disorders such as vagally induced sinus bradycardia.

For treatment of respiratory conditions, administration by inhalation will often be preferred, and in such cases administration of compounds (Ia) which are quaternary ammonium salts will often be preferred. In many cases, the duration of action of quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose. For treatment of gastrointestinal-tract disorders and cardiovascular disorders, administration by the parenteral route, usually the oral route, may be preferred.

Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.

Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is implicated. Terminology

Unless otherwise qualified in the context in which they are used herein, the following terms have the following meanings:

"Acyl" means a -CO-alkyl group in which the alkyl group is as described herein. Exemplary acyl groups include -COCH₃ and -COCH(CH₃)₂.

"Acylamino" means a -NR-acyl group in which R and acyl are as described herein. Exemplary acylamino groups include -NHCOCH₃ and -N(CH₃)COCH₃.

"Alkoxy" and "alkyloxy" means an -O-alkyl group in which alkyl is as described below. Exemplary alkoxy groups include methoxy (-OCH₃) and ethoxy (-OC₂H₅). "Alkoxycarbonyl" means a -COO-alkyl group in which alkyl is as defined below. Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.

"Alkyl" as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain. Exemplary alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl.

"Alkenyl" as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably 2 to 6, carbon atoms and one carbon-carbon double bond in the chain. Exemplary alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl. "Alkynyl" as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain. Exemplary alkenyl groups include ethynyl, 1- propynyl, and 2-propynyl.

"Alkylamino" means a -NH-alkyl group in which alkyl is as defined above. Exemplary alkylamino groups include methylamino and ethylamino.

"Alkylene means an -alkyl- group in which alkyl is as defined previously. Exemplary alkylene groups include -CH₂-, -(CH₂)₂- and -C(CH₃)HCH₂-.

"Alkenylene" means an -alkenyl- group in which alkenyl is as defined previously. Exemplary alkenylene groups include -CH=CH-, -CH=CHCH₂-, and - CH₂CH=CH-.

"Alkynylene" means an -alkynyl- group in which alkynyl is as defined previously. Exemplary alkenylene groups include -CC-, -CCCH₂-, and -CH₂CC-.

"Alkylsulfinyl" means a -SO-alkyl group in which alkyl is as defined above. Exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl. "Alkylsulfonyl" means a -SO₂-alkyl group in which alkyl is as defined above.

Exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl. "Alkylthio" means a -S-alkyl group in which alkyl is as defined above. Exemplary alkylthio groups include methylthio and ethylthio.

"Aminoacyl" means a -CO-NRR group in which R is as herein described. Exemplary aminoacyl groups include -CONH₂ and -CONHCH₃. "Aminoalkyl" means an alkyl-NH₂ group in which alkyl is as previously described. Exemplary aminoalkyl groups include -CH₂NH₂.

"Aminosulfonyl" means a -SO₂-NRR group in which R is as herein described. Exemplary aminosulfonyl groups include -SO₂NH₂ and -SO₂NHCH₃.

"Aryl" as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group may be substituted by one or more substituent groups.

"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C_{1 4} alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl. The aryl part thereof may be substituted by one or more substituent groups.

"Arylalkyloxy" means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a C_{1 4} alkyl moiety. Exemplary arylalkyl groups include benzyloxy. The aryl part thereof may be substituted by one or more substituent groups.

"Aryl-fused-heterocycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein. Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benzodioxolyl, dihydrobenzofuranyl and isoindolonyl. The aryl and heterocycloalkyl rings may each be substituted by one or more substituent groups. The aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.

"Aryloxy" means an -O-aryl group in which aryl is described above. Exemplary aryloxy groups include phenoxy. The aryl part thereof may be substituted by one or more substituent groups.

"Cyclic amine" is a special case of "Heterocycloalkyl" or "heterocyclic" and means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein). Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and Λ/-methylpiperazine. The cyclic amine group may be substituted by one or more substituent groups.

"Cycloalkyl" means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group may be substituted by one or more substituent groups.

"Dialkylamino" means a -N(alkyl)2 group in which alkyl is as defined above.

Exemplary dialkylamino groups include dimethylamino and diethylamino. "Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.

"Haloalkoxy" means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy. "Haloalkyl" means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl.

"Heteroaryl" as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups. The heteroaryl group may be may be substituted by one or more substituent groups. The heteroaryl group may be attached to the remainder of the compound of the invention by any available carbon or nitrogen atom.

"Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridyl methyl. The heteroaryl part thereof may be substituted by one or more substituent groups.

"Heteroarylalkyloxy" means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Preferred heteroarylalkyloxy groups contain a lower alkyl moiety. Exemplary heteroarylalkyloxy groups include pyridylmethyloxy. The hetroaryl part thereof may be substituted by one or more substituent groups. "Heteroaryloxy" means a heteroaryloxy- group in which the heteroaryl is as previously described. Exemplary heteroaryloxy groups include pyridyloxy. The heteroaryl part thereof may be substituted by one or more substituent groups.

"Heterocycloalkyl" or "heterocyclic" means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR and CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl). The heterocycloalkyl group may be be substituted by one or more substituents groups. The heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.

"Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (propyl or /sopropyl) or butyl (butyl, /sobutyl or tert- butyi). "Sulfonyl" means a -SO₂-alkyl group in which alkyl is as described herein.

Exemplary sulfonyl groups include methanesulfonyl.

"Sulfonylamino" means a -NR-sulfonyl group in which R and sulfonyl are as described herein. Exemplary sulfonylamino groups include -NHSO₂CH₃. R means alkyl, aryl, or heteroaryl as described herein. "Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts, pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable quaternary ammonium salts. For example (i) where a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, Λ/-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) where a compound of the invention contains a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that may be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, napadisylates (naphthalene-1 ,5-disulfonates or naphthalene-1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2-disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), maleates, fumarates, succinates and the like; (iii) where a compound contains a quaternary ammonium group acceptable counter- ions may be, for example, chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), napadisylates (naphthalene-1 ,5- disulfonates or naphthalene-1 -(sulfonic acid)-5-sulfonates), edisyiates (ethane-1 ,2- disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), isethionates (2- hydroxyethylsulfonates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, fumarates, xinafoates, p-acetamidobenzoates, succinates and the like; wherein the number of quaternary ammonium species balances the pharmaceutically acceptable counter-ion D- such that compound of formula (I) has no net charge.

It will be understood that, as used herein, references to the compounds of the invention are meant to also include the pharmaceutically acceptable salts.

"Prodrug" refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. For example an ester prodrug of a compound of the invention containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of the invention containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates, isothionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates. As another example an ester prodrug of a compound of the invention containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.

It will be understood that, as used in herein, references to the compounds of the invention are meant to also include the prodrug forms.

"Saturated" pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds. "Optionally substituted" means optionally substituted with up to four susbtituents. Optional substituent groups include acyl (e.g. -COCHJ, alkoxy (e.g., -

OCH₃), alkoxycarbonyl (e.g. -COOCH₃), alkylamino (e.g. -NHCH₃), alkylsulfinyi (e.g. -SOCH₃), alkylsulfonyl (e.g. -SO₂CH₃), alkylthio (e.g. -SCH₃), -NH₂, aminoacyl (e.g. - CON(CHs)₂), aminoalkyl (e.g. -CH₂NH₂), arylalkyl (e.g. -CH₂Ph or -CH₂-CH₂-Ph), cyano, dialkylamino (e.g. -N(CH₃)J, halo, haloalkoxy (e.g. -OCF₃ or -OCHF₂), haloalkyl (e.g. -CF₃), alkyl (e.g. -CH₃Or -CH₂CH₃), -OH, -NO₂, aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (e.g. -CONH₂, -CONHCH₃), aminosulfonyl (e.g. -SO₂NH₂, -SO₂NHCH₃), acylamino (e.g. -NHCOCH₃), sulfonylamino (e.g. -NHSO₂CH₃), heteroaryl alkyl, cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy.

Alkyl, alkoxy, alkylene, alkenylene or alkynylene radicals may be optionally substituted. Optional substituent groups in the foregoing radicals include alkoxy (e.g., -OCHJ, alkylamino (e.g. -NHCHJ, alkylsulfinyl (e.g. -SOCHJ, alkylsulfonyl (e.g. -

SO₂CH₃), alkylthio (e.g. -SCH₃), -NH₂, aminoalkyl (e.g. -CH₂NH₂), arylalkyl (e.g. -CH₂Ph Or -CH₂-CH₂-Ph), cyano, dialkylamino (e.g. -N(CH₃)₂), halo, haloalkoxy (e.g. -OCF₀ or -OCHFJ₁ haloalkyl (e.g. -CFJ, alkyl (e.g. -CH or -CH CHJ, -OH, and -NO₂.

Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and frans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).

Examples of compounds of the invention include those of the Examples herein.

Convenient compounds of the invention include: a/7?/-Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy- 2-0X0-1 , 2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1]hept- 2-yl ester; anf/-9/-/-Xanthene-9-carboxylic acid (1 S,2R)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1 ,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1]hept-2-yl ester; and antf-Biphenyl-2-yl-carbamic acid-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-dihydro- quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1 ]hept-2-yl ester.

The present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention. Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.

Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Accordingly the invention includes a combination of an agent of the invention as hereinbefore described with one or more anti-inflammatory, bronchodilator, antihistamine, decongestant or anti-tussive agents, said agents of the invention hereinbefore described and said combination agents existing in the same or different pharmaceutical compositions, administered separately or simultaneously. Preferred combinations would have two or three different pharmaceutical compositions.

Suitable therapeutic agents for a combination therapy with compounds of the invention include: One or more other bronchodilators such as PDE3 inhibitors;

Methyl xanthines such as theophylline;

A corticosteroid, for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266,

WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;

A non-steroidal glucocorticoid receptor agonist;

A leukotriene modulator, for example montelukast, zafirlukast or pranlukast; protease inhibitors, such as inhibitors of matrix metalloprotease for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333; Human neutrophil elastase inhibitors, such as sivelestat and those described in

WO04/043942, WO05/021509, WO05/021512, WO05/026123, WO05/026124,

WO04/024700, WO04/024701 , WO04/020410, WO04/020412, WO05/080372,

WO05/082863, WO05/082864, WO03/053930;

Phosphodiesterase-4 (PDE4) inhibitors, for example roflumilast, arofylline, cilomilast, ONO-6126 or lC-485;

Phosphodiesterase-7 inhibitors;

An antitussive agent, such as codeine or dextramorphan;

Kinase inhibitors, particularly P38 MAPKinase inhibitors;

P2X7 anatgonists; iNOS inhibitors;

A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen; A dopamine receptor antagonist;

TNF-α inhibitors, for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel;

A2a agonists such as those described in EP1052264 and EP1241176; A2b antagonists such as those described in WO2002/42298;

Modulators of chemokine receptor function, for example antagonists of CCR1 , CCR2,

CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB-

265610, SB-225002, MCP-1 (9-76), RS-504393, MLN-1202, INCB-3284;

Compounds which modulate the action of prostanoid receptors, for example a PGD₂ (DP1 or CRTH2), or a thromboxane A₂ antagonist eg ramatroban;

Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterleukin 10 agonists, such as llodecakin;

HMG-CoA reductase inhibitors (statins); for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;

Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-

333, MSI-1956, gefitinib;

Antiinfective agents (antibiotic or antiviral), and antiallergic drugs including, but not limited to, antihistamines.

The weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route. Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.

The magnitude of prophylactic or therapeutic dose of a compound of the invention will, of course, vary depending upon a range of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment. In general, the daily dose range for inhalation will lie within the range of from about 0.1 μg to about 10 mg per kg body weight of a human, preferably 0.1 μg to about 0.5 mg per kg, and more preferably 0.1 μg to 50μg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. Compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions. The composition may contain 0.01-99% by weight of active compound. Preferably, a unit dose comprises the active compound in an amount of 1 μg to 10 mg. For oral administration suitable doses are 10μg per kg to 100mg per kg, preferably 40μg per kg to 4 mg per kg.

Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids, and salts of quaternary ammonium compounds with pharmaceutically acceptable counter-ions.

For delivery by inhalation, the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation.

By way of example, a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI). Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI₂F₂) and HFA-152 (C₂H₄F₂) and isobutane.

In a preferred embodiment of the invention, a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI). Many types of DPI are known.

Microparticles for delivery by administration may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung. Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, an example is: Compound of the invention 24 mg / canister

Lecithin, NF Liq. Cone. 1.2 mg / canister

Trichlorofluoromethane, NF 4.025 g / canister Dichlorodifluoromethane, NF 12.15 g / canister.

The active compounds may be dosed as described depending on the inhaler system used. In addition to the active compounds, the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®,

Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321). Additionally, compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents. Methods of Synthesis

The invention further provides a process for the preparation of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof as defined above which comprises:

(a) when L¹ represents hydrogen, reacting a compound of formula (II)

wherein LG¹ represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate, and L, L², L³, L⁴, R¹, R⁴,and A are as defined in formula (I), with a compound of formula (III), or a suitable salt thereof such as a hydrobromide, acetate or hydrochloride salt

wherein Ar is as defined in formula (I) and P¹ is hydrogen or a protective group such as te/t-butyldimethyl silyl in the presence of a base such as potassium carbonate, triethylamine or diisopropylethylamine, followed by removal of the protective group (e.g. using a hydrofluoric acid-pyridine complex); or

(b)when L¹ represents hydrogen, reacting a compound of formula (IV), or a suitable salt thereof

wherein L, L², L³, L⁴, R¹, R⁴ and A are as defined in formula (I), with a compound of formula (III) or a suitable salt thereof in the presence of a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst; or (c) when L¹ represents hydrogen, reacting a compound of formula (V)

wherein LG¹ represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate, P² represents a protective group (e.g. tert-butylcarbonyl) and L, L², L³, L⁴, R⁴ and A are as defined in formula (I), with a compound of formula (III), or a suitable salt thereof (e.g. hydrobromide, hydrochloride salt or acetate), in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine) followed by removal of the protective group (e.g. treatment with hydrochloric or trifluoroacetic acid); or

(d) when L¹ represents hydrogen, reacting a compound of formula (Vl)

wherein L, L², L³, L⁴, R⁴ and A are as defined in formula (I), P² represents a protective group (e.g. tert-butylcarbonyl) with a compound of formula (III), or a suitable salt thereof (e.g. hydrobromide, hydrochloride salt or acetate), in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst), followed by removal of the protective group (e.g. treatment with hydrochloric or trifluoroacetic acid); or

(e) when R¹ does not represent hydrogen, reacting a compound of formula (VII), or a suitable salt thereof

wherein L, L¹, L², L³, L⁴, R⁴ and A are as defined in formula (I), P³ represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl) with a compound of formula (VIII), or a suitable salt thereof,

wherein Ar is as defined in formula (I), LG² represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate) and, P¹ is as defined in compound of formula (III) in the presence of a base (e.g. when P³ is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P³ is 3- nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. using hydrofluoric acid-pyridine complex, thiophenol, thioacetic acid); or with a compound of formula (IX), or a suitable salt thereof,

wherein Ar is as defined in formula (I) in the presence of a base (e.g. when P³ is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P³ is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or with a compound of formula (X), or a suitable salt thereof,

wherein Ar is as defined in formula (I), LG² represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate) in the presence of a base (e.g. when P³ is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P³ is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by reduction of the ketone (e.g. using sodium borohydride or a borane/chiral catalyst complex), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or (f) When R¹ represents hydrogen, reacting a compound of formula (Xl)

wherein L, L¹, L², L³, L⁴, A and R⁴ are as defined in formula (I)₁ P² represents a protective group (e.g. tert-butylcarbonyl), P³ represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl), with a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g. when P³ is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and when P³ is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. using trifluoroacetic acid, thiophenol, thioacetic acid); or

(g) when L³ and L⁴ each represents hydrogen, reacting a compound of formula (XII)

wherein Ar, L, L¹, and L² are as defined in formula (I), P¹ is as defined in compound of formula (III), P³ represents a protective group (e.g. terf-butylcarbonyl or 3- nitrophenylsulfonyl) with a compound of formula (XIII), or a suitable salt thereof,

wherein A, R⁴ and R¹ are as defined in formula (I), in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst), followed by removal of the protective groups (e.g. treatment with hydrochloric or trifluoroacetic acid thiophenol, thioacetic acid); or (h) when one or both of L³ and L⁴ represents hydrogen, reacting a compound of formula (XIV)

wherein Ar, L, L¹, and L² are as defined in formula (I), P¹ is as defined in compound of formula (111), P³ represents a protective group (e.g. fe/t-butylcarbonyl or 3- nitrophenylsulfonoyl), LG³ represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate), with a compound of formula (XIII) or a suitable salt thereof, in the presence of a base (e.g. potassium carbonate, triethylamine, diisopropylethylamine), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or

(i) when L¹ and L² each represents hydrogen and R¹ does not represent hydrogen, reacting a compound of formula (XV), or a suitable salt thereof,

wherein Ar₁ L, L³, L⁴, A, R¹ and R⁴ are as defined in formula (I) and P¹ is as defined i formula (III) with a suitable reducing agent (e.g. borane tetrahydrofuran complex), followed by removal of the protective group (e.g. using hydrofluoric acid-pyridine complex); or,

(j) when L¹ and L² each represents hydrogen and R¹ represents hydrogen, reacting a compound of formula (XVI)

wherein Ar, L, L³, L⁴, A and R⁴ are as defined in formula (I) and P² is as defined in compound of formula (Xl) with a suitable reducing agent (e.g. borane tetrahydrofuran complex), followed by removal of the protective group (e.g. using hydrofluoric acid- pyridine complex); and optionally after (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j) carrying out one or more of the following:

• converting the compound obtained to a further compound of the invention

• forming a pharmaceutically acceptable salt of the compound.

In process variants (a), (c), (e), (f) and (h), the reaction may conveniently be carried out in an organic solvent such as Λ/,Λ/-dimethylformamide, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140°C. In process variants (b), (d) and (g), the reaction may conveniently be carried out in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid N- methylpyrolidinone, or Λ/,Λ/-dimethylformamide containing up to 10%w of water and acetic acid.

In process variants (i) and (j), the reaction may conveniently be carried out in an organic solvent such as tetrahydrofuran, at a temperature, for example, in the range from 0 to 80⁰C.

Compounds of formula (II) may be prepared by reacting a compound of formula (XVII), or a suitable salt thereof,

wherein L, L³, L⁴, R¹, R⁴ and A are as defined in formula (II), with a compound of formula (XVIII)

L— Mt _(χvm) wherein L² is as defined in formula (II) and Mt represents a metal such as lithium or magnesium, or aluminium or boron (e.g. methyllithium, methylmagnesium bromide, lithium aluminium hydride, sodium borohydhde) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O⁰C, followed by conversion of the resulting hydroxyl group into a suitable leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate).

Compounds of formula (IV) may be prepared by reacting a compound of formula (XVII) with a compound of formula (XVIII) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O⁰C, followed by oxidation of the resulting hydroxyl group with a suitable oxidating agent (e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate) in an organic solvent such as dichloromethane, Λ/,Λ/-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 6O⁰C. Compounds of formula (V) may be prepared by reacting a compound of formula (XIX)

wherein P², L, L³, L⁴, A and R⁴ are as defined in formula (V), with a compound of formula (XVIII) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O⁰C, followed by conversion of the resulting hydroxyl group into a suitable leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate).

Compounds of formula (Vl) may be prepared by reacting a compound of formula (XVIII) with a compound of formula (XIX), followed by oxidation of the resulting hydroxyl group with a suitable oxidating agent (e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate) in an organic solvent such as dichloromethane, Λ/,Λ/-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 60⁰C. Compounds of formula (VII) in which L¹ represents hydrogen and L, L¹, L², L³, L⁴, R⁴ and A are as defined in formula (VII) may be prepared by

(a) reacting a compound of formula (II) with sodium azide, in an organic solvent for example, tetrahydrofuran, Λ/,/V-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 85⁰C, followed by reduction of the resulting azido compound using a suitable reducing agent (e.g. triphenylphosphine) in an organic solvent for example, tetrahydrofuran and water, and eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine); or,

(b) reacting a compound of formula (IV) with an amine (e.g. benzylamine, σ-methyl benzylamine, 4-methoxybenzylamine or 2,4-methoxybenzylamine) followed by reduction of the resulting imine using a suitable reducing agent (e.g. sodium cyanoborohydride or sodium triacetoxyborohydride) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, Λ/-methylpyrolidinone or N, N- dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the resulting benzyl protective group using the appropriate reagent (e.g. hydrogen and a suitable catalyst (Palladium on carbon or palladium hydroxide), 2,3- dichloro-5,6-dicyanobenzoquinone (DDQ), or ammonium cerium nitrate (CAN)) in an organic solvent, for example, ethanol, methanol, tetrahydrofuran, dichloromethane, acetonitrile, water, or a mixture thereof, at a temperature ranging from 25 to 8O⁰C, and eventually followed by protection of the resulting amine (e.g. treatment with 3- nitrophenylsulfonyl chloride in the presence of a base such as pyridine);

Compounds of formula (VII) in which L, L¹, L², L³, L⁴, R⁴ and A are as defined in formula (VII) may be prepared by reacting a compound of formula (XX)

wherein LG⁴ is a leaving group (e.g. hydroxyl or chloride), L, L¹, L², L³, L⁴, A, R⁴ and R¹ are as defined in formula (VII), with reagents such as, when LG⁴ is hydroxyl, diphenylphosphonic azide, in a presence of an amine (e.g. triethylamine), in an organic solvent, for example, terf-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 100⁰C, or when LG⁴ is chloride, sodium azide, in an organic solvent, for example, ether, tert-butanol, tetrahydrofuran, water, or a mixture thereof, at a temperature ranging from 25 to 100⁰C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine). Compounds of formula (III), (VIII), (IX) and (X) are known in the literature or may be prepared using known techniques.

Compounds of formula (Xl) in which L¹ represents hydrogen may be prepared by (a) reacting a compound of formula (V) with sodium azide in an organic solvent, for example, tetrahydrofuran, Λ/,Λ/-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 85⁰C, followed by reduction of the resulting azido compound using a suitable reducing agent (e.g. triphenylphosphine or hydrogen) in an organic solvent for example, tetrahydrofuran and water, eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine); or

(b) reacting a compound of formula (Vl) with an amine (e.g. benzylamine, a- methyl benzylamine, 4-methoxybenzyl amine or 2,4-methoxybenzyl amine), followed by reduction of the resulting imine using a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid Λ/-methylpyrolidinone, or N, N- dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the resulting benzyl protective group using the appropriate reagent (e.g. hydrogen and a suitable catalyst (Palladium on carbon or palladium hydroxide), 2,3- dichloro-5,6-dicyanobenzoquinone (DDQ), or ammonium cerium nitrate (CAN)) in an organic solvent, for example, ethanol, methanol, tetrahydrofuran, dichloromethane, acetonitrile, water, or a mixture thereof, at a temperature ranging from 25 to 80⁰C, eventually followed by protection of the resulting amine (e.g. treatment with 3- nitrophenylsulfonyl chloride in the presence of a base such as pyridine).

Compounds of formula (Xl) may be prepared by reacting a compound of formula (XXI)

wherein L⁴ is a leaving group (e.g. hydroxyl or chloride), L, L¹, L², L³, L⁴, A, R⁴ and P² are as defined in formula (Xl), with reagents such as, when LG⁴ is hydroxyl, diphenylphosphonic azide, in a presence of an amine (e.g. triethylamine), in an organic solvent, for example, te/t-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 100⁰C, or when LG⁴ is chloride, sodium azide, in an organic solvent, for example, ether, terf-butanol, tetrahydrofuran, water, or a mixture thereof, at a temperature ranging from 25 to 100⁰C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine). Compounds of formula (XII) can be prepared by (a) reacting a compound of formula (XXII)

wherein P⁵ is hydrogen or a protective group (e.g. tert-butyidimethylsilyl, tetrahydropyran) and L, L¹ and L² are as defined in formula (XII), with a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine when P³ is hydrogen and sodium hydride or lithium di-/so-propylamide when P³ is 3-nitrophenylsulfonyl) in an organic solvent such as Λ/,Λ/-dimethylformamide, Λ/-methylpyrolidinone, tetrahydrofuran, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140⁰C. When reacting with compound of formula (X), this is followed by reduction of the ketone (e.g. using sodium borohydride or a borane/chiral catalyst complex). Appropriate selective removal of the protective group (e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol) and oxidation of the resulting alcohol into the corresponding aldehyde with a suitable oxidating agent (pyridinium chlorochromate, Dess-martin reagent or Swern reagent) lead to compound of formula (XII); or (b) reacting a compound of formula (XXIII)

(XXlII) wherein P⁶ and P⁷ represent an acyclic or cyclic carbonyl protective group (e.g. dimetoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane) and L, L¹, L², and P³ are as defined in formula (XII), with a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine when P³ is hydrogen and sodium hydride or lithium di-/sσ- propylamide when P³ is 3-nitrophenylsulfonyl) in an organic solvent such as N, N- dimethylformamide, Λ/-methylpyrolidinone, tetrahydrofuran, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140⁰C. When reacting with compound of formula (X), this is followed by reduction of the ketone (e.g. using sodium borohydride or a borane/chiral catalyst complex). Removal of the protective group (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol) lead to compound of formula (XlI); or (c) when L¹ represents hydrogen, reacting a compound of formula (XXIV)

wherein P⁵ is hydrogen or a protective group (e.g. tert-butyldimethylsilyl, tetrahydropyran) and, L and L² are as defined in formula (XII), with a compound of formula (III), or a suitable salt thereof, in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, N- methypyrolidinone or Λ/,Λ/-dimethylformamide containing up to 10%w of water and acetic acid, followed by appropriate selective removal of the protective group (e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol) and oxidation of the resulting alcohol into the corresponding aldehyde with a suitable oxidating agent (pyridinium chlorochromate, Dess-Martin reagent or Swern reagent); or (d) when R¹ represents hydrogen, reacting a compound of formula (XXV)

wherein P⁶ and P⁷ represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane) and, L and L² are as defined in formula (XII), with a compound of formula (III), or a suitable salt thereof, in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, Λ/-methypyrolidinone or A/,Λ/-dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the protective group (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol).

Compounds of formula (XIV) can be prepared by converting compound of formula (XII), or a precursor to compound of formula (XlI) as decribed above, chosing an appropriate sequence of reactions such as, for example, reduction of an aldehyde to an alcohol (e.g. sodium borohydride), appropriate selective removal of the protective group (e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol) and conversion of an alcohol into a suitable leaving group (e.g. halogen, mesylate, tosylate); or,

Compounds of formula (XV) and (XVI) can be prepared by similar methods by reacting a compound of formula (XXVI)

wherein L, L³, L⁴, A and R⁴ are as defined in formula (XV), P⁸ represents either R¹ as defined in compound of formula (XV) or P² as defined in compound of formula (XVI) and LG⁶ represent hydroxyl or a leaving group (e.g. chloride) with a compound of formula (III), or a suitable salt thereof.

When LG⁶ represents hydroxyl, the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, Λ/,Λ/-dimethylformamide or dichloromethane, at a temperature, for example in the range from 0 to 6O⁰C, When LG⁶ represents chloride, the reaction is conveniently carried out in the presence of a base, for example, triethylamine or diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25⁰C.

Compounds of formula (XIII) in which A is an oxygen atom may be prepared according to the following schemes

(Xlll-b) (XXXVIII)

Scheme 1 wherein R⁴ is as defined in compound of formula (I), when R¹ does not represent hydrogen, P⁹ represents R¹; when R¹ represents hydrogen then P⁹ represents an appropriate nitrogen protecting group, such as te/t-butoxycarbonyl or benzyl, - for compound of formula (VII), P⁹ represents R¹, P¹⁰ represents

wherein L, L¹, L², L³, L⁴ and P³ are as defined in compound of formula (VII); - for compound of formula (Xl), P⁹ represents P², P¹⁰ represents

wherein L, L¹, L², L³, L⁴, P² and P³ are as defined in compound of formula (Xl);

- for compound of formula (XIII), P⁹ and P¹⁰ represents represents an appropriate nitrogen protecting group, such as tert-butoxycarbonyl, followed by suitable deprotection (e.g. trifluoroacetic acid acid);

- for compound of formula (XVII), P⁹ represents R¹, P¹⁰ represents

wherein L, L³, and L⁴ are as defined in compound of formula (XVII), wherein P and P represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane), followed by suitable deprotection (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol);

- for compound of formula (XIX), P⁹ represents P², P¹⁰ represents

wherein L, L³, and L⁴ are as defined in compound of formula (XIX), wherein P¹¹ and P¹² represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane), followed by suitable deprotection (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol);

- for compound of formula (XX), P⁹ represents R¹, P¹⁰ represents

wherein L, L¹, L², L³, and L⁴ are as defined in compound of formula (XX), wherein P¹⁴ represent an acid protective group (e.g. methyl, ethyl or tert-butyl), followed by suitable deprotection (e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid);

- for compound of formula (XXI), P⁹ represents P², P¹⁰ represents

wherein L, L¹, L², L³, and L⁴ are as defined in compound of formula (XXI), wherein P¹⁴ represent an acid protective group (e.g. methyl, ethyl or tert-butyl), followed by suitable deprotection (e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid);

- for compound of formula (XXVI), P⁹ represents P⁸, P¹⁰ represents

Compounds of formula (Xlll-a) wherein W is the group of formula (a), and R³⁸, Ar¹ and R⁸⁰ are as defined above for formula (I) may be prepared from compounds of formula (XXVII) wherein R⁹ and R¹⁰ are as defined above, by reaction with a compound of formula (XXVIII):

(XXVIII) wherein Ar¹, R⁸⁰ and n are as defined for formula (I). The reaction may take place in a range of non-nucleophilic organic solvents such as DMF or toluene at a range of temperatures, preferably between 0⁰C and the reflux temperature of the solvent.

Compounds of formula ((XXVIII) are well known in the art and are readily available or can be prepared by known methods.

Compounds of formula (Xlll-a) in which R⁴ is the group of formula (b) as defined above, may be prepared from compounds of formula (XXVII) by reaction with a compound of formula (XXIX):

wherein R^8a, R^8b, and R^8c are as defined for formula (I) and LG⁷ is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group. The reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF or dichloromethane at a range of temperatures, preferably between 0 ⁰C and the reflux temperature of the solvent.

Compounds of formula (XXIX) wherein R^8a, R^8b, and R^8c are as defined for formula (I) and LG⁷ is an O-alkyl, halogen or 1-imidazolyl group can be prepared from compounds of formula (XXX) by known methods.

Compounds of formula (XXX) are well known in the art and are readily available or can be prepared by known methods such as those described in WO01/04118

Compounds of formula (Xlll-a) in which R⁴ is the group of formula (c) as defined above, may be prepared from compounds of formula (XXVII) by reaction with a compound of formula (XXXI):

wherein Ar² and R^8c are as defined for formula (I) and LG⁸ is a leaving group, for example, an O-alkyl, halogen or 1 -imidazolyl group. The reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF or dichloromethane at a range of temperatures, preferably between 0 °C and the reflux temperature of the solvent.

(XXXII)

Compounds of formula (XXXI)) can be prepared from compounds of formula (XXXII) by known methods.

Compounds of formula (XXXII) are well known in the art and are readily available or can be prepared by known methods.

Compounds of formula (Xlll-a) in which W is the group of formula (d) as defined above and R^8c is -OH, may be prepared from compounds of formula (XXVII) by reaction with a compound of formula (XXXIII):

(XXXIII)

The reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF, preferably DMSO at a range of temperatures, preferably between 0 ⁰C and the reflux temperature of the solvent.

Compounds of formula (XXXIII) are well known in the art and are readily available or can be prepared by known methods. Compounds of formula (XXVII) can be prepared from compounds of formula (XXXIV- a) by reaction with a suitable reducing agent, preferably a bulky reducing agent such as LiAIH(O¹Bu)₃. The reaction is carried out in a polar organic solvent preferably THF at a range of temperatures, preferably from -78 ⁰C up to the reflux temperature of the solvent.

Compounds of formula (XXXIV-a) can be prepared from compounds of formula (XXXV-a) by reaction with a tin reagent, preferably Bu₃SnH and a radical initiator, preferably AIBN. The reaction can be performed in a range of solvents, preferably toluene, at a range of temperatures, preferably between ambient temperature and the reflux temperature of the solvent.

Compounds of formula (XXXV-a) can be prepared from compounds of formula (XXXVI) by reaction with an amine formula (XXXVII)):

R⁹R¹⁰NH (XXXVII)

The reaction is performed in a range of solvents, preferably THF/DCM at a range of temperatures, preferably between 0 and 100 ⁰C.

Compounds of formula (XXXVI) are known in the art: J. Chem. Soc. Perkin Trans I (1975) 1767-1773; Synthesis (1997), 155-166.

Compounds of formula (XXXVII) are well known in the art and can be prepared by known methods, or are commercially available, or may be prepared by methods described above.

Compounds of formula (Xlll-b) may be prepared from compounds of formula (XXXVIII) by reaction with a tin reagent, preferably Bu₃SnH and a radical initiator, preferably AIBN. The reaction can be performed in a range of solvents, preferably toluene, at a range of temperatures, preferably between ambient temperature and the reflux temperature of the solvent.

Compounds of formula (XXXVIII) may be prepared from compounds of formula (XXXIX) by reaction with a brominating agent, preferably triphenylphosphine in carbon tetrabromide as solvent. Compounds of formula (XXXIX) can be prepared from compounds of formula (XL) by reaction with a suitable reducing agent, preferably sodium borohydride. The reaction is carried out in a polar organic solvent preferably THF at a range of temperatures, preferably from -78⁰C up to the reflux temperature of the solvent.

Compounds of formula (XL) can be prepared from compounds of formula (XLI) by analogous methods to those used to prepare compounds of formula (Xlll-a) from compounds of formula (XXVII).

Compounds of formula (XLI) can be prepared from compounds of formula (XLII):

by reaction with an amine of formula (XXXVII). The reaction is performed in a range of solvents, preferably THF/DCM at a range of temperatures, preferably between 0 and 100⁰C.

Compounds of formula (XLII) are described in GB2075503.

(XLIII) (XLIV)

Scheme 2 The preparation of compounds of formula (XLIII) wherein A is a group NR³⁷, W is a group (b) and R¹ and R² are all as described in formula (I) above, and and R³ is OH, is outlined in Scheme 2.

Compounds of Formula (XLIII) may be prepared from compounds of Formula (XLIV) by treatment with an organometallic reagent of Formula (XLV);

R² - Mt (XLV) Where Mt is a metal species such as lithium or Mg-halide, especially a Grignard reagent in a suitable inert solvent such as THF or diethyl ether at a temperature between -78° and the reflux temperature of the solvent, preferably between 0° and ambient temperature. Compounds of Formula (XLV) are known in the art or may be prepared according to known methods.

Compounds of Formula (XLIV) may be prepared from compounds of Formula (XLVI) by treatment with a compound of formula (XLVII);

(XLVII) Wherein R¹ is as described in formula (I) and LG⁹ is a leaving group, especially a halogen group, optionally in the presence of a suitable solvent such as dichloromethane, in the absence or presence of a base such as diisopropylethylamine. Compounds of formula (XLVII) are commercially available or readily prepared according to the literature.

Compounds of Formula (XLVI) may be prepared from compounds of Formula (XLVIII) by reduction of the oxime with a suitable reducing agent, such as a borohydride reagent, specifically NaBH₄ZNiCI₂ in a suitable solvent such as methanol at a suitable temperature, such as 20° C.

Compounds of Formula (XLVIII) may be prepared from compounds of Formula (XXXIV-a) by treatment with hydroxylamine or a salt thereof in the presence of a suitable solvent such as methanol, optionally in the presence of a base such as sodium acetate, at a temperature between 0° C and the reflux temperature of the solvent, preferably at ambient temperature. Compounds of formula (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV) and (XXVIII), (XXIX), (XXX) and (XXXI) are either commercially available, known in the literature, or can be readily prepare by those skilled in the art using one of the process described above or using known techniques.

Compounds of formula (Xlll-a) and (XIII-JD) exist in two enantiomeric forms which can be separated by chiral preparative HPLC using conditions know to those skilled in the art and exemplified below. Alternatively, as the absolute configuration of compounds (Xlll-a) and (Xlll-b) are dictated by the absolute configuration of compounds (XXXVI) and (XLII) respectively, and compounds (XXXVI) and (XLII) are known in the literature (see EP0074856A2) one skilled in the art will recognise that use of homochiral starting material will deliver homochiral product of defined stereochemistry.

When R¹⁰ in compounds of formula (I) or (Ia) is a group of formula

it will be recognised by those skilled in the art that a similar set of reactions as described above may be used, employing a compound of formula (Ilia) in place of a compound of formula (III), optionally suitably protected, or a suitable salt thereof such as a hydrobromide, hydrochloride or acetate salt

Compounds of formula (Ilia) are known in the art, for example J. Med. Chem.

1987, 30, 1166.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.

The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3^rd edition, T.W. Greene and P. G. M. Wuts, Wiley-lnterscience (1999).

Compounds of formula (I) or (Ia) can be converted into further compounds of formula (I) or (Ia) using standard procedures.

The present invention also comprises intermediate compounds having utility in the synthesis of the compounds of formula (1) and (Ia). In a first embodiment, such intermediate compounds are selected from the group including anf/-(1 S)-5-bromo-7- {[9-(tert-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}-bicyclo[2.2.1 ]heptan-2-one; a/?f/-(1 S)-7-{[9-(tert-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}- bicyclo[2.2.1]heptan-2-one; anf/-(1 S,2R)-7-{[9-(tert-butyl-dimethyl-silanyloxy)-nonyl]- methyl-amino}-bicyclo[2.2.1]heptan-2-ol; artf/-hydroxy~di-thiophen-2-yl-acetic acid (1 S,2R)-7-{[9-(tert-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}-bicyclo[2.2.1]hept- 2-yl ester; antf-hydroxy-di-thiophen^-yl-acetic acid (1 S,2R)-7-[(9-hydroxy-nonyl)- methyl-amino]-bicyclo[2.2.1]hept-2-yl ester; arrt/-hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-[methyl-(9-oxo-nonyl)-amino]-bicyclo[2.2.1]hept-2-yl ester; antf-hydroxy-di- thiophen-2-yl-acetic acid (1 S,2R)-7-({9-[(R)-2-(tert-butyl-dimethyl-silanyloxy)-2-(8- hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yI)-ethylamino]-nonyl}-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester; artf/-9H-Xanthene-9-carboxylic acid (1 S,2R)-7-{[9-(tert- butyl-dimethyl-siIanyloxy)-nonyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; (+/-)- anti-7-{[9-(tert-Butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}-bicyclo[2.2.1]heptan-2- ol, and (+/-)-an/v-Biphenyl-2-yl-carbamic acid-7-[(9-hydroxy-nonyl)-methyl-amino]- bicyclo[2.2.1]hept-2-yl ester.

In an alternative embodiment such intermediate compounds are selected from the group including anf/-9H-Xanthene-9-carboxylic acid (1 S,2R)-7-{[9-(tert-butyl-dimethyl- silanyloxy)-nonyl]-methyl-amino}-bicycIo[2.2.1]hept-2-yl ester; and (+/-)-anf/-Biphenyl- 2-yl-carbamic acid-7-[(9-hydroxy-nonyl)-methyl-amino]-bicyclo[2.2.1 ]hept-2-yl ester.

The compounds of formula (I) and (Ia) have activity as pharmaceuticals, in particular as dual adrenergic β2 receptor agonists and anticholinergic agents including muscarinic receptor (M1 , M2, and M3) antagonists, in particular M3 antagonists. Diseases and conditions which may be treated with the compounds of formula (I) or (Ia) and their pharmaceutically acceptable salts 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) or adenovirus; or eosinophilic esophagitis;

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; osteoporosis; 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;

1 1. 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.

Thus, the present invention provides a compound of formula (Ia) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof 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.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

The invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

In particular, the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg).

Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) or (Ia) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) or (Ia) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler^®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally. Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 μm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C₈-C_2O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound. Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler^® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.

For oral administration the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above- mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions. The invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 the following agents: nonsteroidal 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-alLI6R) or T-Lymphocytes (CTLA4-lg, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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-11) 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, ablukast, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian 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, or a pharmaceutically acceptable salt thereof, 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 nonsteroidal anti-inflammatory agent.

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

A compound of the present invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interieukin 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-B.subi . - or B.sub2. -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 NK.subi . or NK.SUD3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-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; (xxvii) inhibitor of transcription factor activation such as NFkB, API or STATS; or (xxviii) a glucocorticoid receptor (GR-receptor) agonist.

In a further aspect the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) and one or more agents selected from the list comprising: o a non-steroidal glucocorticoid receptor (GR-receptor) agonist; o a PDE4 inhibitor including an inhibitor of the isoform PDE4D; o a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); o a steroid (such as budesonide); and o an inhibitor of p38 kinase function. A compound of the invention, or a pharmaceutically acceptable salt thereof, 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, letrozoie, vorazoie 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)quinazoiin-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.

The following non-limiting Examples illustrate the invention.

General Methods Silica gel used for medium pressure column chromatography is 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure up to 10 psi accelerated column elution. Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using plates, typically 3 x 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm) (e.g. Fluka 60778). All solvents and commercial reagents were used as received. Purification by prepacked SCX-2 cartridge refers to Isolute® SCX-2, a strong cation exchange sorbent (Argonaut/I ST). Purification over NH2-silica gel refers to Isolute® flash NH2 prepacked cartridges (Argonaut/IST).

All compounds containing a basic centre(s) and purified by reversed-phase HPLC were obtained as the TFA salt, unless stated otherwise.

Preparative HPLC conditions: HPLC system 1 C18-reverse-phase column (100 x 22.5 mm i.d. Genesis column with 7 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1 % TFA) at a flow rate of 5 mLymin with UV detection set at 230 nm.

HPLC system 2 Phenyl hexyl column (250 x 21.20 mm i.d. Luna column with 5 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1% TFA) at a flow rate of 18 mL/min with UV detection set at 254 nm.

The Liquid Chromatography Mass Spectroscopy (LC-MS) systems used:

LC-MS method 1

Micromass Platform LCT with a C18-reverse-phase column (100 x 3.0 mm i.d. Higgins Clipeus with 5 μm particle size), elution with solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid). Gradient:

Gradient - Time flow mL/min %A %B

0.00 1.0 95 ^" 5

1.00 1.0 95 5

15.00 1.0 5 95

20.00 1.0 5 95

22.00 1.0 95 5

25.00 1.0 95 5

Detection - MS, ELS, UV (100 μL split to MS with in-line UV detector). MS ionisation method - Electrospray (positive ion).

LC-MS method 2

Micromass Platform LCT with a C18-reverse-phase column (30 x 4.6 mm i.d. Phenomenex Luna 3 μm particle size), elution with solvent A (water with 0.1 % formic acid) and solvent B (acetonitrile with 0.1 % formic acid). Gradient:

Gradient - Time flow mL/min %A %B

0.00 2.0 95 5 00..5500 22..00 9955 5

4.50 2.0 5 95

5.50 2.0 5 95 6.00 2.0 95 5

Detection - MS, ELS, UV (100 μL split to MS with in-line UV detector). MS ionization method - Electrospray (positive and negative ion).

LC-MS method 3

Waters Micromass ZQ with a C18-reverse-phase column (30 x 4.6 mm i.d. Phenomenex Luna 3 μm particle size), elution with solvent A (water with 0.1 % formic acid) and solvent B (acetonitrile with 0.1% formic acid). Gradient:

Gradient - Time flow mL/min %A %B

0.00 2.0 95 5

0.50 2.0 95 5

4.50 2.0 5 95

5.50 2.0 5 95

6.00 2.0 95 5

Detection - MS, ELS, UV (100 μL split to MS with in-line UV detector).

MS ionisation method - Electrospray (positive and negative ion).

LC-MS method 4

Waters ZMD with a C18-reverse-phase column (30 x 4.6 mm i.d. Phenomenex Luna with 3 μm particle size), elution with solvent A (water with 0.1 % formic acid) and solvent B (acetonitrile with 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 (200μL/min split to MS with in-line Waters 996 DAD detection). MS ionisation method - Electrospray (positive and negative ion).

Abbreviations used in the experimental section: AIBN = (2,2'-azobis(2-methylproprionitrile)

DCE = 1 ,2-dichloroethane

DCM = dichloromethane

DMSO = dimethylsulfoxide

EtOH = ethanol

IMS = industrially methylated spirit

HATU = O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluroniumhexafluoro- phosphate

MeOH = methanol

TBDMS = tert-butyldimethyl silyl

TFA = trifluoroacetic acid

THF = tetrahydrofuran

RT = room temperature

Rt = retention time satd = saturated

Compound names were generated using the commercially available chemical naming software package MDL^® AutoNom.

Example 1 anf/-Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-({9-[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester naphthalene-1,5-disulfonate.

a) (9-Bromo-nonyloxy)-terf-butyl-dimethyl-silane.

7e/t-butyl-dimethylsilyl chloride (28.16 g, 186.8 mmol) was added in portions to a solution of 9-bromo-nonan-1 -ol (27.8 g, 124.6 mmol) and imidazole (25.4 g, 373 mmol) in dry DCM (400 mL) at -10 ⁰C under a nitrogen atmosphere. The reaction mixture was allowed to warm to RT overnight. The solids were removed by filtration and the filtrate was washed with 10% citric acid (aq), then brine, dried (MgSO₄), filtered, and concentrated to dryness to afford the title compound as a yellow oil.

Yield: 41.4 g, 98%.

TLC: Rf 0.91 (50% diethyl ether/cyclohexane).

b) [9-(tert-Butyl-dimethyl-silanyloxy)-nonyl]-methyl-amine.

A solution of methylamine (120 mL, 2 M) was added to a solution of (9-bromo- nonyloxy)-te/t-butyl-dimethyl-silane (41.4 g, 123 mmol) in IMS (200 mL) at -10 ⁰C and then allowed to warm to RT overnight. After evaporation of the solvent the residue was triturated with diethyl ether and the solids were removed by filtration to afford the title compound as the HBr salt. The filtrate was concentrated in vacuo, suspended in K₂CO₃ (aq), and extracted with DCM. The combined organic layers were dried (MgSO₄), filtered, and concentrated to afford the title compound as an oil. Yield: 24.1 g, 68% (1 1.1 g of HBr salt, 24%). LC-MS (method 2): Rt 2.80 min, m/z 288 [MH+].

c) a/7fHiS)-5-Bromo-7-fr9-(terf-butyl-dimethyl-silanyloxy)-nonvn-methyl- amino)-bicyclor2.2.1lheptan-2-one.

To a solution of (1 S)-2,3-dibromo-bicyclo[3.2.0]heptan-6-one (2.15 g, 8.02 mmol) in acetone (20 mL) was added [9-(fert-butyl-dimethyl~silanyloxy)-nonyl]-methyl-amine (5.77 g, 12.3 mmol) and the reaction mixture was stirred at RT for 3 days. After evaporation of the solvent the residue was taken up in diethyl ether/ethyl acetate and washed with a satd NaHCO₃ (aq)/brine mixture. The aqueous layer was extracted with diethyl ether. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to dryness to afford a dark brown oil, which was purified by column chromatography over silica gel using a gradient of 5-15% diethyl ether/pentane as eluent. After evaporation of the volatiles the title compound was obtained as a light yellow/brown oil.

Yield: 1.67 g, 44%.

LC-MS (method 3): Rt 4.83 min, m/z 474+476 [MH+].

d) anf/-(1S)-7-|f9-(fert-Butyl-dimethyl-silanyloxy)-nonyll-methyl-amino>- bicvclor2.2.11heptan-2-one.

To a solution of (1 S)-5-bromo-7-{[9-(te/t-butyl-dimethyl-silanyloxy)-nonyl]-methyl- amino}-bicyclo[2.2.1]heptan-2-one (1.97 g, 4.2 mmol) and AIBN (70 mg, 0.42 mmol) in dry, degassed toluene (40 ml_) under a nitrogen atmosphere was added tri-n- butyltin hydride (1.25 ml_, 4.65 mmol) and heated at 80 °C on a preheated sand bath. After 2 h at 80 ⁰C the reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel using a gradient of 1 -40% diethyl ether/pentane as eluent. After evaporation of the volatiles the title compound was obtained as a light yellow/brown oil.

Yield: 2.41 g, quantitative (contains butyltin residues). LC-MS (method 3): Rt 3.10 min, m/z 396 [MH+].

e) anf/-(1S,2R)-7-{r9-(ferf-Butyl-dimethyl-silanyloxy)-nonyll-methyl-amino>- bicvclor2.2.11heptan-2-o)

To a solution of (1 S)-7-{[9-(tert-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}- bicyclo[2.2.1]heptan-2-one (4.1 1 g, 10.4 mmol max) in dry THF (41 mL) at -5 ⁰C under a nitrogen atmosphere was added lithium tri-te/t-butoxyaluminum hydride (3.44 g, 13.5 mmol). After 1.5 h at -5 ⁰C more lithium tri-te/t-butoxyaluminum hydride (2.64 g, 10.4 mmol) was added. After 1 h at -5 ⁰C the reaction was quenched with satd ammonium chloride solution (aq) and partitioned between ethyl acetate and water. The solids were removed by filtration and washed with ethyl acetate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with satd NaHCO₃ (aq), brine, dried (Na₂SO₄), filtered, and concentrated to dryness to afford a turbid yellow oil. The crude product was purified by column chromatography over silica gel using a gradient of 7.5-10% MeOH/DCM as eluent. After evaporation of the volatiles a light yellow/brown viscous oil was obtained. Yield: 2.36 g, 57%.

LC-MS (method 2): Rt 2.95 min, m/z 398 [MH+].

f) anf/-Hvdroxy-di-tr)iopherι-2-yl-acetic acid (1 S,2R)-7-{r9-(te/^*frbutyl-dimethyl- silanyloxy)-nonvn-methyl-amino)-bicvclof2.2.11hept-2-yl ester.

Sodium hydride (254 mg, 60% suspension in mineral oil, 6.35 mmol) was added to a solution of (1 S,2R)-7-{[9-(terf-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}- bicyclo[2.2.1]heptan-2-ol (1.01 g, 2.54 mmol) in dry toluene (20 mL) at 0 ⁰C under a nitrogen atmosphere. As soon as the gas evolution subsided hydroxy-di-thiophen-2- yl-acetic acid ethyl ester (817 mg, 3.04 mmol) was added in portions, and when the gas evolution stopped the reaction mixture was heated at 80 ⁰C on a preheated sand bath. After 2.5 h the reaction mixture was poured onto satd ammonium chloride (aq) and ether. The layers were separated, the aqueous layer extracted with ether, and the combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated to dryness to afford a light brown viscous oil. The crude product was purified by column chromatography over silica gel using a gradient of 1-40% ethyl acetate in DCM as eluent to afford the product as a very light brown viscous oil.

Yield: 0.76 g, 48%. LC-MS (method 3): Rt 3.44 min, m/z 620 [MH+].

g) anf/-Hvdroxy-di-thiophen-2-yl-acetic acid (1 S.2R)-7-[Y9-hvdroxy-nonvD- methyl-amino1-bicvclor2.2.1lhept-2-yl ester.

A solution of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R)-7-{[9-(te/f-butyl-dimethyl- silanyloxy)-nonyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester (0.51 g, 0.82 mmol) in THF (7 ml_) was treated with 1 M HCI (3.5 ml_) and stirred at RT for 45 min. The reaction mixture was neutralised with satd NaHCO₃ (aq) and extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to dryness to afford a light brown oil, which was used without further purification. Yield: 273 mg, 66%. LC-MS (method 3): Rt 2.39 min, m/z 506 [MH+].

h) an.y-Hvdroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-rmethyl-(9-oxo-nonvO- amino1-bicycloF2.2.1 lhept-2-yl ester.

Dess-Martin periodinane (450 mg, 1.06 mmol) was added to a solution of hydroxy-di- thiophen-2-yl-acetic acid (1 S,2R)-7-[(9-hydroxy-nonyl)-methyl-amino]- bicyc!o[2.2.1]hept-2-yl ester (370 mg, 0.732 mmol) in dry DCM (3 ml_) at 0 ⁰C, and then allowed to warm to RT. After 1 h at RT the reaction mixture was treated with satd NaHCO₃ (aq) and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated to dryness. The residue was triturated with ether, and the solids removed by filtration. The filtrate was concentrated to afford an orange/brown viscous oil and used directly without further purification.

Yield: 456 mg, 0.73 mmol max.

i) anft-Hydroxy-di-thiophen^-yl-acetic acid (1 S,2RV7-((9-r(FQ-2-( fert-butyl- dimethyl-silanyloxy)-2-(8-hvdroxy-2-oxo-1 ,2-dihvdro-quinolin-5-yl)-ethylamino1- nonyl}-methyl-amino)-bicvclor2.2.1 lhept-2-yl ester.

A mixture of hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-[methyl-(9-oxo-nonyl)- amino]-bicyclo[2.2.1]hept-2-yl ester (max 0.73 mmol), 5-[(R)-2-amino-1-(te/?-butyl- dimethyl-silanyloxy)-ethyl]-8-hydroxy-1 /-/-quinolin-2-one (245 mg, 0.73 mmol), sodium triacetoxyborohydride (186 mg, 0.88 mmol), and acetic acid (2 drops) in dry 1 ,2-dichloroethane was stirred at RT overnight. The reaction mixture was partitioned between DCM and satd NaHCO₃ (aq). The organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo to afford a dark green/brown gum that solidified on standing, which was purified by preparative HPLC (system 2, 35% B + 1% B/min). The pure fractions were concentrated, neutralised with satd NaHCO₃ (aq), and extracted with DCM. After concentration in vacuo a green/brown oil was obtained.

Yield: 72 mg, 12%.

LC-MS (method 3): Rt 2.51 min, m/z 822 [MH+]. j) anf/-HydiOxy-di-thiophen-2-yl-acetic acid (1S,2R)-7-({9-[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester.

A solution of hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-({9-[(R)-2-(tert-butyl- dimethyl-silanyloxy)-2-(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}- methyl-amino)-bicyclo[2.2.1]hept-2-yl ester (72 mg, 0.087 mmol) and triethylamine trihydrofluoride (60 μl_, 0.37 mmol) was stirred in THF/DCM (1 :1 , 2 ml_) at RT overnight. The reaction mixture was neutralised with satd NaHCO₃ (aq) and extracted with DCM. The organic layer was concentrated to dryness to afford a green/brown oil, which was purified by preparative HPLC (system 1 , 15% B + 1% B/min for 20 min, then 6% B/min for 10 min). The pure fractions were concentrated, neutralised with satd NaHCO₃ (aq), and extracted with THF. After concentration in vacuo a light brown oil was obtained.

Yield: 50 mg, 81 %.

LC-MS (method 3): Rt 2.04 min, m/z 708 [MH+].

k) anfy-Hydroxy-di-thioprien^-yl-acetic acid (1S,2R)-7-({9-[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester naphthalene-1,5-disulfonate.

A solution of naphthalene-1 ,5-disulfonic acid tetrahydrate (25 mg, 0.069 mmol) in MeOH (1 ml_) was added to a solution of hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)- ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1]hept-2-yl ester (50 mg, 0.071 mmol) in THF (1 ml_). The reaction mixture was stirred vigorously at 30 ⁰C overnight, then concentrated and triturated with MeOH. The solvent was decanted and the solids dried under vacuum at 50 °C. The product contained about 8% of dithienyl methoxy ester derivative, which was removed by preparative HPLC (system 1 , 30% B + 0.5% B/min) after liberating the salt by treating it with satd NaHCO₃ (aq) and neutralising with 1 M HCI (aq). After freeze-drying the residue (21 mg) was treated with naphthalene-1 ,5-disulfonic acid tetrahydrate (1 equiv.) in water/acetonitrile at 30 °C for 6.5 h. After freeze-drying the product was obtained as a light pink solid. ¹H NMR (400 MHz) showed 1.4 equiv. of naphthalene-1 ,5-disulfonic acid relative to hydroxy- di-thiophen-2-yl-acetic acid (1 S,2R)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1 ]hept-2-yl ester.

Yield: 17 mg, 76%.

LC-MS (method 1): Rt 6.15 min, m/z 708 [MH+].

Example 2 antf-ΘH-Xanthene-θ-carboxylic acid (1S,2R)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2- oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester bis(naphthalene-1,5-disulfonate).

a) anf/-9H-Xanthene-9-carboxylic acid (1S,2R)-7-{[9-(terf-butyl-dimethyl- silanyloxy)-nonyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester.

To a solution of (1 S,2R)-7-{[9-(te/?-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}- bicyclo[2.2.1]heptan-2-ol (620 mg, 1.56 mmol) in dry THF (10 ml_) at 0 ⁰C was added sodium hydride (69 mg, 60% suspension in mineral oil, 1.7 mmol) in portions. The reaction mixture was allowed to warm to RT for 15 min, then re-cooled in an ice-bath, followed by a dropwise addition of 9H-xanthene-9-carbonyl chloride (458 mg, 1.87 mmol) as a solution in THF (10 ml_). The reaction mixture was allowed to warm to RT, then heated at reflux for 6 h. After cooling to RT the reaction was quenched by the dropwise addition of water (30 ml_) and then extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to dryness to afford an orange oil. Purification by column chromatography over silica gel using 3% MeOH/DCM as eluent provided the title compound as a yellow oil as well as the desilylated analogue, 9H-xanthene-9-carboxylic acid (1S,2R)-7-[(9-hydroxy-nonyl)- methyl-amino]-bicyclo[2.2.1]hept-2-yl ester. Yield: 510 mg, 54% (title compound). LC-MS (Method 3): Rt 3.68 min, m/z 606 [MH+].

Yield: 170 mg, 22% (desilylated compound). LC-MS (Method 3): Rt 2.70 min, m/z 492 [MH+].

b) an/7-9W-Xanthene-9-carboxylic acid (iS,2R)-7-({9-[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)- bicyclo[2.2.1]hept-2-yl ester bis(naphthalene-1 ,5-disulfonate).

The title compound was prepared using a method analogous to that used in Example 1 , steps g to k. LC-MS (Method 1 ): Rt 7.14 min, m/z 693 [MH+].

Example 3 anf/-Biphenyl-2-yl-carbamic acid-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydro-quinolin-S-yO-ethylaminol-nony^-methyl-aminoJ-bicyclo^^.ilhept^-yl ester naphthalene-1,5-disulfonate (+/- at 2C position)

a) (+/-)-a/?f/-7-{r9-(terf-Butyl-dimethyl-silanyloxy)-nonyll-nnethyl-amino)- bicyclor2.2.πheptan-2-ol.

The title compound was prepared using a method analogous to that used in Example 1 , steps c-e, starting from 2,3-dibromo-bicyclo[3.2.0]heptan-6-one. LC-MS (method 2): Rt 2.97 min, m/z 398 [MH+].

b) (+/-)-a/7f/_::Biphenyl-2-yl-carbamic acid-7-[(9-hydroxy-nonyl)-methyl-amino]- bicyclo[2.2.1]hept-2-yl ester.

A solution of {+/-)-anth -7-{[9-(terf-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}- bicyclo[2.2.1]heptan-2-ol (1.86 g, 4.2 mmol) and 2-biphenylylisocyanate (0.91 g, 4.7 mmol) in dry toluene (40 ml_) was heated at 50 ⁰C under a nitrogen atmosphere for 6 h. Then more 2-biphenylylisocyanate (0.90 g, 4.7 mmol) was added and the reaction mixture heated at 50 ⁰C overnight. The mixture was concentrated to dryness, redissolved in dry toluene (15 mL), 2-biphenylylisocyanate (0.60 g, 3.1 mmol) was added, and the reaction mixture heated at 50 ⁰C for 4 h. The mixture was concentrated, the residue taken up in MeOH, passed over a SCX-2 cartridge, and liberated using 2 M ammonia solution in MeOH. Evaporation of the solvent in vacuo afforded a light brown oil, which was purified by column chromatography over silica gel using a gradient of 20-50% ethyl acetate/cyclohexane as eluent. After evaporation of the volatiles the title compound was obtained as a very light brown oil. Yield: 1.62 g, 81 %. LC-MS (method 2): Rt 3.54 min, m/z 593 [MH+] (TBDMS intermediate).

c) an.Y-Biphenyl-2-yl-carbamic acid-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2- dihydro-quinolin-S-ylJ-ethylaminol-nonylJ-methyl-aminoJ-bicyclo^^.ilhept^-yl ester naphthalene-1 ,5-disulfonate (+/- at 2C position)

The title compound was prepared using a method analogous to that used in Example 1 , steps f-k, starting from (+/-)-anf/_:biphenyl-2-yl-carbamic acid-7-[(9-hydroxy- nonyl)-methyl-amino]-bicyclo[2.2.1]hept-2-yl ester.

LC-MS (method 3): Rt 2.36 min, m/z 681 [MH+].

The compounds of the invention may be tested for pharmaceutical activity using assays know in the art, such as for example:

Muscarinic Receptor Radioligand Binding Assays

Radioligand binding studies utilising [³H]-N-methyl scopolamine ([³H]-NMS) and commercially available cell membranes expressing the human muscarinic receptors (M2 and M3) were used to assess the affinity of muscarinic antagonists for M2 and M3 receptors. Membranes in TRIS buffer were incubated in 96-well plates with [³H]- NMS and M3 antagonist at various concentrations for 3 hours. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Canberra Packard Topcount scintillation counter

The half-life of antagonists at each muscarinic receptor was measured using the alternative radioligand [³H]-QNB and an adaptation of the above affinity assay. Antagonists were incubated for 3 hours at a concentration 10-fold higher than their Ki, as determined with the [³H]-QNB ligand, with membranes expressing the human muscarinic receptors. At the end of this time, [³H]-QNB was added to a concentration 25-fold higher than its Kd for the receptor being studied and the incubation continued for various time periods from 15 minutes up to 180 minutes. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Canberra Packard Topcount scintillation counter. The rate at which [3H]-QNB is detected binding to the muscarinic receptors is related to the rate at which the antagonist dissociates from the receptor, ie. to the half life of the antagonists on the receptors.

M3 binding K₁ <1 nM "+++"; Kj 1 -1 OnM "++"; K₁ > 10nM "+"

By way of further illustration, Example 1 had a Ki of 0.3nM and Example 2 had a Ki of 0.7nM in a M3 binding assay.

β- Adrenergic Receptor Radioligand Binding Assays

Radioligand binding studies utilising [ⁱ²⁵l]-lodocyanopindolol and commercially available cell membranes expressing the human β₂ adrenergic receptor were used to assess the affinity of antagonists for β₂-adrenergic receptor. Membranes and SPA- beads were incubated with [¹²⁵l]-lodocyanopindolol and β₂ antagonist at various concentrations for 3 hours at room temperature in TRIS buffer. The assay was performed in 96-well plates which were read using the Wallac Microbeta counter. Example 77 exhibited a K₁ value of <100nM in this assay.

β2 Ki <100nM "+++"; Ki 100-20OnM "++"; Ki > 20OnM "+"

As a further illustration of the invention, Example 1 exhibited a Ki of 56nM and Example 3 exhibited a Ki of 33nM in the β2 binding assay.

Analysis of Inhibition of M3 Receptor Activation via Calcium Mobilization CHO cells expressing the human M3 receptor were seeded and incubated overnight in 96 well collagen coated plates (black-wall, clear bottom) at a density of 50000 / 75μl of medium in 3% serum. The following day, a calcium-sensitive dye (Molecular Devices, Cat # R8041 ) was prepared in HBSS buffer with the addition of 5mM probenecid (pH 7.4). An equal volume of the dye solution (75μl) was added to the cells and incubated for 45 minutes followed by addition of 50μl of muscarinic antagonists or vehicle. After a further 15 minutes the plate was read on a FLEXstation™ (excitation 488nm, emission 525nm) for 15 seconds to determine baseline fluorescence. The muscarinic agonist Carbachol was then added at an EC₈₀ concentration and the fluorescence measured for a further 60 seconds. The signal was calculated by subtracting the peak response from the mean of the baseline fluorescence in control wells in the absence of antagonist. The percentage of the maximum response in the presence of antagonist was then calculated in order to generate IC₅₀ curves. All compounds tested in this assay showed an IC50 value of <50nM.

Evaluation of potency and duration of action in Isolated Guinea Pig Trachea Experiments were carried out at 37⁰C in modified Krebs-Henseleit solution, (114mM NaCI, 15mM NaHCO₃, 1 mM MgSO₄, 1.3mM CaCI₂, 4.7mM KCI, 11.5mM glucose and 1.2mM KH₂PO₄ , pH 7.4) gassed with 95% O₂/5% CO₂. lndomethacin was added to a final concentration of 3μM

Tracheae were removed from adult male Dunkin Hartley Guinea pigs and dissected free of adherent tissue before being cut open longitudinally in a line opposite the muscle. Individual strips of 2-3 cartilage rings in width were cut and suspended using cotton thread in 10mI water-jacketed organ baths and attached to a force transducer ensuring that the tissue is located between two platinum electrodes. Responses were recorded via a MPI OOW/Ackowledge data acquisition system connected to a PC. Tissues were equilibrated for one hour under a resting tone of 1 g and were then subjected to electrical field stimulation at a frequency of 80Hz with a pulse width of 0.1 ms, a unipolar pulse, triggered every 2 minutes. A "voltage-response" curve was generated for each tissue and a submaximal voltage then applied to every piece of tissue according to its own response to voltage. Tissues were washed with Krebs solution and allowed to stabilize under stimulation prior to addition of test compound. Concentration response curves were obtained by a cumulative addition of test compound in half-log increments. Once the response to each addition had reached a plateau the next addition was made. Percentage inhibition of EFS-stimulated contraction is calculated for each concentration of each compound added and dose response curves constructed using Graphpad Prism software and the EC₅₀ calculated for each compound.

Onset time and duration of action studies were performed by adding the previously determined EC₅₀ concentration of compound to EFS contracted tissues and the response allowed to plateau. The time taken to reach 50% of this response was determined to be the onset time. Tissues were then washed free of compound by flushing the tissue bath with fresh Krebs solution and the time taken for the contraction in response to EFS to return to 50% of the response in the presence of compound is measured. This is termed the duration of action. All compounds tested in this assay showed an EC50 value of <100nM.

Assay for adrenergic β2 mediated cAMP production

CELL PREPARATION

H292 cells are grown in RPMI (Roswell Park Memorial Institute) medium containing, 10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine. Cells are grown in 225cm2 flasks containing 25 mL media in a humidified incubator at 37°C, 5% CO₂. Cells are harvested from the flask and passaged at a 1 in 10 dilution once per week. EXPERIMENTAL METHOD The media from flasks containing H292 cells is removed, rinsed with 10 mL

PBS (phosphate buffered saline) and replaced with 10 mL Accutase™ cell detachment solution. Flasks are incubated for 15 minutes in a humidified incubator at 37°C, 5% CO₂. The cell suspension is counted and the cells re-suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 x 10⁶ cells per mL. 5000 cells in 100 μL are added to each well of a tissue-culture-treated 96-well plate and the cells incubated overnight in a humidified incubator at 37°C, 5% CO₂. The culture media is removed, washed twice with 100 μL assay buffer and replaced with 50 μL assay buffer. Cells are rested at room temperature for 20 minutes after which time 25 μL of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) is added. Cells are incubated with rolipram for 10 minutes after which time test compounds (made up as x4 concentrated stocks in assay buffer containing 4% (v/v) dimethylsulphoxide) are added and the cells are incubated for 10 minutes at room temperature. Final rolipram concentration in the assay is 300 μM and final vehicle concentration is 1.6% (v/v) dimethylsulphoxide. The reaction is stopped by removing supernatants, washing once with 100 μL assay buffer and replacing with 50 μL lysis buffer. The cell monolayer is frozen at -80⁰C for 30 minutes (or overnight).

AlphaScreen™ cAMP Detection The concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined using the AlphaScreen™ methodology. The frozen cell plate is thawed for 20 minutes on a plate shaker then 10 μL of the cell lysate is transferred to a 96-well white plate. 40 μL of mixed AlphaScreen™ detection beads (containing equal volumes of donor beads (pre-incubated with biotinylated cAMP in the dark for 30 minutes) and acceptor beads), is added to each well and the plate incubated at room temperature for 10 hours in the dark. The AlphaScreen™ signal is measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings. cAMP concentrations are determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations (made up in lysis buffer in a 96-well tissure-culture-treated plate and frozen/thawed alongside the test samples) and detected using the same protocol. Concentration response curves for agonists are constructed to determine both the pEC₅₀ and Intrinsic Activity. Intrinsic Activity is expressed as a fraction relative to the maximum activity determined for formoterol in each experiment.

Alternative assay for Adrenergic β2 mediated cAMP production

Cell preparation

H292 cells are grown in 225cm2 flasks incubator at 37°C, 5% CO₂ in RPMI medium containing10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine. Experimental Method Adherent H292 cells re removed from tissue culture flasks by treatment with

Accutase™ cell detachment solution for 15 minutes. Flasks are incubated for 15 minutes in a humidified incubator at 37°C, 5% CO₂. Detached cells are re- suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 x 10⁶ cells per mL. 5000 cells in 100 μL are added to each well of a tissue-culture- treated 96-well plate and the cells incubated overnight in a humidified incubator at 37°C, 5% CO₂. The culture media is removed and cells are washed twice with 100 μL assay buffer and replaced with 50 μL assay buffer (HBSS solution containing 1 OmM HEPES pH7.4 and 5 mM glucose). Cells are rested at room temperature for 20 minutes after which time 25 μL of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) is added. Cells are incubated with rolipram for 10 minutes after which time test compounds are added and the cells are incubated for 60 minutes at room temperature. The final rolipram concentration in the assay is 300 μM and final vehicle concentration is 1.6% (v/v) dimethylsulphoxide. The reaction is stopped by removing supernatants, washing once with 100 μL assay buffer and replacing with 50 μL lysis buffer. The cell monolayer is frozen at -80⁰C for 30 minutes (or overnight). AlphaScreen™ cAMP detection

The concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined using AlphaScreen™ methodology. The frozen cell plate is thawed for 20 minutes on a plate shaker then 10 μl_ of the cell lysate is transferred to a 96-well white plate. 40 μl_ of mixed AlphaScreen™ detection beads pre-incubated with biotinylated cAMP, is added to each well and the plate incubated at room temperature for 10 hours in the dark. The AlphaScreen™ signal is measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings. cAMP concentrations are determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations. Concentration response curves for agonists are constructed and data is fitted to a four parameter logistic equation to determine both the pEC₅₀ and Intrinsic Activity. Intrinsic Activity is expressed as a fraction relative to the maximum activity determined for formoterol in each experiment.

Alphascreen cAMP beta functional assay

Cell line

CHO-B2 (clone 11) 5000 cells/well

Stimulation Buffer pH7.4 IxHBSS

0.1 % BSA (1 mg/ml) 5mM HEPES (1/200 dilution of 1 M stock)

0.5mM IBMX (1/1000 dilution of 50OmM stock)

Lysis Buffer pH7.4 MiIIi-Q H2O 0.1 % BSA (1 mg/ml)

5mM HEPES (1/200 dilution of 1 M stock) 0.3% Tween-20 (1/333 of stock)

Control: 9μM Isoproterenol (max stimulation obtained, lowest counts) Blank: 0.1 nM Isoproterenol 1 % DMSO (no stimulation, highest counts) Detection positive control: 10μM cAMP (1/200 dilution of 1 OmM stock, then 1/5 in assay)

Detection negative control: stimulation buffer

Standard Isoproterenol and Formoterol (EC50~7nM, 0.05nM respectively)

Compound Dilutions

Prepare compound dilutions x11 1.1 desired required final concentration in DMSO.

-1/55.6 from DMSO to stimulation buffer (1.8% DMSO)

-1/2 dilution in well

Streptavidin Donar bead/biotinylated cAMP detection mix (15μl/well)

Donar bead (1/150 dilution)

Biotinylated cAMP (1/2000 dilution)

Make up in lysis buffer Prepare at least 30 minutes before use.

Cell preparation

Remove growth medium. Add 1-2ml cell dissociation buffer for ~5mins to detach cells. Collect cells and centrifuge for 5 minutes at 1200rpm. Aspirate supernatant and resuspend pellet in stimulation buffer. Perform a cell count and adjust cell number to 2x106/ml in stimulation buffer. Prepare immediately prior to use.

Cells/anti-cAMP Acceptor bead mix (5ul/well) Beads (1/25 dilution)

Make in stimulation buffer (10U/μl stock to 0.4U/μl).

Dilute above solution 1 :1 with cells (2x106/ml) to give 0.2U/μl beads and 2000cell/μl

Final well conditions: 1 U/well acceptor beads and 5000 cells/well/5μl

Addition to Plate

To a 384 well Optiplate add in triplicate;

5μl cells/anti-cAMP acceptor bead mix

5μl compound or control/blank

Shake plate for 3 mins and leave in dark for 30 mins at room temperature 15μl donor beads/biotinylated cAMP mix

Shake plate for 3 mins and leave in dark for 2 hours at room temperature Read on Packard Fusion

Final Well Conditions 5μl acceptor beads/5000 cells 5μl agonist in buffer

15μl donor beads/biotinylated cAMP 25μl final volume 0.4% DMSO

Data Calculation The data is analysed using an in house Excel-Fit template.

All compounds tested in β adrenergic functional assays were shown to have an EC50 of < 5OnM.

Muscarinic 3 receptor binding assay The affinity (plC₅₀) of compounds to the M₃ receptor is determined by competition binding of [³H]N-methyl scopolamine (NMS) to CHO-K1 (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M₃ receptor (M₃-ACh) in a scintillation proximity assay (SPA) format. SPA beads are precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of compounds of the invention, [³H]NMS at 0.2nM, half Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCI₂). The assay is conducted in a final volume of 200 μl_, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [³H]NMS is determined in the absence of competing compound and non-specific binding of [³H]NMS is determined in the presence of 1 μM atropine. The plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta^™ using a normalised ³H protocol. The plC₅₀, defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [³H]-NMS binding, is determined.

Pharmacokinetics in the Rat

A dose solution of a test compound is prepared using a suitable dose vehicle. The concentration of the compound in the dose solution is assayed by diluting an aliquot to a nominal concentration of 50μg-ml^"1 and calibrating against duplicate injections of a standard solution and a QC standard at this concentration.

Compounds are administered intravenously as a bolus into a caudal vein to groups of three 250-35Og rats (approximately 1 ml-kg^"1). For the oral dose, a separate group of 2 or 3 animals are dosed by oral gavage (3 ml-kg^"1). Delivered doses are estimated by weight loss. Food is not usually withdrawn from animals prior to dosing, although this effect can be investigated if necessary. Blood samples (0.25ml) are taken into 1 ml syringes from the caudal vein, transferred to EDTA tubes and plasma is prepared by centrifugation (5 min at 13000rpm) soon after sample collection, before storage at -20⁰C. Typical sampling times were 2, 4, 8, 15, 30, 60, 120, 180, 240, 300 (min) or until the terminal t1/2 was accurately described. The concentration of the analyte(s) are determined in plasma by quantitative mass spectrometry. Standard and quality control stock solutions are prepared at a concentration 1 mg/ml in methanol. A range of standard and QC stocks produced by serial dilution are added to control rat plasma (50μl). The range of concentrations covered the range of levels of analyte present in the rat samples. Standards, QCs and samples undergo liquid extraction using 50μl of organic solvent and 100μl of organic solvent containing an internal standard, are chosen to closely resemble the analyte. The samples are then mixed by repeated inversion, stored at -20°C for at least 1 h, and centrifuged at 3500 rpm in a centrifuge for 20 minutes. Aliquots (120 μl) of each sample are transferred for analysis using LC-MSMS. Standard and quality control samples covering the range of concentrations found in the test samples should be within 25 % of the nominal concentration.

Pharmacokinetic data analysis is achieved using WinNonlin. A standard non- compartmental analysis is used to estimate the parameters such as Tmax, Cmax, Lambda_z, t1/2_Lambda_z, AUCaII, AUCINF(observed), Cl(observed), Vss(observed).

Claims

Claims:

1. Use of a compound of formula (I):

wherein

A is an oxygen atom or group -N(R¹²)-;

(i) R¹ is CrC_δ-alkyl or a hydrogen atom; and R² is a hydrogen atom or a group -R⁵, or a group, -Z-Y-R⁵, or a group -Z-NR⁹R¹⁰; or a group -Z-CO-NR⁹R¹⁰; or a group -Z- NR⁹-CO-R⁵; or a group -Z-CO₂-R⁵; or a group -Z-CO₂H; and R³ is a lone pair, or R³ is Ci~C₆~alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or

R⁴ is selected from one of the groups of formula (a), (b), (c) or (d);

(a) (b) (C) (d) Z is a C_rC₁₆-alkylene, C₂-C₁₆~alkenylene or C₂-C₁₆-alkynylene group;

Y is a bond or oxygen atom;

R⁵ is an C_rC₆-alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(Ci-C₈-alkyl)-, heteroaryl(C₁-C₈-alkyl)-_! cycloalkyl or heterocycloalkyl group;

R⁶ is C_rC₆-alkyl or a hydrogen atom;

R^7a and R^7b are a Ci-C₆-alkyl group or halogen;

n and m are independently 0, 1 , 2 or 3;

R^8a and R^8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, CrC₆-alkyl, cycloalkyl;

R^8α is -OH, C_rC₆-alkyl, hydroxy-C_rC₆-alkyl, nitrile, a group CONR^8d ₂ or a hydrogen atom;

R^8d is CrC₆-alkyl or a hydrogen atom;

R⁹ and R¹⁰ are independently a hydrogen atom, C_rC₆-alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryKCrCβ-alkyl)-, or heteroaryl(Ci- C₆-alkyl)- group; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;

R¹² is C_rC₆-alkyl or a hydrogen atom;

Ar¹ is aryl, heteroaryl or cycloalkyl;

Ar² are independently aryl, heteroaryl or cycloalkyl; and

Q is an oxygen atom, -CH₂-, -CH₂CH₂- or a bond; wherein, unless otherwise specified, each occurrence alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted;

or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof;

2. A compound of formula (Ia):

wherein

A is an oxygen atom or group -N(R¹²)-; (i) R¹ is Ci-C₆-alkyl or hydrogen; and R² is a group-Z-NR⁹R¹⁰; and R³ is a lone pair, or R³ is CrCe-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or

(ii) R¹ and R³ together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R² is a group -Z-NR⁹R¹⁰ in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or

(iii) R¹ and R² together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR⁹R¹⁰; and R³ is a lone pair, or R³ is C_rC₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;

R⁴ is selected from one of the groups of formula (a), (b), (c) or (d);

(a) (b) (C) (d)

Z is a C₉-C₁₅-alkylene, C₉-C₁₅-alkenylene or C₉-C₁₅-alkynylene group; or alternatively Z is an C₈-alkylene, C₈-alkenylene or C₈-alkynylene group;

or Z is a divalent linker radical of formula (A):

L³ and L⁴ each independently represent hydrogen, Ci_-6 alkyl or C₃.₆ cycloalkyl, wherein C_1-6 alkyl and C₃.₆ cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and * denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R¹ and R³, and ^** denotes the point of attachment to the group NR⁹R¹⁰;

R⁶ is Ci-C₆-alkyl or a hydrogen atom;

R^7a and R^7b are a CrC₆-alkyl group or halogen;

n and m are independently 0, 1 , 2 or 3;

R^8a and R^8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, C_rC₆-alkyl, cycloalkyl; R^8c is -OH, C_rC₆-alkyl, hydroxy-C_rC₆-alkyl, nitrile, a group CONR^8d ₂ or a hydrogen atom;

R^8d is C_rC₆-alkyl or a hydrogen atom;

R⁹ is a hydrogen atom or CrCValkyl;

R¹⁰ is an aryl(C_rC₆-alkyl)-, or heteroaryl(C_rC₆-alkyl) group, in which the C_rC₆-alkyl group is optionally substituted by hydroxy;

R¹² is CrC₆-alkyl or a hydrogen atom;

Ar¹ is aryl, heteroaryl or cycloalkyl;

Ar² are independently aryl, heteroaryl or cycloalkyl; and

Q is an oxygen atom, -CH₂-, -CH₂CH₂- or a bond;

or a pharmaceutically acceptable salt thereof.

3. A compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 2 wherein: A is an oxygen atom;

R¹ is Ci-C₆-alkyl; R² is a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is C_rC₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or:

R¹ and R² together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is Ci-C₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or: R¹ and R³ together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R² is a group -Z-NR⁹R¹⁰ in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;

R⁴ is selected from one of the groups of formula (a), (b) or (c):

(a) (b) (C)

Z is a divalent linker radical of formula (A):

L¹ and L² each independently represent hydrogen, Ci_₆ alkyl or C₃.₆ cycloalkyl;

L³ and L⁴ each independently represent hydrogen, C_1-6 alkyl or C_3-6 cycloalkyl, wherein Ci_-6 alkyl and C₃.₆ cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and ^* denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R¹ and R³, and *^* denotes the point of attachment to the group NR⁹R¹⁰;

R⁶ is a hydrogen atom;

R and R are independently a C_rC₆-alkyl group or halogen;

n and m are independently 0, 1 , 2 or 3; R^8a and R^8b are independently selected from the group consisting of aryl, heteroaryl, d-Ce-alkyl, cycloalkyl;

R^8c is -OH, Ci-C₆-alkyl, hydroxy-C_rC₆-alkyl, or a hydrogen atom;

R⁹ is a hydrogen atom or CrC₆-alkyl;

R¹⁰ is an aryl(C_rC₆-alkyl)-, or heteroaryl(C₁-C₆-alkyl) group, in which the C_rC₆-alkyl group is optionally substituted by hydroxy.

4. A compound, or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein:

A is an oxygen atom;

R¹ is C_rC₆-alkyl ; R² is a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is C_rC₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or: R¹ and R² together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR⁹R¹⁰ and R³ is a lone pair or R³ is CVC₆-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or: R¹ and R³ together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R² is a group -Z-NR⁹R¹⁰ in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;

R⁴ is selected from one of the groups of formula (a), (b) or (c):

(a) (b) (C) Z is a divalent linker radical of formula (A):

L¹ and L² each independently represent hydrogen, C_1-6 alkyl or C₃.₆ cycloalkyl;

L³ and L⁴ each independently represent hydrogen, Ci_-6 alkyl or C₃.₆ cycloalkyl, wherein Ci_-6 alkyl and C₃.₆ cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and ^* denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R¹ and R³, and ^** denotes the point of attachment to the group NR⁹R¹⁰;

In the group (a):

Ar¹ is a phenyl group; R⁶ is a hydrogen atom; n and m are 0;

In the group (b):

R^8a and R^8b are both a phenyl group; or, R^8a and R^8b are both a thienyl group, or R^8a is a phenyl group and R^8b is a cycloalkyl group;

R^8c is -OH or d-Cβ-alkyl;;

In the group (c):

Ar² is a phenyl ring

Q is an oxygen atom

R^8c is hydrogen, Ci_-6 alkyl or -OH;

R⁹ is a hydrogen atom or Ci-C₆-alkyl; R¹⁰ is an aryl(G_rC₆-alkyl)-, or heteroaryl(C_rC₆-alkyl) group, selected from the groups

5. A compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 2 or claim 3, wherein R¹⁰ is a group selected from

6. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 2 to 5, wherein compounds of the invention exist in either the syn- or anti- forms.

7. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 2 to 5, wherein compounds of the invention exist in either the exo- or endo- forms.

8. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 2 to 7, wherein compounds of the invention exist in the endo- anti- form

anti-, endo-

9. A compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 2, selected from the group consisting of: antf-Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy- 2-OXO-1 , 2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1]hept- 2-yl ester; anf/-9H-Xanthene-9-carboxylic acid (1 S,2R)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo- 1 ,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1]hept-2-yl ester; and anf/-Biphenyl-2-yl-carbamic acid-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2-dihydro- quinolin-5-yl)-ethylamino]-nonyl}-methyl-amino)-bicyclo[2.2.1]hept-2-yl ester.

10. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 2 to 9, for use in therapy.

11. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 2 to 9 and a pharmaceutically acceptable carrier or excipient.

12. A pharmaceutical composition as claimed in claim 1 1 , in a form suitable for inhalation.

13. Use of a compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 2 to 9 for the manufacture of a medicament for use in the treatment of prevention of a disease or condition in which M3 muscarinic receptor activity and β-adrenergic receptor activity is implicated.

14. A method of treatment of a disease or condition in which M3 muscarinic receptor activity and β-adrenergic receptor activity is implicated comprising administration to a subject in need thereof of an effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 2 to 9.

15. Use as claimed in claim 13 or a method as claimed in claim 14, wherein the disease or condition is a respiratory-tract disorder.

16. Use as claimed in claim 13 or a method as claimed in claim 14, wherein the disease or condition is chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, or allergic rhinitis.

17. Use of a compound as claimed in any one of claims 2 to 9 in combination with (i) an inhaled corticosteroid such as fluticasone propionate, ciclesonide, mometasone furoate or budesonide and/or (ii) an inhaled PDE4 inhibitor, such as roflumilast, cilomilast or tofimilast.