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WO2009058076A1 - Dérivés de 2-pyrazinone et leur utilisation comme inhibiteurs de l'élastase des neutrophiles - Google Patents

Dérivés de 2-pyrazinone et leur utilisation comme inhibiteurs de l'élastase des neutrophiles Download PDF

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Publication number
WO2009058076A1
WO2009058076A1 PCT/SE2008/051220 SE2008051220W WO2009058076A1 WO 2009058076 A1 WO2009058076 A1 WO 2009058076A1 SE 2008051220 W SE2008051220 W SE 2008051220W WO 2009058076 A1 WO2009058076 A1 WO 2009058076A1
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alkyl
compound
formula
ring
phenyl
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Frank Burkamp
Peter Hansen
Nafizal Hossain
Annéa LISIUS
Hans LÖNN
Michael Lundkvist
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to 2-pyrazinone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • 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.
  • NE 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.
  • 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).
  • 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 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.
  • neutrophil recruitment into the lungs which is associated with increased lung elastase burden and emphysema in ⁇ i-proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab. Invest. 75, 273-280).
  • Individuals with higher levels of the NE-(X 1 protease inhibitor complex in bronchoalveolar lavage fluid show significantly accelerated decline in lung functions compared to those with lower levels (Betsuyaku et al.
  • 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).
  • 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.
  • NE 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: ⁇ i.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).
  • 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).
  • 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 K. (TNFH.) and phorbol myristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki et al., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).
  • TNFH. tumour necrosis factor K.
  • PMA phorbol myristate acetate
  • NE 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).
  • 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).
  • 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).
  • 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 ⁇ i-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 ⁇ i-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.
  • diseases such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia reperfusion injury, rheumatoid arthritis and pulmonary hypertension.
  • R represents hydrogen or Q-C ⁇ alkyl
  • W represents phenyl or a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms; and wherein the phenyl or heteroaromatic ring is optionally substituted by at least one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, CN, OH, NO2, C1-C3 alkyl substituted by one or more F atoms, Q-C3 alkoxy substituted by one or more F atoms, NR 10 R 11 , C ⁇ CR 15 , CONR 16 R 17 , CHO, C 2 -C 4 alkanoyl, S(O) x R 18 and OSO 2 R 19 ;
  • R represents phenyl or a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms; said ring being optionally substituted in the 4- (para) position with F, Cl, CN or CF 3 ;
  • R , R , R and R independently represent H, Ci -C ⁇ alkyl, formyl or C 2 -Cg alkanoyl; or the group -NR R or -NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR 26 ;
  • R and R independently represent H, Q-C3 alkyl or Si(CH 3 ⁇ ; R , R , R and R independently represent H or C1-C3 alkyl; said alkyl being optionally substituted by one or more F atoms;
  • R represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said ring being optionally substituted with at least one substituent selected from halogen, Ci-Cg alkyl, cyano, Ci-Cg alkoxy, nitro, methylcarbonyl, NR R , C1-C3 alkyl substituted by one or more F atoms or C1-C3 alkoxy substituted by one or more F atoms;
  • R and R independently represent H or Ci -C3 alkyl; said alkyl being optionally further substituted by one or more F atoms;
  • R represents hydrogen or Ci-Cg alkyl optionally substituted with at least one substituent selected from fluoro, hydroxyl and Q-Cg alkoxy;
  • 24 X represents a single bond, O, NR or a group -Ci-Cg alkylene-Y-, wherein Y
  • alkylene 24 represents a single bond, oxygen atom, NR or S(0) w ; and said alkylene being optionally further substituted by OH, halogen, CN, NR 37 R 38 , C x -C 3 alkoxy, CONR 39 R 40 , CO 2 R 66 ,
  • R represents a monocyclic ring system selected from i) phenoxy, ii) phenyl, iii) a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, iv) a saturated or partially unsaturated C3-C6 cycloalkyl ring, or v) a saturated or partially unsaturated 4- to 7-membered heterocyclic ring comprising at
  • ring heteroatom selected from oxygen, S(O) r and NR , wherein at least one of the ring carbon atoms may be optionally replaced by a carbonyl group,
  • R represents a bicyclic ring system in which the two rings are independently selected from the monocyclic ring systems defined in ii), iii), iv) and v) above, wherein the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group selected from oxygen, S(O)t or Ci-Cg alkylene optionally comprising one or more internal or terminal heteroatoms selected from oxygen, sulphur
  • the monocyclic or bicyclic ring system being optionally substituted by at least one
  • Q-C3 alkyl substituted by SO 2 R or by one or more F atoms; said Q-C 6 alkyl being optionally further substituted with at least one substituent selected from cyano, hydroxyl, Ci-C 6 alkoxy, Ci-C 6 alkylthio and -C(O)NR 22 R 23 ;
  • R represents hydrogen, Ci -C ⁇ alkyl, Ci -C ⁇ alkylcarbonyl or
  • R represents hydrogen, Ci-C ⁇ alkyl or C3-C8 cycloalkyl; said alkyl or cycloalkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, Ci -C 3 alkoxy and CONR 59 R 60 ;
  • R and R independently represent H, Ci-Cg alkyl, formyl or C2-Cg alkanoyl
  • R and R independently represent H, Q-C ⁇ alkyl, formyl, C2-C6 alkanoyl,
  • alkyl group being optionally further substituted by halogen, CN, C1-C4 alkoxy or CONR 64 R 65 ;
  • R and R independently represent H, Q-C ⁇ alkyl or C3-C6 cycloalkyl
  • p O, 1 or 2; q is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 or 2; w is 0, 1 or 2; x is 0, 1 or 2; v is 0, 1 or 2;
  • R 16 R 17 R 22 R 23 R 24 R 26 R 27 R 31 R 32 R 39 R 4 ° R 42 R 43 R 44 R 45 R 46 R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 6 °, R 62 , R 63 , R 64 , R 65 and R 66 each independently represent hydrogen or Ci-C ⁇ alkyl;
  • an alkyl, alkenyl or alkynyl substituent group or an alkyl moiety in a substituent group may be linear or branched.
  • an alkylene group may be linear or branched.
  • R represents hydrogen or Q-C ⁇ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
  • R represents a C1-C4 or Ci -C 2 alkyl group, in particular a methyl group.
  • W represents phenyl or a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms; and wherein the phenyl or heteroaromatic ring is optionally substituted by at least one substituent selected from halogen (e.g. fluorine, chlorine, bromine or iodine), C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C1-C4 alkoxy (e.g.
  • halogen e.g. fluorine, chlorine, bromine or iodine
  • C1-C4 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl
  • C1-C4 alkoxy e.g.
  • Ci-C 3 alkoxy substituted by one or more F atoms e.g. OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 2 F, OCH 2 CF 3 , OCF 2 CF 3 , OCH(CF 3 ) 2 and OCH 2 CH 2 CF 3
  • F atoms e.g. OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 2 F, OCH 2 CF 3 , OCF 2 CF 3 , OCH(CF 3 ) 2 and OCH 2 CH 2 CF 3
  • NR 10 R 11 C ⁇ CR 15 -C(O)NR 16 R 17 , CHO
  • C 2 -C4 alkanoyl e.g. methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonyl or isopropylcarbonyl
  • -S(O) x R e.g. methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonyl or isopropylcarbonyl
  • -S(O) x R e.g. methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonyl or isopropylcarbonyl
  • -S(O) x R e.g. methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonyl or isopropylcarbonyl
  • -S(O) x R e.g. methylcarbonyl (acetyl), ethylcarbonyl, n
  • the group R and the pyrazinone ring are bonded to the phenyl or 6- membered heteroaromatic ring W in a 1,2-relationship.
  • W represents a phenyl ring, especially an unsubstituted phenyl ring.
  • W represents a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms, especially an unsubstituted 6-membered heteroaromatic ring.
  • W represents a pyrazinyl, pyrimidinyl or pyridinyl ring, especially an unsubstituted pyrazinyl, pyrimidinyl or pyridinyl ring.
  • R represents phenyl or a 6-membered heteroaromatic ring comprising 1 to 3 (e.g. one, two or three) ring nitrogen atoms; said ring being optionally substituted in the 4- (para) position with F, Cl, CN or CF3.
  • 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms
  • examples of a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • R represents phenyl or pyridinyl; said ring being optionally substituted in the 4- (para) position with F, Cl, CN or CF3.
  • R represents phenyl or pyridinyl; said ring being 4-
  • R represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 (e.g. one, two or three) heteroatoms independently selected from O, S and N; 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-Cg alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), cyano, Q-Cg alkoxy (e.g.
  • Ci -C 3 alkyl substituted by one or more F atoms e.g. CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CF 3 , CF 2 CF 3 , CH(CF 3 ) 2 and CH2CH2CF3 and C1-C3 alkoxy substituted by one or more F atoms (e.g. OCH2F, OCHF 2 , OCF 3 , OCH 2 CH 2 F, OCH 2 CF 3 , OCF 2 CF 3 , OCH(CF 3 ) 2 and OCH 2 CH 2 CF 3 ).
  • F atoms e.g. CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CF 3 , CF 2 CF 3 , CH(CF 3 ) 2 and CH2CH2CF3
  • C1-C3 alkoxy substituted by one or more F atoms e.g. OCH2F, OCHF 2 , OCF 3
  • 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, trifiuoromethyl and methylcarbonyl.
  • substituent e.g. one, two or three substituents
  • R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine, cyano, nitro and trifiuoromethyl.
  • R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine and trifiuoromethyl.
  • R represents a phenyl group substituted with a trifiuoromethyl substituent (preferably in the meta position).
  • R represents a phenyl group substituted in the meta position with Br, Cl, CF 3 or CN.
  • Ci-Cg alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • at least one substituent e.g. one or two substituents
  • Q-Cg alkoxy e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n- pentoxy or n-hexoxy.
  • R represents hydrogen or C1-C4 alkyl optionally substituted with one or two substituents independently selected from hydroxyl and C1-C4 alkoxy. 4 In another embodiment, R represents hydrogen.
  • X represents a single bond or a group -Ci-Cg
  • alkylene-Y- wherein Y represents a single bond, oxygen atom, NR or S(O) W ; said alkylene being optionally further substituted by OH, halogen, CN, NR R , Q-C3
  • X represents a single bond or a group -Ci-Cg
  • X represents a group -Ci-Cg alkylene-Y- and Y represents a single bond and the alkylene moiety is a linear or branched Ci-Cg or C1-C4 or Ci-C 2 alkylene, optionally substituted by OH, halogen, CN, CO 2 R or C1-C3 alkoxy.
  • X represents unsubstituted Ci-C 2 alkylene, particularly methylene.
  • X represents a single bond.
  • R and X are joined together such that the group
  • 4 -NR X together represents a 5 to 7 membered azacyclic ring optionally incorporating one
  • Ci-Cg alkyl or NR R said alkyl being optionally further substituted by OH.
  • heteroatom selected from O, S and NR include pyrrolidine, piperidine, piperazine, morpholine and perhydroazepine.
  • R represents a monocyclic ring system selected from i) phenoxy, ii) phenyl, iii) a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, iv) a saturated or partially unsaturated C3-C6 cycloalkyl ring, or v) a saturated or partially unsaturated 4- to 7-membered heterocyclic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently
  • R represents a bicyclic ring system in which the two rings are independently selected from the monocyclic ring systems defined in ii), iii), iv) and v) above, wherein the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group selected from oxygen, S(O)t or Ci-C ⁇ alkylene optionally comprising one or more (e.g. one or two) internal or terminal heteroatoms selected from
  • oxygen, sulphur and NR being optionally substituted by at least one substituent (e.g. one or two substituents) independently selected from hydroxyl, oxo and Ci-C ⁇ alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy); the monocyclic or bicyclic ring system being optionally substituted (on a ring atom) by at least one substituent (e.g. one, two or three substituents) independently selected from oxygen (e.g. to form an N-oxide), CN, OH, Q-C ⁇ alkyl (e.g.
  • Q-C ⁇ alkoxy e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy
  • halogen e.g. fluorine, chlorine, bromine or io
  • Q-Cg alkyl being optionally further substituted with at least one substituent selected from cyano, hydroxyl, Ci-Cg alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy), Q-Cg alkylthio (e.g. methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio,
  • R 22 tert-butylthio, n-pentylthio or n-hexylthio) and -C(O)NR R ; or R may also represent hydrogen.
  • Examples of a 5- or 6-membered heteroaromatic ring include furanyl, thienyl, pyrrolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl.
  • Preferred heteroaromatic rings include isoxazolyl, pyridinyl, imidazolyl and triazolyl.
  • a "saturated or partially unsaturated C 3 -Cg cycloalkyl ring” denotes a 3- to 6-membered non-aromatic cycloalkyl ring optionally incorporating one or more double bonds, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.
  • a preferred cycloalkyl ring is cyclopropyl.
  • a "saturated or partially unsaturated 4- to 7-membered heterocyclic ring" as specified above denotes a 4- to 7-membered non-aromatic heterocyclic ring optionally incorporating one or more double bonds and optionally incorporating a carbonyl group, examples of which include tetrahydro furanyl, tetramethylenesulfonyl, tetrahydropyranyl, 4-oxo-4H-pyranyl (4H-pyran-4-onyl), pyrrolidinyl, 3-pyrrolinyl, imidazolidinyl, 1,3-dioxolanyl (1,3-dioxacyclopentanyl), piperidinyl, piperazinyl, morpholinyl, perhydroazepinyl (hexamethylene iminyl), pyrrolidonyl and piperidonyl.
  • a preferred saturated or partially unsaturated 4- to 7- membered heterocyclic ring is pyr
  • bicyclic ring systems in which the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group
  • a linker group examples include biphenyl, thienylphenyl, pyrazolylphenyl, phenoxyphenyl, phenylcyclopropyl, naphthyl, indanyl, quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl, quinoxalyl, chromanyl, isocromanyl, 3H-indolyl, lH-indazolyl, quinuclidyl, tetrahydronaphth
  • R represents a substituted monocyclic ring system as defined above.
  • R represents a substituted bicyclic ring system as defined above.
  • R represents H.
  • X represents a single bond and R represents H.
  • R represents a monocyclic ring system selected from i) phenoxy, ii) phenyl, iii) a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur, iv) a saturated or partially unsaturated C3-C6 cycloalkyl ring, or v) a saturated or partially unsaturated 4- to 7-membered heterocyclic ring comprising one
  • R represents a bicyclic ring system in which the two rings are independently selected from the monocyclic ring systems defined in ii), iii), iv) and v) above, wherein the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group selected from oxygen, methylene and S(O)t; the monocyclic or bicyclic ring system being substituted by one or two substituents
  • R represents a monocyclic ring system selected from phenyl or a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms independently selected from nitrogen and oxygen, the monocyclic ring system being substituted by one or two substituents independently selected from OH,
  • R represents phenyl or pyridinyl substituted
  • R represents phenyl substituted by one or
  • R represents an unsubstituted C3-C6 cycloalkyl ring, particularly cyclopropyl.
  • x is 2. In one embodiment, p is 2.
  • R and R independently represent H, Ci-C 3 alkyl or C2-C3 alkylcarbonyl.
  • R and R independently represent H, Ci-C 3 alkyl or
  • R represents hydrogen, methyl, ethyl, methylcarbonyl (acetyl), ethylcarbonyl, methoxycarbonyl or ethoxycarbonyl.
  • v is 2.
  • R represents hydrogen, Q-C ⁇ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C 3 -Cs cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl); said alkyl or cycloalkyl group being optionally further substituted by one or more substituents selected independently from OH,
  • Q-C ⁇ alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • C 3 -Cs cycloalkyl cyclo
  • R represents C1-C4 alkyl or C 3 -Cg cycloalkyl.
  • R represents Ci-C 3 alkyl (particularly methyl, ethyl or isopropyl) or cyclopropyl.
  • R represents Ci-C 3 alkyl (particularly methyl, ethyl or isopropyl) or cyclopropyl.
  • R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R" R 5S , R 59 , R 60 , R 62 , R 63 , R 64 , R 65 and R 66 each independently represent hydrogen or C1-C3 alkyl, particularly methyl, ethyl, 1 -propyl or 2-propyl.
  • R 38 R 47 R 48 R 61 R 22 R 23 R 24 R 26 R 27 R 31 R 32 R 39 R 4 ° R 42 R 43 R 44 R 45 R 46 R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 5 ', R 6 °, R 62 , R 63 , R 64 , R 65 and R 66 each independently represent hydrogen or methyl.
  • R represents hydrogen
  • R represents methyl
  • 2-pyrazinone ring are bonded to the phenyl ring W in a 1,2-relationship
  • R represents phenyl or pyridinyl; said ring being optionally substituted in the A- (para) position with F, Cl, CN or CF3;
  • R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine, cyano, nitro or trifluoromethyl;
  • X represents unsubstituted C1-C2 alkylene, particularly methylene
  • R represents phenyl substituted by one or two substituents independently selected
  • R represents methyl
  • W represents a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen
  • R represents phenyl or pyridinyl; said ring being optionally substituted in the A-
  • R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine, cyano, nitro or trifluoromethyl;
  • X represents unsubstituted Q-C2 alkylene, particularly methylene
  • R represents phenyl substituted by one or two substituents independently selected
  • R represents methyl
  • 14 W represents a phenyl ring, and the group R and the 2-pyrazinone ring are bonded to the phenyl ring W in a 1,2-relationship;
  • R represents phenyl or pyridinyl; said ring being optionally substituted in the A-
  • R represents a phenyl group substituted with one or two substituents independently selected from fluorine, chlorine, cyano, nitro or trifluoromethyl;
  • X represents a single bond or unsubstituted C1-C2 alkylene, particularly methylene; and R represents H.
  • R represents methyl
  • W represents a 6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen
  • R represents phenyl or pyridinyl; said ring being 4- (para) substituted with F, Cl or
  • R represents a phenyl group substituted in the meta position with Br, Cl, CF3 or CN;
  • X represents a single bond or unsubstituted C1-C2 alkylene, particularly methylene
  • R represents H.
  • Examples of compounds of the invention include:
  • L represents a leaving group (such as halogen or hydroxyl) and R , R , R and W are as defined in formula (I), with a compound of formula
  • Hal represents a halogen atom and X, R , R , R and R are as defined in formula
  • Hal represents a halogen atom and W, X, R , R , R and R are as defined in formula (I),
  • R is as defined in formula (I) and M represents an organo-tin or organo boronic acid group; and optionally after (a), (b) or (c) carrying out one or more of the following:
  • the reaction may conveniently be carried out in an organic solvent such as dichloromethane or N-methylpyrrolidinone at a temperature, for example, in the range from 0 0 C to the boiling point of the solvent.
  • a base and/or a coupling reagent such as HATU (O-(7-Azabenzotriazol-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.
  • HATU O-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • HOAT l-Hydroxy-7-azabenzo
  • the reaction may conveniently be carried out in an organic solvent such as DMF, NMP or toluene or a mixture thereof at elevated temperature (i.e. above ambient temperature, 20 0 C), for example, in the range from 50 0 C to 150 0 C and in the presence of a suitable transition metal catalyst such as bis(tri-t-butylphosphine)palladium. If necessary or desired, a base such as potassium carbonate may be added.
  • an organic solvent such as DMF, NMP or toluene or a mixture thereof at elevated temperature (i.e. above ambient temperature, 20 0 C)
  • a suitable transition metal catalyst such as bis(tri-t-butylphosphine)palladium
  • a base such as potassium carbonate may be added.
  • 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.
  • an acid addition salt such as a hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or/?-toluenesulphonate.
  • 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 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
  • 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
  • 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).
  • 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 osteon
  • 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 in
  • 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; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial.
  • diseases of the eye such as blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; 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, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, non-inflammatory diarrhoea, and food-related allergies which may have effects remote from the gut (for example, migraine, rhinitis or eczema).
  • diseases of the gastrointestinal tract such as 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, non-inflammatory diarrhoe
  • 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 autoimmune 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.
  • diseases of the cardiovascular system such as atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and autoimmune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infect
  • 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.
  • 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 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' disease, ulcerative colitis and gastric mucosal injury.
  • ARDS adult respiratory distress syndrome
  • cystic fibrosis pulmonary emphysema
  • bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension
  • asthma including refractive asthma,
  • the compounds of formula (I) and their pharmaceutically acceptable salts may be used in the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, asthma and rhinitis.
  • COPD chronic obstructive pulmonary disease
  • cystic fibrosis cystic fibrosis
  • bronchiectasis asthma and rhinitis.
  • the compounds of formula (I) and their pharmaceutically acceptable salts may be used in the treatment of chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention provides a compound of formula (I) or a pharmaceutically- acceptable salt thereof as hereinbefore defined for use in therapy.
  • 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.
  • 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.
  • 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.
  • 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' disease, ulcerative colitis and gastric mucosal injury.
  • ARDS adult respiratory distress syndrome
  • cystic fibrosis pulmonary emphysema
  • bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary
  • 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).
  • COPD chronic obstructive pulmonary disease
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for the treatment of human diseases or conditions in which modulation of neutrophil elastase activity is beneficial.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for the treatment of an inflammatory disease or condition.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for 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'disease, ulcerative colitis and gastric mucosal injury.
  • ARDS adult respiratory distress syndrome
  • cystic fibrosis pulmonary emphysema
  • bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hyper
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for the treatment of chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • 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'disease, ulcerative colitis and 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.
  • ARDS adult respiratory distress syndrome
  • cystic fibrosis pulmonary emphysema
  • bronchitis including chronic bronchi
  • 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.
  • COPD chronic obstructive pulmonary disease
  • 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.
  • 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.
  • 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.
  • 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, heptafiuoroalkane (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.
  • HFA heptafiuoroalkane
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a Cs-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.
  • a dispersant such as a Cs-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the active ingredient with or without a carrier substance, is delivered to the patient.
  • 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.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • 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.
  • 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.
  • 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 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.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents 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, intravepiroxicam, rt
  • 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- ⁇ ) 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.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signal
  • 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).
  • 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,
  • 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 metallopro tease (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-IO), and stromelysin-3 (MMP- 11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metallopro tease
  • 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, M
  • 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.
  • 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.
  • PDE phosphodiesterase
  • 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.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochlor
  • 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.
  • 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.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • 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.
  • 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.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • 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 transcripta
  • 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.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as
  • 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.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dop
  • 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);
  • - or B.sub2. -receptor antagonist for example colchicine;
  • anti-gout agent for example colchicine;
  • xanthine oxidase inhibitor for example allopurinol;
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone;
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.
  • NKP-608C sub 1. or NK.sub3.
  • receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418;
  • elastase inhibitor such as UT-77 or ZD-0892;
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7; or
  • 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
  • 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,
  • 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 5 ⁇ -reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasm
  • 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 ⁇ v ⁇ 3 function or an angiostatin);
  • 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
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin
  • 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;
  • 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;
  • 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.
  • GDEPT gene-directed enzyme pro-drug therapy
  • 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 ⁇ -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 kina
  • Reagents a) (2-chlorophenyl)boron ⁇ c acid, Pd(Pph 3 ) 4 , aq Na 2 CO 3 , tol, b) fert-butyl glycinate hydrochloride, 1 ,1 '-carbonyl diimidazole, DMF, c) (4-cyanophenyl) boronic acid, Pd(Pph 3 ) 4 , aq Na 2 CO 3 , tol
  • Aqueous Na 2 CO 3 (6 ml, 2M) was added to a mixture of SM2 (1.6 g, 4.09 mmol) and (2- chlorophenyl)boronic acid (1.28 g, 8.18 mmol) in toluene (10 mL). This mixture was degassed by flushing with N 2 gas. Pd(PpIi 3 ) 4 (0.2 g) was added and the reaction mixture was stirred at 105 0 C for 3h, cooled to RT, and partitioned between ethyl acetate (400 ml) and water (100 ml).
  • Methyl 6-bromo-5-methyl-3- oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (SM2, 147 mg, 0.38 mmol) was added to the solution and the reaction mixture was stirred at RT. After 4h, the solids were allowed to settle. The dark supernatant was withdrawn with a syringe and transferred to a dry flask furnished with a magnetic stirrer, septum and argon inlet.
  • Methyl 3'-(4-cyanophenyl)-3-methyl-5-oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro- 2,2'-bipyrazine-6-carboxylate (0.016 g, 0.03 mmol) and 7.0M ammonia in methanol (1 mL, 7.00 mmol) were mixed in a vial and run in a Biotage microwave reactor at 60 0 C for 7 minutes. The solution was concentrated in a stream of dry nitrogen.
  • 6-r4-(4-Cvanophenyl)pyrimidin-5-yll-5-methyl-3-oxo-4-r3-(trifluoromethyl)phenyll-3,4- dihydropyrazine-2-carboxamide iPrMgCl-LiCl (23.5 ml, 23.8 mmol, 14% in THF) was added to a dried argon flushed container and was cooled in an ethanol/CC> 2 -bath in order to get an internal temperature of around -15 0 C.
  • 4-Iodobenzonitrile (5.2 g, 22.7 mmol) was added in one portion and the mixture was stirred for 30 min at -10 0 C.
  • Tri-tertbutyl phosphine (1.45 mg, 0.0072 mmol) was added and the mixture was degassed three times and then stirred at 45 0 C overnight. EtOAc was added and the mixture was washed with a solution of NaHCO ⁇ . The organic phase was evaporated. The crude product was purified by preparative HPLC (water/MeCN/1% TFA) to give methyl 6-[4-(4-cyanophenyl)pyrimidin-5-yl]-5-methyl-3-oxo-4-[3- (trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (18 mg, 23 %). APCI-MS m /z: 492 [MH + ].
  • Methyl 6-[4-(4-cyanophenyl)pyrimidin-5-yl]-5-methyl-3-oxo-4-[3- (trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (18 mg, 0.04 mmol) and 7M ammonia in methanol (500 ⁇ l) were stirred at 50 0 C for 0.5h.
  • N-(2-Hydroxypropyl)-N'-[3-(trifluoromethyl)phenyl]-ethanediamide (2.2 g, 7.58 mmol) was dissolved in CH 3 CN (50 ml) and water (7 ml). To the stirred solution was added NaBrO 3 (1.15 g, 7.58 mmol) and a solution of RuCl 3 XH 2 O in CH 3 CN (3 ml). The mixture was stirred for Ih, and the reaction was monitored by LC-MS and TLC. The organic solvent was removed in vacuo, and the residue was partitioned between DCM (200 ml) and water (200 ml).
  • N-(2-Oxopropyl)-N'-[3-(trifluoromethyl)phenyl] ethanediamide (1.6 g, 5.5 mmol) and glacial acetic acid (15 ml) were placed in a vial (20 ml). To this solution was added concentrated sulfuric acid (40 drops), and the flask was sealed, and heated with stirring to 100 0 C for 90 minutes.
  • a high-pressure steel reactor (Parr) with CO-gas inlet was charged with 3-bromo-6- methyl-l-[3-(trifluoromethyl)phenyl]pyrazin-2(lH)-one (0.25 g, 0.75 mmol), Pd(OAc) 2 (0.015 g, 0.067 mmol), PPh 3 (0.030 g, 0.11 mmol ) and methanol (25 ml). To this mixture was added triethylamine (0.5 ml, 0.36 g, 3.6 mmol), and a magnetic stirrer bar. The reactor was ventilated with CO, and 6 atmospheres CO-pressure was applied to the system.
  • Methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (1.5 g, 4.8 mmol), dry DCM (7.0 mL), TFA (3.0 mL) and N-iodosuccinimide (1.0 g, 4.5 mmol) were mixed and stirred at RT in the dark (flask covered with aluminum foil). After 5h, water (5 mL) was added and the mixture was concentrated by rotary evaporation.
  • the assay uses Human Neutrophil Elastase (HNE) purified from serum (Calbiochem art.
  • HNE Human Neutrophil Elastase
  • HNE was stored in 50 mM sodium acetate (NaOAc), 200 mM sodium chloride (NaCl), pH 5.5 with added 30% glycerol at -20 0 C.
  • 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 -20 0 C.
  • the assay additions were as follows: Test compounds and controls were added to black 96- well flat-bottom plates (Greiner 655076), 1 ⁇ L in 100% DMSO, followed by 30 ⁇ L 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 ⁇ l 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 ⁇ M, respectively.
  • the assay was then stopped by adding 60 ⁇ l 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.

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Abstract

L'invention propose de nouveaux composés de formule (I) NR3NR1ONR4XR5OWR14 (I), dans laquelle R1, R3, R4, R5, R14, X et W sont tels que définis dans la description, et des isomères optiques, racémiques et tautomères, et des sels acceptables du point de vue pharmaceutique de ceux-ci. L'invention propose conjointement des procédés permettant de les préparer, des compositions pharmaceutiques les contenant et leur utilisation en thérapie. Les composés sont des inhibiteurs de l'élastase des neutrophiles humains.
PCT/SE2008/051220 2007-11-02 2008-10-29 Dérivés de 2-pyrazinone et leur utilisation comme inhibiteurs de l'élastase des neutrophiles Ceased WO2009058076A1 (fr)

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US8063073B2 (en) 2003-09-18 2011-11-22 Astrazeneca Ab 2-pyridone derivatives as neutrophil elastase inhibitors and their use
US8114881B2 (en) 2006-05-08 2012-02-14 Astrazeneca Ab 2-pyrazinone derivatives for the treatment of disease or condition in which inhibition of neutrophil elastase activity is beneficial
US8232296B2 (en) 2009-02-20 2012-07-31 Astrazeneca Ab Salt 628
WO2012148622A1 (fr) 2011-04-28 2012-11-01 E. I. Du Pont De Nemours And Company Pyrazinones herbicides
US8436024B2 (en) 2009-10-02 2013-05-07 Astrazeneca Ab 2-pyridone compounds
US8466284B2 (en) 2007-11-06 2013-06-18 Astra Zeneca Ab Some 2-pyrazinone derivatives and their use as inhibitors of neutrophile elastase
WO2014029830A1 (fr) 2012-08-23 2014-02-27 Boehringer Ingelheim International Gmbh 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
WO2014029831A1 (fr) 2012-08-23 2014-02-27 Boehringer Ingelheim International Gmbh 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
WO2014029832A1 (fr) 2012-08-23 2014-02-27 Boehringer Ingelheim International Gmbh 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
WO2021023193A1 (fr) * 2019-08-08 2021-02-11 漳州片仔癀药业股份有限公司 Procédé de préparation d'un composé de pyrazine-2 (1h)-cétone
WO2021023194A1 (fr) * 2019-08-08 2021-02-11 漳州片仔癀药业股份有限公司 Formes cristallines c et e d'un composé pyrazin-2(1h)-one et leur procédé de préparation
WO2021053058A1 (fr) 2019-09-17 2021-03-25 Mereo Biopharma 4 Limited Alvélestat destiné à être utilisé dans le traitement du rejet de greffe, du syndrome de bronchiolite oblitérante et de la maladie du greffon contre l'hôte
WO2021209740A1 (fr) 2020-04-16 2021-10-21 Mereo Biopharma 4 Limited Procédés impliquant l'alvélestat, un inhibiteur de l'élastase des neutrophiles, pour le traitement d'une infection à coronavirus
WO2023067103A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'élastase neutrophile utilisés dans le traitement de la fibrose
US11666888B2 (en) 2018-02-05 2023-06-06 Bio-Rad Laboratories, Inc. Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand

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WO2007129963A1 (fr) * 2006-05-08 2007-11-15 Astrazeneca Ab Dérivés de 2-pyrazinone destinés au traitement d'une maladie ou d'un état dans lequel l'inhibition de l'élastase neutrophile humaine a un effet bénéfique

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US8063073B2 (en) 2003-09-18 2011-11-22 Astrazeneca Ab 2-pyridone derivatives as neutrophil elastase inhibitors and their use
US8501784B2 (en) 2003-09-18 2013-08-06 Astrazeneca Ab 2-pyridone derivatives as neutrophil elastase inhibitors and their use
US8114881B2 (en) 2006-05-08 2012-02-14 Astrazeneca Ab 2-pyrazinone derivatives for the treatment of disease or condition in which inhibition of neutrophil elastase activity is beneficial
US7998984B2 (en) 2006-05-08 2011-08-16 Astrazeneca Ab 2-pyridone derivatives for the treatment of disease or condition in which inhibition of neutrophil elastase activity is beneficial
US8466284B2 (en) 2007-11-06 2013-06-18 Astra Zeneca Ab Some 2-pyrazinone derivatives and their use as inhibitors of neutrophile elastase
US8232296B2 (en) 2009-02-20 2012-07-31 Astrazeneca Ab Salt 628
US8436024B2 (en) 2009-10-02 2013-05-07 Astrazeneca Ab 2-pyridone compounds
WO2012148622A1 (fr) 2011-04-28 2012-11-01 E. I. Du Pont De Nemours And Company Pyrazinones herbicides
WO2014029830A1 (fr) 2012-08-23 2014-02-27 Boehringer Ingelheim International Gmbh 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
WO2014029831A1 (fr) 2012-08-23 2014-02-27 Boehringer Ingelheim International Gmbh 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
WO2014029832A1 (fr) 2012-08-23 2014-02-27 Boehringer Ingelheim International Gmbh 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
US12194432B2 (en) 2018-02-05 2025-01-14 Bio-Rad Laboratories, Inc. Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand
US11666888B2 (en) 2018-02-05 2023-06-06 Bio-Rad Laboratories, Inc. Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand
WO2021023194A1 (fr) * 2019-08-08 2021-02-11 漳州片仔癀药业股份有限公司 Formes cristallines c et e d'un composé pyrazin-2(1h)-one et leur procédé de préparation
CN114174271A (zh) * 2019-08-08 2022-03-11 漳州片仔癀药业股份有限公司 吡嗪-2(1h)-酮类化合物的c晶型和e晶型及其制备方法
CN114174272A (zh) * 2019-08-08 2022-03-11 漳州片仔癀药业股份有限公司 吡嗪-2(1h)-酮类化合物的制备方法
JP7121218B1 (ja) 2019-08-08 2022-08-17 ▲ザン▼州片仔▲ファン▼薬業股▲フン▼有限公司 ピラジン－２（１ｈ）－オン系化合物の製造方法
JP2022538931A (ja) * 2019-08-08 2022-09-06 ▲ザン▼州片仔▲ファン▼薬業股▲フン▼有限公司 ピラジン－２（１ｈ）－オン系化合物の製造方法
US11535609B2 (en) 2019-08-08 2022-12-27 Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd. Pyrazine-2(1H)-ketone compound preparation method
CN114174272B (zh) * 2019-08-08 2023-05-12 漳州片仔癀药业股份有限公司 吡嗪-2(1h)-酮类化合物的制备方法
US11680061B2 (en) 2019-08-08 2023-06-20 Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd. Crystal forms C and E of pyrazin-2(1H)-one compound and preparation method therefor
CN114174271B (zh) * 2019-08-08 2023-09-12 漳州片仔癀药业股份有限公司 吡嗪-2(1h)-酮类化合物的c晶型和e晶型及其制备方法
WO2021023193A1 (fr) * 2019-08-08 2021-02-11 漳州片仔癀药业股份有限公司 Procédé de préparation d'un composé de pyrazine-2 (1h)-cétone
WO2021053058A1 (fr) 2019-09-17 2021-03-25 Mereo Biopharma 4 Limited Alvélestat destiné à être utilisé dans le traitement du rejet de greffe, du syndrome de bronchiolite oblitérante et de la maladie du greffon contre l'hôte
WO2021209740A1 (fr) 2020-04-16 2021-10-21 Mereo Biopharma 4 Limited Procédés impliquant l'alvélestat, un inhibiteur de l'élastase des neutrophiles, pour le traitement d'une infection à coronavirus
WO2023067103A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'élastase neutrophile utilisés dans le traitement de la fibrose

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