WO2008104752A1

WO2008104752A1 - Dihydropyridones as elastase inhibitors

Info

Publication number: WO2008104752A1
Application number: PCT/GB2008/000633
Authority: WO
Inventors: Tomas Klingstedt; Matti Lepistö; Michael Lundkvist; Hans LÖNN
Original assignee: AstraZeneca UK Ltd; AstraZeneca AB
Current assignee: AstraZeneca UK Ltd; AstraZeneca AB
Priority date: 2007-02-26
Filing date: 2008-02-26
Publication date: 2008-09-04
Anticipated expiration: 2009-08-26

Abstract

The invention provides compounds of formula wherein R1, R2, R3, R4, R5, R6, R7, X1, X2, X3 and X4 are as defined in the specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds are inhibitors of human neutrophil elastase.

Description

DIHYDROPYRIDONES AS ELASTASE INHIBITORS

Field of the Invention

The present invention relates to dihydropyridone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Background of the Invention

Elastases are possibly the most destructive enzymes in the body, having the ability to degrade virtually all connective tissue components. The uncontrolled proteolytic degradation by elastases has been implicated in a number of pathological conditions. Human neutrophil elastase (hNE), a member of the chymotrypsin superfamily of serine proteases is a 33-KDa enzyme stored in the azurophilic granules of the neutrophils. In neutrophils the concentration of NE exceeded 5 mM and its total cellular amount has been estimated to be up to 3 pg. Upon activation, NE is rapidly released from the granules into the extracellular space with some portion remaining bound to neutrophil plasma membrane (See Kawabat et al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellular physiological function of NE is degradation of foreign organic molecules phagocytosed by neutrophils, whereas the main target for extracellular elastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128, 1137-1155). NE is unique, as compared to other proteases (for example, proteinase 3) in that it has the ability to degrade almost all extracellular matrix and key plasma proteins (See Kawabat et al., 2002, Eur. J. Pharmacol. 451, 1-10). It degrades a wide range of extracellular matrix proteins such as elastin, Type 3 and type 4 collagens, laminin, fibronectin, cytokines, etc: (Ohbayashi, H., 2002, Expert Opin. Investig. Drugs, 11, 965-980). NE is a major common mediator of many pathological changes seen in chronic lung disease including epithelial damage (Stockley, R. A. 1994, Am. J. Resp. Crit. Care Med. 150, 109-113).

The destructive role of NE was solidified almost 40 years ago when Laurell and Eriksson reported an association of chronic airflow obstruction and emphysema with deficiency of serum αi -antitrypsin (Laurell and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140). Subsequently it was determined that αi -antitrypsin is the most important endogenous inhibitor of human NE. The imbalance between human NE and endogenous antiprotease is believed to cause excess human NE in pulmonary tissues which is considered as a major pathogenic factor in chronic obstructive pulmonary disease (COPD). The excessive human NE shows a prominent destructive profile and actively takes part in destroying the normal pulmonary structures, followed by the irreversible enlargement of the respiratory airspaces, as seen mainly in emphysema. There is an increase in neutrophil recruitment into the lungs which is associated with increased lung elastase burden and emphysema in cti -proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab. Invest. 75, 273-280). Individuals with higher levels of the NE-αi protease inhibitor complex in bronchoalveolar lavage fluid show significantly accelerated decline in lung functions compared to those with lower levels (Betsuyaku et al. 2000, Respiration, 67, 261-267). Instillation of human NE via the trachea in rats causes lung haemorrhage, neutrophil accumulation during acute phase and emphysematous changes during chronic phase (Karaki et al., 2002, Am. J. Resp. Crit. Care Med., 166, 496-500). Studies have shown that the acute phase of pulmonary emphysema and pulmonary haemorrhage caused by NE in hamsters can be inhibited by pre-treatment with inhibitors of NE ( Fujie et al.,1999, Inflamm. Res. 48, 160-167).

Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of COPD, including cystic fibrosis and chronic bronchitis. NE impairs mucin production, leading to mucus obstruction of the airways. NE is reported to increase the expression of major respiratory mucin gene, MUC5AC (Fischer, B. M & Voynow, 2002, Am. J. Respir. Cell Biol., 26, 447-452). Aerosol administration of NE to guinea pigs produces extensive epithelial damage within 20 minutes of contact (Suzuki et al., 1996, Am. J. Resp. Crit. Care Med., 153, 1405-1411). Furthermore NE reduces the ciliary beat frequency of human respiratory epithelium in vitro (Smallman et al., 1984, Thorax, 39, 663-667) which is consistent with the reduced mucociliary clearance that is seen in COPD patients (Currie et al., 1984, Thorax, 42, 126-130). The instillation of NE into the airways leads to mucus gland hyperplasia in hamsters (Lucey et al., 1985, Am. Resp. Crit. Care Med., 132, 362-366). A role for NE is also implicated in mucus hypersecretion in asthma. In an allergen sensitised guinea pig acute asthma model an inhibitor of NE prevented goblet cell degranulation and mucus hypersecretion (Nadel et al., 1999, Eur. Resp. J., 13, 190-196). NE has been also shown to play a role in the pathogenesis of pulmonary fibrosis. NE: αi.protenase inhibitor complex is increased in serum of patients with pulmonary fibrosis, which correlates with the clinical parameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11, 120-125). In a murine model of human pulmonary fibrosis, a NE inhibitor reduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am. J. Resp. Crit. Care Med., 156, 260-265). Furthermore investigators have shown that NE deficient mice are resistant to bleomycin-induced pulmonary fibrosis (Dunsmore et al., 2001, Chest, 120, 35S-36S). Plasma NE level was found to be elevated in patients who progressed to ARDS implicating the importance of NE in early ARDS disease pathogenesis. (Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151, 428-1433). The antiproteases and NE complexed with antiprotease are increased in lung cancer area (Marchandise et al., 1989, Eur. Resp. J. 2, 623-629). Recent studies have shown that polymorphism in the promoter region of the NE gene are associated with lung cancer development (Taniguchi et al., 2002, Clin. Cancer Res., 8, 1115-1120.

Acute lung injury caused by endotoxin in experimental animals is associated with elevated levels of NE ( Kawabata, et al., 1999, Am. J. Resp. Crit. Care, 161, 2013-2018). Acute lung inflammation caused by intratracheal injection of lipopolysaccharide in mice has been shown to elevate the NE activity in bronchoalveolar lavage fluid which is significantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J. Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8, 1293-1299). NE also plays an important role in the neutrophil- induced increase of pulmonary microvascular permeability observed in a model of acute lung injury caused by tumour necrosis factor ct (TNFK) and phorbol myristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki et al., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).

A role for NE has also been suggested in monocrotoline-induced pulmonary vascular wall thickening and cardiac hypertrophy (Molteni et al., 1989, Biochemical Pharmacol. 38, 2411-2419). Serine elastase inhibitor reverses the monocrotaline-induced pulmonary hypertension and remodelling in rat pulmonary arteries (Cowan et al., 2000, Nature Medicine, 6, 698-702). Recent studies have shown that serine elastase, that is, NE or vascular elastase are important in cigarette smoke-induced muscularisation of small pulmonary arteries in guinea pigs (Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166, 954-960).

NE plays a key role in experimental cerebral ischemic damage (Shimakura et al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lung injury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) and myocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J. Physiol., 433, 563-570). Human NE levels in plasma are significantly increased above normal in inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26, 1306-1311). In addition NE has also been assumed to be involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol. Int., 6, 57). The development of collagen induced arthritis in mice is suppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol. 165, 26-32).

Thus, human NE is known as one of the most destructive serine proteases and has been implicated in a variety of inflammatory diseases. The important endogenous inhibitor of human NE is αi -antitrypsin. The imbalance between human NE and antiprotease is believed to give rise to an excess of human NE resulting in uncontrolled tissue destruction. The protease/ antiprotease balance may be upset by a decreased availability of αi -antitrypsin either through inactivation by oxidants such as cigarette smoke, or as a result of genetic inability to produce sufficient serum levels. Human NE has been implicated in the promotion or exacerbation of a number of diseases such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia reperfusion injury, rheumatoid arthritis and pulmonary hypertension.

Disclosure of the Invention

In accordance with the present invention, there is provided a compound of formula (I)

(I)

wherein

R represents hydrogen or C i -C4 alkyl;

2 3 2 3

R and R independently represent hydrogen or C\ -C4 alkyl; or R and R together with the carbon to which they are attached form a saturated or partially unsaturated C3-C6 cycloalkyl ring;

4

R represents phenyl or a six-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms; said ring being optionally substituted with at least one substituent selected from halogen, Cj -C₆ alkyl, cyano, Cj -CO alkoxy, nitro, methylcarbonyl,

NR R , C1-C3 alkyl substituted by one or more F atoms and Ci -C3 alkoxy substituted by one or more F atoms;

R represents hydrogen or C 1 -C₆ alkyl;

R represents hydrogen, OH, CN, CHO, C₁-C₆ alkyl, C3-C6 cycloalkyl, C₂-C₆ alkanoyl, CONR¹²R¹³, SO₂R¹², SO₂NR¹²R¹³ or CO₂R¹²; said alkyl, cycloalkyl or alkanoyl group being optionally substituted with one or more F atoms or being optionally substituted with one or more substituents selected from CN, OH, i ? π i ? π 1 2 i ?

CONR R , NR R , SO₂R and CO₂R ;

R represents halogen, C1-C4 alkoxy, CN, OH, NO₂, C1-C3 alkyl substituted by one

17 18 or more F atoms, Cj -C3 alkoxy substituted by one or more F atoms, CONR R ,

CHO, C₂-C₄ alkanoyl, S(O)_pR¹⁹ or OSO₂R²⁰;

X , X , X and X independently represent N or CR , provided that at least one of X ,

X , X and X represents CR ;

0

R at each occurrence independently represents H, halogen, Cj-C₄ alkyl, Cj-C₄ alkoxy, CN or OH;

R and R independently represent H or C 1 -C3 alkyl; said alkyl being optionally further substituted by one or more F atoms;

At each occurrence, eac ,h ^ R12 , ™ R^{1 3} , T R. ¹⁷ , T R. ^{1 8} , R π ¹⁹ and J T R.²⁰ i-nd JependJentl,y represent H or C]-C₄ alkyl;

p represents an integer O, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In the context of the present specification, unless otherwise stated, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. Similarly, an alkylene group may be linear or branched. R represents hydrogen or C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl).

In one embodiment of the invention, R represents H.

In one embodiment of the invention, R represents a C1-C4 or C1-C2 alkyl group, in particular a methyl group.

2 3 R and R represent hydrogen or Cj -C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-

2 3 butyl, isobutyl or tert-butyl), or R and R together with the carbon to which they are attached form a saturated or partially unsaturated C3-C6 cycloalkyl ring (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl).

4 R represents phenyl or a six-membered heteroaromatic ring containing 1 to 3 (e.g. one, two or three) N atoms; said ring being optionally substituted with at least one (e.g. one, two, three or four) substituent selected from halogen (e.g. fluorine, chlorine, bromine or iodine), Ci -Cβ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n- pentyl or n-hexyl), cyano, Ci-Cg alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy), nitro, methylcarbonyl, NR R , Ci -C₃ alkyl substituted by one or more F atoms (e.g. CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CF₃, CF₂CF₃, CH(CF₃)₂ and CH₂CH₂CF₃) and Ci-C₃ alkoxy substituted by one or more F atoms (e.g. OCH₂F, OCHF₂, OCF₃, OCH₂CH₂F, OCH₂CF₃, OCF₂CF₃, OCH(CF₃)₂ and OCH₂CH₂CF₃). 4 In one embodiment, R represents a phenyl or pyridinyl ring substituted with at least one substituent (e.g. one, two or three substituents) independently selected from halogen, cyano, nitro, methyl, trifluoromethyl or methylcarbonyl.

4 In one embodiment, R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine, cyano, nitro and trifluoromethyl.

4 In another embodiment, R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine and trifluoromethyl.

4 In still another embodiment, R represents a phenyl group substituted with a trifluoromethyl substituent (preferably in the meta position).

4 In still another embodiment, R represents a phenyl group substituted with a trifluoromethyl substituent in the meta position.

R represents hydrogen or Cj -Cβ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

R represents hydrogen, OH, CN, CHO, Cj-Cg alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C3-C6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C2-C6 alkanoyl (e.g. methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonyl or isopropylcarbonyl), CONR R , SO2R , 12 13 12

SO2NR R or CO2R ; said alkyl, cycloalkyl or alkanoyl group being optionally substituted with one or more F atoms or being optionally substituted with one or more substituents selected from CN, OH, CONR¹²R¹³, NR¹²R¹³, SO₂R¹² and CO₂R¹².

7 R represents halogen (e.g. fluorine, chlorine, bromine or iodine), C1-C4 alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy), CN, OH, NO₂, C1-C3 alkyl substituted by one or more F atoms (e.g. CH₂F, CHF₂, CF₃, CH₂CH₂F,

CH₂CF₃, CF₂CF₃, CH(CF₃)₂ and CH₂CH₂CF₃), C₁-C₃ alkoxy substituted by one or more F atoms (e.g. OCH₂F, OCHF₂, OCF₃, OCH₂CH₂F, OCH₂CF₃, OCF₂CF₃, OCH(CF₃)₂

17 18 and OCH₂CH₂CF₃), CONR R , CHO, C₂-C₄ alkanoyl (e.g. methylcarbonyl (acetyl),

19 20 ethylcarbonyl, n-propylcarbonyl or isopropylcarbonyl), S(O)_pR or OSO₂R .

In an embodiment of the invention, R represents F, Cl, CN or CF₃.

0 R at each occurrence independently represents H, halogen (e.g. fluorine, chlorine, bromine or iodine), C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-buryl), C1-C4 alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy), CN or OH.

In an embodiment of the invention, each R independently represents H, F, Cl or CN.

Q

In an embodiment of the invention, each R represents H.

1 2 3 4 8 1 2

X , X , X and X independently represent N or CR , provided that at least one of X , X ,

3 4 8 X and X represents CR . Examples of a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. A preferred ring system is pyridinyl. 1 2 3 4

In one embodiment of the invention, each of X , X , X and X independently represents

CR . In this embodiment, the ring comprising X , X , X and X represents a phenyl ring.

1 2 3 4 In one embodiment of the invention, each of X , X , X and X represents CH.

1 2 3 4

In one embodiment of the invention, one of X , X , X and X represents N and the other

8 1 2 3 three independently represents CR . In this embodiment, the ring comprising X , X , X

4 and X represents a pyridinyl ring.

1 2 3 4

In one embodiment of the invention, one of X , X , X and X represents N and the other three represent CH.

In one embodiment, p is 2.

In one embodiment, R and R independently represent H or C1-C3 alkyl (e.g. methyl, ethyl, 1 -propyl or 2-propyl); said alkyl being optionally further substituted by one or more F atoms (e.g. CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CF₃, CF₂CF₃, CH(CF₃)₂ and

CH₂CH₂CF₃).

12 13 17 18 19 20

In an embodiment of the invention, R , R , R , R , R and R each independently represent hydrogen or C1-C4 alkyl, particularly methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, isobutyl and tert-butyl.

12 13 17 18 19 20 In an embodiment of the invention, R , R , R , R , R and R each independently represent hydrogen or methyl.

In an embodiment of the invention, R represents hydrogen or methyl;

4 R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine, cyano, nitro and trifluoromethyl;

R represents hydrogen or methyl;

7 R represents F, Cl, CN or CF3; and

X , X , X and X each represents CR .

In another embodiment of the invention,

R represents hydrogen or methyl;

4 R represents a phenyl group substituted by trifluoromethyl;

R represents hydrogen or methyl;

R represents F, Cl, CN or CF3; and

1 2 3 4

X , X , X and X each represents CH.

Examples of compounds of the invention include :

4-{(2S)- 1 ,4-dimethyl-6-oxo-5-[3-(trifluoromethyl)phenyl]- 1 ,2,3,6-tetrahydropyridin-2- yl}benzonitrile;

4-{(2S)-4-methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridin-2- yl}benzonitrile; (6S)-6-(4-cyanophenyl)-4-methyl-2-oxo-N-propan-2-yl-3-[3-(trifluoromethyl)-phenyl]-

5,6-dihydropyridine- 1 -carboxamide; and pharmaceutically acceptable salts of any one thereof.

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

(H)

wherein R , R , R , R , R , R , X , X , X and X are as defined for formula (I), with a compound R -L wherein L represents a leaving group or with an isocyanate

12 12 R NCO wherein R is as defined for formula (I);

and optionally thereafter:

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

• forming a pharmaceutically acceptable salt of the compound.

In the process, the reaction may conveniently be carried out in an organic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide or N-methylpyrrolidinone at a temperature, for example, in the range from 0 °C to the boiling point of the solvent. If necessary or desired, a base, such as sodium hydride, and/or a coupling reagent such as HATU (O-(7-Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU (O-Benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate), HOAT (l-Hydroxy-7-azabenzotriazole), HOBT (1 -Hy droxybenzotriazole hydrate) or DIEA (N,N-Diisopropylethylamine) may be added. Suitable leaving groups L include halo (for example, bromo, chloro or iodo), sulfonates and hydroxyl (OH). Specific processes for the preparation of compounds of formula (I) are disclosed within the Examples section of the present specification. Such processes form an aspect of the present invention.

The necessary starting materials are either commercially available, are known in the literature or may be prepared using known techniques. Specific processes for the preparation of certain key starting materials are disclosed within the Examples section of the present specification and such processes form an aspect of the present invention.

Thus, for example, dihydropyridones (II) may be prepared by cyclisation of a compound of formula (III)

(III)

4 7 1 2 3 4 wherein R , R , X , X , X and X are as defined above, using a base such as sodium methoxide.

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

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 may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition and/or 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- Interscience (1999).

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or/?-toluenesulphonate.

Compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators of serine proteases such as proteinase 3 and pancreatic elastase and, especially, human neutrophil elastase, and may therefore be beneficial in the treatment or prophylaxis of inflammatory diseases and conditions.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used in the treatment of diseases of the respiratory tract such as obstructive diseases of the airways including: asthma, including refractive, 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); adult respiratory distress syndrome (ARDS), bronchitis, including chronic, infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of bone and joints such as arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal- induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle- Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of 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).

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of skin such as 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.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the eye such as 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.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the gastrointestinal tract such as glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, microscopic colitis, indeterminant colitis, proctitis, pruritis ani; peptic ulcers; coeliac disease, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhoea, and food-related allergies which may have effects remote from the gut (for example, migraine, rhinitis or eczema). The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the cardiovascular system such as 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.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in oncology such as in the 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.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the abdomen such as hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; and pancreatitis, both acute and chronic.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the genitourinary tract such as 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; vulvo-vaginitis; Peyronie's disease; and erectile dysfunction (both male and female).

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of allograft rejection such as acute and chronic rejection following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or following blood transfusion; or chronic graft versus host disease. The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the CNS such as Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; ischaemia; 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 tumour invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV- associated neuropathies; neurosarcoidosis; and central and peripheral nervous system complications of malignant, infectious or autoimmune processes.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome and antiphospholipid syndrome.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of other disorders with an inflammatory or immunological component including acquired immune deficiency syndrome (AIDS), systemic inflammatory response syndrome (SIRS), chronic wound, leprosy, Sezary syndrome and paraneoplastic syndromes.

In particular, the compounds of formula (I) and their pharmaceutically acceptable salts may be used in the treatment of adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, systemic inflammatory response syndrome (SIRS), chronic wound, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis or gastric mucosal injury. More particularly, the compounds of formula (I) and their pharmaceutically acceptable salts may be used in the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis, asthma and rhinitis.

Even more particularly, the compounds of formula (I) and their pharmaceutically acceptable salts may be used in the treatment of chronic obstructive pulmonary disease (COPD).

Thus, the present invention provides a compound of formula (I) 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 (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of neutrophil elastase activity is beneficial.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in the treatment of an inflammatory disease or condition.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, systemic inflammatory response syndrome (SIRS), chronic wound, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis or gastric mucosal injury. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease (COPD).

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 also provides a method of treating, or reducing the risk of, a disease or condition in which inhibition of neutrophil elastase activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

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

The invention still further provides a method of treating, or reducing the risk of, adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, systemic inflammatory response syndrome (SIRS), chronic wound, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis or gastric mucosal injury which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

The invention still further provides a method of treating, or reducing the risk of, chronic obstructive pulmonary disease (COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

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. The daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.

The compounds of formula (I) 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) 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 (I) 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 (I) 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-C₂₀ 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. Thus, the invention 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 agents listed below. Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-I / 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-I); interleukins (IL) including ILl to 23, 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-aIL16R and T-Lymphocytes, CTLA4-Ig, 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 CCRl , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl,

CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CRl 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-I), 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-ls 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- l/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 an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof. 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-IgE (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 antiinflammatory 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, nelfϊnavir, 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 non-steroidal 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) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib 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.subl. - 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.subl. or NK.sub3. 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; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.

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, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), 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 (CI 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 BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or

(ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

In particular the compounds of the invention may be administered in conjunction with a second active ingredient which is selected from: a) a PDE4 inhibitor including an inhibitor of the isoform PDE4D; b) a β-adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol; c) a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; d) a modulator of chemokine receptor function (such as a CCRl or CCR8 receptor antagonist); e) an inhibitor of kinase function; f) a non-steroidal glucocorticoid receptor agonist; g) a steroidal glucocorticoid receptor agonist; and h) a protease inhibitor (such as a MMP 12 or MMP9 inhibitor);

The present invention will now be further explained by reference to the following illustrative examples.

General Methods

¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 400 MHz or a Varian Mercury-YX 300 MHz instrument. The central peaks of chloroform-c/ (δ_H 7.27 ppm), dimethylsulfoxide-<i_<5 (δ_H 2.50 ppm), acetonitrile-dj (5_H 1.95 ppm) or methanol-*^ (5_H 3.31 ppm) were used as internal references. Column chromatography was carried out using silica gel (0.040-0.063 mm, Merck). Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received. The following method was used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate 0.7 ml/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA ; Gradient 15-95%/B 8 min, 95% B 1 min.

Analytical chromatography was run on a Symmetry Ci₈-column, 2.1 x 30 mm with 3.5 μm particle size, with acetonitrile/water/0.1% trifluoroacetic acid as mobile phase in a gradient from 5% to 95% acetonitrile over 8 minutes at a flow of 0.7 ml/min.

10

The abbreviations or terms used in the examples have the following meanings:

DCM Dichloromethane

DIEA N,N-Diisopropylethylamine

DMF N,N-Dimethylformamide

I₅ DMSO Dimethyl sulphoxide

HBTU O-Benzotriazol- 1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate

RT Room temperature

SM Starting material

THF Tetrahydrofuran

20

Example 1

₂₅ 4-(αS)-1.4-Dimethyl-6-oxo-5-r3-(trifluoromethvnphenyll-1.2.3.6-tetrahvdropyridin-2- vUbenzonitrile 4- {(2S)-4-Methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]- 1 ,2,3,6-tetrahydropyridin-2- yl}benzonitrile (0.06 g, 0.168 mmol) was dissolved in dry DMF (0.9 niL). Methyl iodide (0.047 g, 0.337 mmol) was added followed by sodium hydride (0.008 g, 0.202 mmol). The reaction mixture was stirred at RT for 0.5 h. The product was purified by preparative HPLC to give the title compound (0.048 g, 0.130 mmol, 77 %).

¹H NMR (400 MHz, d₆-DMSO) δ 7.89 (d, J= 8.3 Hz, 2H), 7.71 - 7.53 (m, 2H), 7.46 (d, J

= 8.1 Hz, 2H), 7.43 - 7.34 (m, 2H), 4.95 (d, J= 9.4 Hz, IH), 3.28 (dd, J= 7.8, 17.9 Hz, IH), 2.86 (s, 3H), 2.55 (d, J= 2.5 Hz, IH), 1.57 (s, 3H).

APCI-MS ^m/z: 371.1 [MH⁺].

Example 2

4- ((2Sy4-Methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]- 1.2,3,6-tetrahvdropyridin-2- vUbenzonitrile

N-[(l S)-I -(4-Cyanophenyl)-3-oxobutyl]-2-[3-(trifluoromethyl)phenyl]acetamide (0.141 g, 0.38 mmol) was added to ethanol (1.9 mL). To the stirred mixture was added sodium methoxide (0.95 mL, 0.095 mmol) in ethanol. A solution was obtained. The reaction was stirred at 50 ⁰C for 4 h. The product was purified by preparative HPLC giving the title compound (0.073 g, 0.20 mmol, 54 %).

¹H NMR (300 MHz, d₆-DMSO) δ 8.06 (d, J= 2.2 Hz, IH), 7.87 (d, J= 8.4 Hz, 2H), 7.72 -

7.53 (m, 4H), 7.47 - 7.36 (m, 2H), 4.85 (t, J= 7.8 Hz, IH), 2.86 (dd, J= 6.2, 17.6 Hz, IH), 2.58 (dd, J= 7.9, 17.6 Hz, IH), 1.69 (s, 3H). APCI-MS ^m/z: 357.1 [MH⁺]. Example 3

(6S)-6-(4-Cyanophenyl)-4-methyl-2-oxo-N-propan-2-yl-3-r3-(trifluoromethyl^')-phenyll- 5,6-dihvdropyridine- 1 -carboxamide

A solution of 4-{(2S)-4-methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-l,2,3,6- tetrahydropyridin-2-yl}benzonitrile (0.021 g, 0.060 mmol), isopropyl isocyanate (0.0090 mL, 0.090 mmol) and dry THF (1.3 mL) was added dropwise in 1 minute to 60% sodium hydride in mineral oil (0.0036 g, 0.090 mmol) at ice-bath temperature. After stirring for 10 minutes at RT enough 10% acetic acid was added dropwise to the reaction to adjust the pH to 4 to 5. Then the resulting solution was concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.020 g, 75%) as a white solid.

¹H NMR (400 MHz, CD₂Cl₂) δ 9.24 (d, J= 7.2 Hz, IH), 7.69 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.4 Hz, 2H), 7.61 (d, J= 8.0 Hz, IH), 7.51 (t, J= 8.0 Hz, IH), 7.37 (d, J= 8.0 Hz, 2H), 7.33 (br s, IH), 7.23 (d, J= 8.0 Hz, IH), 6.14 (d, J= 6.8 Hz, IH), 3.94 (sext, J= 6.8 Hz, IH), 3.30 (dd, J= 7.6, 18.8 Hz, IH), 2.71 (dd, J= 1.6 Hz₅ J= 18.0 Hz, IH), 1.65 (s, 3H), 1.18 (d, J= 6.8 Hz, 3H), 1.15 (d, J= 6.8 Hz, 3H).

APCI-MS ^m/z: 442.0 [MH⁺] 357.

Preparation of Starting Materials

Starting material SM2

Tert-butyl { ( 1 S)- 1 -(4-cyanophenyl)-3 -rmethoxy(methyl)aminol -3 -oxopropyl } carbamate (3S)-3-[(Tert-butoxycarbonyl)amino]-3-(4-cyanophenyl)propanoic acid (SMl ; commercially available) (2.0 g, 6.90 mmol), N,O-dimethylhydroxylamine hydrochloride (0.70 g, 7.24 mmol) and HBTU (2.88 g, 7.59 mmol) were added to dry DMF (28 niL). DIEA (3.71 mL, 21.7 mmol) was added and the reaction mixture was stirred at RT overnight. The solution was poured into a mixture of ethyl acetate and water. The organic layer was separated and the water phase was washed twice with ethyl acetate. The combined organic phases were washed with a small portion of water and dried over sodium sulphate. The solvent was removed by evaporation at reduced pressure and the crude residue was used directly in the synthesis of SM3.

APCI-MS "Vz: 234.0 [MH⁺-IOO (BOC-group)].

Starting material SM3

(3S)-3-(4-Cvanophenyl)-N-methoxy-N-methyl-3-(U3-(trifluoromethyl)phenyl1acetvU amino)propanamide

Crude tert-butyl {(lS)-l-(4-cyanophenyl)-3-[methoxy(methyl)amino]-3- oxopropyl} carbamate (SM2) was dissolved in DCM (10 mL) and trifluoroacetic acid (10 mL). The reaction mixture was stirred for 1.5 h. The solvents were evaporated and the crude product dissolved in sodium carbonate (IM in water) and ethyl acetate. After shaking, the organic layer was separated. The water phase was washed several times with ethyl acetate until no product was detected. The combined organic phases were dried over sodium sulphate. The solvent was removed by evaporation under reduced pressure and the crude product was dissolved in DMF (30 mL). [3 -(Trifluoromethyl)phenyl] -acetic acid (1.48 g, 7.25 mmol), HBTU (3.02 g, 7.97 mmol) and finally DIEA (3.72 mL, 21.75 mmol) were added. The reaction was stirred at RT overnight. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and the water phase was washed twice with ethyl acetate. The combined organic layers were washed once with a small amount of water and dried over sodium sulphate. Flash chromatography gave the title compound (2.33 g, 5.56 mmol, 80 % from SMl).

¹H NMR (400 MHz, d₆-DMSO) δ 8.75 (d, J= 7.5 Hz, IH), 7.82 - 7.43 (m, 8H), 5.33 - 5.19 (m, IH), 3.61 (s, 3H), 3.57 (s, 3H), 3.03 (s, 3H), 2.97 - 2.80 (m, 3H), 1.86 (s, 3H). APCI-MS ^m/z: 420.0 [MH⁺].

Starting material SM4

N-[Cl S)-l-(4-Cvanophenyl)-3-oxobutyll-2-[3-(trifluoromethyl)phenyl]acetamide A solution of (3S)-3-(4-cyanophenyl)-N-methoxy-N-methyl-3-({[3- (trifluoromethyl)phenyl] acetyl }amino)propanamide (SM3) (0.20 g, 0.48 mmol) in dry THF (3 mL) under argon was cooled to - 78 °C. 1.6M Methyl lithium in THF (0.89 mL, 1.43 mmol) was added. The reaction was stirred for 15 min. The cooling bath was removed. After 5 min, the reaction was quenched by the addition of hydrochloric acid in methanol. The crude mixture was poured into a mixture of ethyl acetate and water. After shaking, the organic layer was separated. The water phase was washed with ethyl acetate. The combined organic phases were dried over sodium sulphate. The product was purified by preparative HPLC giving the title compound (0.036 g, 0.096 mmol, 20%).

¹H NMR (400 MHz, d₆-DMSO) δ 8.71 (d, J= 7.7 Hz, IH), 7.78 - 7.44 (m, 8H), 5.28 - 5.21 (m, IH), 3.55 (s, 2H), 2.93 (d, J= 6.8 Hz, 2H), 2.07 (s, 3H). APCI-MS "Vz: 375.0 [MH⁺]. Human Neutrophil Elastase Quenched-FRET Assay The assay uses Human Neutrophil Elastase (HNE) purified from serum (Calbiochem art. 324681; Ref. Baugh, RJ. et al., 1976, Biochemistry. 15, 836-841). HNE was stored in 50 mM sodium acetate (NaOAc), 200 mM sodium chloride (NaCl), pH 5.5 with added 30% glycerol at -2O⁰C. The protease substrate used was Elastase Substrate V Fluorogenic, MeOSuc- AAPV- AMC (Calbiochem art. 324740; Ref. Castillo, MJ. et al., 1979, Anal. Biochem. 99, 53-64). The substrate was stored in dimethyl sulphoxide (DMSO) at -20⁰C. The assay additions were as follows: Test compounds and controls were added to black 96- well flat-bottom plates (Greiner 655076), 1 μL in 100% DMSO, followed by 30 μL HNE in assay buffer with 0.01% Triton (trade mark) X-100 detergent. The assay buffer constitution was: 100 mM Tris(hydroxymethyl)aminomethane (TRIS) (pH 7.5) and 500 mM NaCl. The enzyme and the compounds were incubated at room temperature for 15 minutes. Then 30 μl substrate in assay buffer was added. The assay was incubated for 30 minutes at room temperature. The concentrations of HNE enzyme and substrate during the incubation were 1.7 nM and 100 μM, respectively. The assay was then stopped by adding 60 μl stop solution (140 mM acetic acid, 200 mM sodium monochloroacetate, 60 mM sodium acetate, pH 4.3). Fluorescence was measured on a Wallac 1420 Victor 2 instrument at settings: Excitation 380 nm, Emission 460 nm. IC50 values were determined using Xlfit curve fitting using model 205.

When tested in the above screen, the compounds of the Examples gave IC50 values for inhibition of human neutrophil elastase activity of less than 30 μM (micromolar), indicating that the compounds of the invention are expected to possess useful therapeutic properties. Specimen results are shown in the following Table:

Claims

C L A I M S

1. A compound of formula (I)

(I)

wherein

R represents hydrogen or C1-C4 alkyl;

2 3 2 3

4 R represents phenyl or a six-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms; said ring being optionally substituted with at least one substituent selected from halogen, Cj-Cg alkyl, cyano, Cj-Cg alkoxy, nitro, methylcarbonyl,

NR R , C] -C3 alkyl substituted by one or more F atoms and C \ -C3 alkoxy substituted by one or more F atoms; R represents hydrogen or C i -C₆ alkyl;

R⁶ represents hydrogen, OH, CN, CHO, Cj-C₆ alkyl, C₃-C₆ cycloalkyl,

C₂-C₆ alkanoyl, CONR¹²R¹³, SO₂R¹², SO₂NR¹²R¹³ or CO₂R¹²; said alkyl, cycloalkyl or alkanoyl group being optionally substituted with one or more F atoms or being optionally substituted with one or more substituents selected from CN, OH,

CONR¹²R¹³, NR¹²R¹³, SO₂R¹² and CO₂R¹²;

17 18 or more F atoms, C1-C3 alkoxy substituted by one or more F atoms, CONR R ,

CHO, C₂-C₄ alkanoyl, S(O)_pR¹⁹ or OSO₂R²⁰;

X , X and X represents CR ;

R at each occurrence independently represents H, halogen, C1-C4 alkyl, Cj-C₄ alkoxy, CN or OH;

R and R independently represent H or C1-C3 alkyl; said alkyl being optionally further substituted by one or more F atoms;

At each occurrence, each R , R , R , R , R and R independently represent H or Cj-C₄ alkyl;

p represents an integer O, 1 or 2;

pharmaceutically acceptable salt thereof. 4 2. A compound according to Claim 1, wherein R represents a phenyl group substituted

with one or two substituents independently selected from F, Cl, CN, NO2 and CF3.

1 2 3 4

3. A compound according to Claim 1 or Claim 2, wherein each of X , X , X and X

O independently represents CR .

1 2 3 4

4. A compound according to Claim 1 or Claim 2, wherein one of X , X , X and X g represents N and the other three independently represent CR .

5. A compound according to any one of Claims 1 to 4, wherein R represents F, Cl, CN or CF₃.

O

6. A compound according to any one of Claims 1 to 5, wherein R represents H, F, Cl or

CN.

7. A compound according to any one of Claims 1 to 6, wherein R represents C1-C4 alkyl.

8. A compound of formula (I) as defined in Claim 1 selected from: 4-{(2S)-l,4-dimethyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridin-2- yl}benzonitrile;

4-{(2S)-4-methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridin-2- yl}benzonitrile;

(6S)-6-(4-cyanophenyl)-4-methyl-2-oxo-N-propan-2-yl-3-[3-(trifluoromethyl)-phenyl]- 5,6-dihydropyridine- 1 -carboxamide; and pharmaceutically acceptable salts of any one thereof.

9. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which comprises reacting a compound of formula (II)

(H)

wherein R¹, R², R³, R⁴, R⁵, R⁷, X¹, X², X³ and X⁴ are as defined in Claim 1, with a compound R -L wherein L represents a leaving group or with an isocyanate R NCO wherein R is as defined in Claim 1 ; o and optionally thereafter:

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

• forming a pharmaceutically acceptable salt of the compound.

10. A pharmaceutical composition comprising a compound of formula (I) or as pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A process for the preparation of a pharmaceutical composition as claimed in claim 10 which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salto thereof as claimed in any one of claims 1 to 8 with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. A compound of formula (I) or a pharmaceutically-acceptable salt thereof as claimed in any one of claims 1 to 8 for use in therapy.

13. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of neutrophil elastase activity is beneficial.

14. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, systemic inflammatory response syndrome (SIRS), chronic wound, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis or gastric mucosal injury.

15. A method of treating, or reducing the risk of, a disease or condition in which inhibition of neutrophil elastase activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8.

16. A method of treating, or reducing the risk of, an inflammatory disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8.

17. A method according to Claim 15 or Claim 16, wherein the disease or condition is adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, systemic inflammatory response syndrome (SIRS), chronic wound, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis or gastric mucosal injury.