WO2008099165A1 - Dérivés de pipéridine et leur utilisation pour le traitement de maladies à médiation par ccr8 - Google Patents

Dérivés de pipéridine et leur utilisation pour le traitement de maladies à médiation par ccr8 Download PDF

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WO2008099165A1
WO2008099165A1 PCT/GB2008/000490 GB2008000490W WO2008099165A1 WO 2008099165 A1 WO2008099165 A1 WO 2008099165A1 GB 2008000490 W GB2008000490 W GB 2008000490W WO 2008099165 A1 WO2008099165 A1 WO 2008099165A1
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Prior art keywords
methyl
dihydro
dimethyl
piperidin
benzofuran
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PCT/GB2008/000490
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English (en)
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Stephen Connolly
Anna Kristoffersson
Marco Skrinjar
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008099165A1 publication Critical patent/WO2008099165A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted piperidines, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • the chemokines are a large family (>50 members) of small 8 - to 15- kDa secreted, heparin-binding polypeptides with the primary function of controlling trafficking and activation of leukocytes. They are distinct from classical chemoattractants (i.e. bacterial derived N-formyl peptides, complement components, lipid molecules and platelet activating factor) on the basis of shared structural similarities. All chemokines have four conserved cysteines residues that form disulfide bonds, which are critical for the 3-D structure. The chemokines are further subclassed according to the position of the first two cysteines.
  • the two major subclasses are the CC-chemokines, that have the cysteines adjacent, and the CXC-cytokines, that have the cysteines separated by one amino acid.
  • the two other families, the C and the CX3C chemokines, are much smaller and only comprise one or a few members.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating peptide 2
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes, such as human monocyte chemotactic proteins 1-3 (MCP-I, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1 ⁇ and 1 ⁇ (MIP- 1 ⁇ and MIP- 1 ⁇ ) and CCL 1.
  • MCP-I human monocyte chemotactic proteins 1-3
  • RANTES Registered on Activation, Normal T Expressed and Secreted
  • eotaxin and the macrophage inflammatory proteins 1 ⁇ and 1 ⁇ (MIP- 1 ⁇ and MIP- 1 ⁇ ) and CCL 1.
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO, CXCRl, CXCR2, CXCR3 and CXCR4.
  • the human CCR8 receptor has been shown to interact with the human chemokine CCLl (1-309).
  • This chemokine is a potent eosinophil, T-, dentritic and endothelial cell chemoattractant.
  • the receptor has been shown to be transiently upregulated on polarized TH2 cells after optimal TCR cross linkage in the presence of costimulatory signals (i.e. CD28).
  • CD28 costimulatory signals
  • WO 03/037271 describes a broad class of phenyl derivatives that are said to be effective as CCR8 antagonists.
  • C 2 -C 6 alkenyl (optionally substituted by -C(O)NR 3 R 1 ), C3-C 6 cycloalkyl (optionally substituted by at least one substituent selected from halogen, hydroxyl and cyano), -NHSO 2 -R , and a saturated or unsaturated 5- to 6-membered heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the heterocycylic ring itself being optionally substituted by at least one substituent selected from halogen, hydroxyl, carboxyl and Ci-C 6 alkyl; n is O or 1 ; 2 3
  • R and R each independently represent hydrogen, hydroxyl, CJ-CO alky 1,
  • R and R together with the carbon atom to which they are attached form a 3- to 6- membered saturated carbocyclic ring;
  • ring B together with the two carbon atoms of ring A to which it is fused, represents a 5- to 6-membered, saturated or unsaturated, non-aromatic heterocyclic ring comprising one ring oxygen atom and optionally one or more ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the group (P) being optionally substituted with at least one substituent selected from halogen, Cj-Cg alkyl, C ⁇ -Cg cycloalkyl and phenyl, the phenyl itself being optionally substituted with at least one substituent selected from halogen, hydroxyl and Cj-Cg alkoxy;
  • R and R each independently represent hydrogen, Cj-Cg alkyl or C3 -Cg cycloalkyl, or R and R together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocyclic ring optionally substituted by at least one substituent selected from hydroxyl, Cj-Cg alkoxy and Cj-Cg alkoxy-Cj-Cg alkyl;
  • R and R each independently represent hydrogen, Cj-Cg alkyl or C3 ⁇ Cg cycloalkyl
  • R and R each independently represent hydrogen, Cj-Cg alkyl or C3-Cg
  • R and R each independently represent hydrogen, Ci-Cg alkyl or C3-C6
  • R and R each independently represent hydrogen, Ci-Cg alkyl or C3-Cg
  • R represents a Ci-Cg alkyl group or a 6-membered saturated or unsaturated heterocyclic ring comprising at least one ring nitrogen atom, the heterocyclic ring being optionally substituted with at least one substituent selected from halogen, oxo, Ci-Cg alkyl and Ci-Cg alkoxy; or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are effective as CCR8 antagonists and may, additionally, possess properties such as low toxicity, good selectivity and/or good metabolic stability which are advantageous for pharmaceutical compounds.
  • an alkyl/alkenyl substituent group or alky/alkenyl moiety in a substituent group may be linear or branched.
  • a haloalkyl or haloalkoxy substituent group will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms.
  • An aryl group is an aromatic carbocyclic ring structure having from 6 to 10 carbon atoms, the ring structure being monocyclic or fused bicyclic.
  • ring B in group (F) (and other heterocyclic groups referred to in formula (I)) is not intended to include unstable structures and is not intended to include any 0-0, O-S or S-S bonds.
  • the substituent(s) on group (F) may be attached to any suitable ring atom. Unless otherwise specified, an unsaturated ring or ring system will be partially or fully unsaturated. Further, when R and
  • R , or R and R , or R and R , or R and R , or R and R represent a 4- to 7-membered saturated heterocyclic ring, it should be understood that the only heteroatom present is the nitrogen atom to which R and R , or R and R , or R and R , or R and R are attached.
  • substituent e.g. chlorine, fluorine, bromine or iodine
  • Ci-Cg preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy),
  • Q-Cg preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl or n-hexoxycarbonyl),
  • alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl or n-hexoxycarbonyl
  • Ci-Cg preferably C1-C4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl),
  • alkylcarbonyl e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl
  • Cj-Cg preferably C1-C4, alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl, optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. chlorine, fluorine, bromine or iodine), hydroxyl, cyano, carboxyl, Cj-Cg or C1-C4 or
  • substituent e.g. one, two, three or four substituents independently
  • halogen e.g. chlorine, fluorine, bromine or iodine
  • C 2 -Cg or C 2 -C4 alkenyl such as ethenyl, prop-1-enyl, prop-2-enyl, but-1-enyl, pent-1-enyl, hex-1-enyl or 2-methyl-pent-2-enyl, optionally substituted by -C(O)NR 13 R 14 ,
  • C3-Cg cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. chlorine, fluorine, bromine or iodine), hydroxyl and cyano,
  • substituent e.g. one, two, three or four substituents independently
  • halogen e.g. chlorine, fluorine, bromine or iodine
  • a saturated or unsaturated 5- to 6-membered heterocyclic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur (such as one or more of pyrrolidinyl, piperidinyl, piperazinyl, dithiolanyl, morpholinyl, tetrahydropyranyl, thiomorpholinyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolidinyl, thienyl, isoxazolyl, pyrimidinyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl and pyridinyl, preferably pyrazolyl), the heterocycylic ring itself being optionally substituted by at least one substituent (
  • halogen e.g. chlorine, fluorine, bromine or iodine
  • hydroxyl carboxyl
  • Ci-C ⁇ alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl.
  • the saturated or unsaturated 5- to 15-membered ring system in R may be carbocylic or heterocyclic.
  • suitable ring systems which may be monocyclic or polycyclic (e.g. bicyclic or tricyclic) where the two or more rings are fused, include one or more of cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazabicyclo[2.2.1]hept-2-yl, naphthyl, benzofuranyl, benzothienyl, benzodioxolyl, isoquinolinyl, quinolinyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydiObenzo
  • Preferred ring systems include phenyl, pyrrolidinyl, piperazinyl, morpholinyl, benzofuranyl, benzothienyl, 3,4-dihydrobenzoxazinyl, indazolyl, 5,6,7,8-tetrahydro- 1,8- naphthyridinyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, pyrazolyl, pyrazinyl, thiazolidinyl, indanyl, oxadiazolyl, isoxazolyl, pyrrolyl, thiazolyl, indolyl, 2,3- dihydroisoindolyl, imidazolyl, pyrimidinyl, 1,6-dihydropyrimidinyl, triazolyl, tetrazolyl, pyridinyl, oxazolidinyl, imidazolidinyl, azaindo
  • R represents a saturated or, particularly, unsaturated 5- to 13-membered ring system, particularly a 5-, 6-, 9- or 10-membered ring system, optionally comprising one, two, three or four ring heteroatoms, particularly one or two ring heteroatoms, independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted as described above.
  • R represents a saturated or, particularly, unsaturated 5- to 13- membered ring system, particularly a 5-, 6-, 9- or 10-membered ring system, optionally comprising one, two, three or four ring heteroatoms, particularly one or two ring heteroatoms, independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted with at least one substituent (e.g. one, two, three or fouro substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), oxo, mercapto, nitro, hydroxyl, -NR R , Cj-Cg or Ci-C4 alkoxy, Cj -CO or
  • substituent e.g. one, two, three or fouro substituents independently
  • halogen e.g. fluorine, chlorine, bromine or iodine
  • C1-C4 alkoxycarbonyl, Cj-Cg or C1-C4 alkyl (optionally substituted by one, two, three or four substituents independently selected from halogen (such as fluorine, chlorine, bromine
  • R represents a saturated or, particularly, unsaturated 5- to 13- membered ring system, particularly a 5-, 6-, 9- or 10-membered ring system, optionally comprising one, two, three or four ring heteroatoms, particularly one or two ring S heteroatoms, independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g.
  • R represents a saturated or, particularly, unsaturated 5- to
  • 13-membered ring system particularly a 5-, 6-, 9- or 10-membered ring system, optionally comprising one, two, three or four ring heteroatoms, particularly one or two ring heteroatoms, independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted with at least one substituent (e.g.
  • substituents independently selected from fluorine, chlorine, bromine, oxo, mercapto, nitro, hydroxyl, -NH2, Ci-C2 alkoxy, ethoxycarbonyl, C 1-C2 alkyl (optionally substituted by one, two or three substituents independently selected from fluorine, methoxycarbonyl and -C(O)NH2), and pyrazolyl substituted by two methyl groups.
  • R represents a saturated or unsaturated 5- to 15-membered ring system (optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur) selected from phenyl, pyrrolidinyl, piperazinyl, morpholinyl, benzofuranyl, benzothienyl, 3,4-dihydrobenzoxazinyl, indazolyl, 5,6,7,8-tetrahydro-l,8- naphthyridinyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, pyrazolyl, pyrazinyl, thiazolidinyl, indanyl, oxadiazolyl, isoxazolyl, pyrrolyl, thiazolyl, indolyl, 2,3- dihydroisoindolyl, imidazolyl, pyrimidinyl, 1 ,6-dihydropyrimidin
  • substituents independently selected from fluorine, chlorine, bromine, oxo, mercapto, nitro, hydroxyl, -NH2, Ci-C2 alkoxy, ethoxycarbonyl, C 1-C2 alkyl (optionally substituted by one, two or three substituents independently selected from fluorine, methoxycarbonyl and -C(O)NH2), and pyrazolyl substituted by two methyl groups.
  • n 0.
  • n 1
  • R and R each independently represent hydrogen, hydroxy 1,
  • Cj-Cg preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl),
  • alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • Cj -CO preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy), Q-Cg, preferably C1-C4, haloalkyl (e.g. trifluoromethyl or pentafluoroethyl),
  • Cj-Cg preferably C1-C4, haloalkoxy (e.g. trifluoromethoxy or pentafluoroethoxy), C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or
  • Cg-Cio aryl such as phenyl or naphthyl
  • the aryl group being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, Cj-Cg, preferably
  • alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • Cj-Cg preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy), or
  • R and R each independently represent hydrogen, hydroxyl, C1-C3 alkyl, C1-C2 alkoxy, Ci-C2 haloalkyl, C5-C6 cycloalkyl or phenyl, or
  • R and R together with the carbon atom to which they are attached form a 3- to 6- membered saturated carbocyclic ring.
  • R and R each independently represent hydrogen, hydroxyl
  • ring B together with the two carbon atoms of ring A to which it is fused, represents a 5- to 6-membered, saturated or unsaturated, non-aromatic heterocyclic ring comprising one ring oxygen atom and optionally one or more (e.g. one or two) ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the group (F) being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), Ci-Cg, preferably C1-C4, alkyl (e.g.
  • substituent e.g. fluorine, chlorine, bromine or iodine
  • substituent e.g. one, two, three or four substituents independently
  • R represents a group (F) as shown above in which ring B, together with the two carbon atoms of ring A to which it is fused, represents a 5- to 6-membered, saturated or unsaturated, non-aromatic heterocyclic ring comprising one or two ring oxygen atoms, the group (P) being optionally substituted as defined above.
  • R represents a group (F) as shown above in which ring B, together with the two carbon atoms of ring A to which it is fused, represents a 5- to 6-membered, saturated heterocyclic ring comprising one or two ring oxygen atoms, the group (F) being optionally substituted as defined above.
  • R represents a group (F) as shown above in which ring B, together with the two carbon atoms of ring A to which it is fused, represents a 5- membered, saturated heterocyclic ring comprising one or two ring oxygen atoms, the group (F) being optionally substituted as defined above.
  • Preferred substituents in group (F) are halogen atoms (particuarly fluorine) and alkyl groups (particularly methyl).
  • group (F) is substituted in ring B by one or two methyl groups and, optionally, by one or two halogen atoms (particularly fluorine).
  • R represents a group
  • n 0, 1 or 2; each R independently represents a halogen atom or Ci-Cg alkyl group;
  • R 22 23 independently represents a hydrogen atom or C ⁇ -Cg alkyl group and R and R may additionally represent a halogen atom;
  • R and R each independently represent hydrogen, Cj-Cg alkyl, C3-C6 cycloalkyl, or phenyl (optionally substituted with at least one substituent selected from halogen, 1 s hydroxy 1 and C 1 -C $ alkoxy) .
  • R and R each independently represent a hydrogen atom or Q-Cg alkyl, preferably
  • C1-C4 alkyl e.g. methyl.
  • R and R are both methyl.
  • R and R each independently represent a hydrogen or halogen atom or Cj-Cg alkyl
  • R 22 23 preferably Ci -C4 alkyl, e.g. methyl.
  • R and R are both hydrogen.
  • R and R each independently represent a hydrogen atom or Cj-Cg alkyl, preferably
  • R and R are both hydrogen.
  • R and R are both methyl.
  • R and R each independently represent hydrogen, Cj-Cg, preferably Cj -C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C3 ⁇ Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or phenyl
  • alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • C3 ⁇ Cg cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • substituent e.g. one, two, three or four substituents independently
  • substituent selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl and Ci-Cg, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy)).
  • substituent e.g. one, two, three or four substituents independently
  • halogen e.g. fluorine, chlorine, bromine or iodine
  • hydroxyl hydroxyl
  • Ci-Cg preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy)).
  • R and R are both C1-C4 alkyl (e.g. methyl).
  • R and R each independently represent a hydrogen atom or Ci-Cg alkyl, preferably
  • R and R are either both hydrogen or both methyl.
  • R and R each independently represent a hydrogen atom or Ci-Cg alkyl, preferably
  • R and R are either both hydrogen or both methyl.
  • R and R each independently represent a hydrogen atom or Cj-Cg alkyl, preferably
  • R and R are both methyl.
  • R and R each independently represent a hydrogen atom or Ci-Cg alkyl, preferably
  • R and R are both 10 hydrogen.
  • R and R each independently represent a hydrogen atom or Ci-Cg alkyl, preferably
  • R and R are both hydrogen.
  • R and R each independently represent a hydrogen atom or Ci-Cg alkyl, preferably
  • C1-C4 alkyl e.g. methyl.
  • R and R are both methyl.
  • R , R , R , R , R , R , R and R each independently represent hydrogen or methyl.
  • n and R are as defined above.
  • R represents a group selected from: wherein n and R are as defined above.
  • R and R each independently represent hydrogen, Cj-Cg or CJ-C4 alkyl (e.g. methyl,
  • C5-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered or 5- to 6-membered saturated heterocyclic ring optionally substituted by at least one substituent
  • C1-C4 alkoxy e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert- butoxy, n-pentoxy or n-hexoxy
  • Cj-Cg or C1-C4 alkoxy-Cj-Cg or C1-C4 alkyl e.g. methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl or methoxy hexyl.
  • R and R are both hydrogen.
  • R and R each independently represent hydrogen, Cj-Cg or Cj -C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C ⁇ -Cg or
  • C5-Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one (e.g. one or two)
  • R and R are both hydrogen.
  • R and R each independently represent hydrogen, Cj-Cg or Cj -C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C3-Cg or
  • C5-Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered or 5- to 6-membered saturated heterocyclic ring optionally substituted by at least one substituent
  • CJ-C4 alkoxy e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert- butoxy, n-pentoxy or n-hexoxy
  • Cj-Cg or CJ-C4 alkoxy-C j -Cg or Q-C4 alkyl e.g. methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl or
  • R and R are both hydrogen.
  • R and R each independently represent hydrogen, Ci-Cg or Ci-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C ⁇ -Cg or
  • Cs-Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one (e.g. one or two)
  • R and R are both hydrogen.
  • R and R each independently represent hydrogen, Ci-Cg or Ci -C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C3-C6 or
  • Cs-Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one (e.g. one or two)
  • R and R are both hydrogen.
  • R represents a Ci-Cg or C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group or a 6-membered saturated or unsaturated heterocyclic ring comprising at least one (e.g. one or two) ring nitrogen atom(s) (e.g. pyridinyl, pyrimidinyl or piperidinyl), the heterocyclic ring being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g.
  • Ci-Cg or C1-C4 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • Ci-Cg or C1-C4 alkoxy e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy.
  • Preferred substituents in the heterocyclic ring include oxo and methyl.
  • R represents a saturated or unsaturated 5- to 13-membered ring system optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted with at least one substituent selected from fluorine, chlorine, bromine, oxo, mercapto, nitro, hydroxyl, -NH2, C1-C2 alkoxy,
  • n 0 or 1 ;
  • R and R each independently represent hydrogen, hydroxyl, methyl, ethyl,
  • 2 3 isopropyl, methoxy, trifluoromethyl, cyclopentyl or phenyl, or R and R together with the carbon atom to which they are attached form a cyclopropyl ring;
  • Examples of compounds of the invention include: N-( ⁇ l-[(2,2-dimethyl-2 5 3-dihydro-l-benzofuran-7-yl)methyl]piperidin-4-yl ⁇ methyl)-
  • 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)
  • L represents a leaving group (e.g. a hydroxyl group or halogen atom) and n, R ,
  • R is as defined in formula (I)
  • a coupling agent such as carbonyldiimidazole and 1-hydroxybenzotriazole
  • Pj represents a protecting group (an amine protecting group such as tert-butyl
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably a basic addition salt such as a sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine salt, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, trifluoroacetate, benzenesulfonate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or/>-toluenesulphonate salt.
  • a basic addition salt such as a sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine salt
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated, as well as unsolvated forms, and the present invention encompasses all such solvated forms.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may exist as zwitterions.
  • the representation of formula (I) and the examples of the present invention covers zwitterionic forms and mixtures thereof in all proportions.
  • the compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR8) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or dysregulated production of chemokines.
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NS AID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vascula
  • osteoarthritides 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; osteoarthritis; 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
  • 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 such as osteoporosis, Paget's
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanom
  • eyes 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; 6.
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
  • abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 10.
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes;
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema; and
  • the present invention provides a compound of formula (I) or a pharmaceutically- acceptable salt thereof as hereinbefore defined for use in therapy.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ , chronic obstructive pulmonary disease (COPD) or rhinitis.
  • asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ , chronic obstructive pulmonary disease (COPD) or rhinitis.
  • 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 the treatment of sepsis.
  • 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 use in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ , chronic obstructive pulmonary disease or rhinitis.
  • 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 modulation of chemokine receptor activity, particularly CCR8 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 present invention provides a method of treating asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ , chronic obstructive pulmonary disease or rhinitis in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇
  • chronic obstructive pulmonary disease or rhinitis in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (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
  • 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, heptafluoroalkane (HFA) aerosols and diy 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 heptafluoroalkane
  • 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 micrometres ( ⁇ m), 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.
  • 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.
  • a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
  • Suitable carriers are sugars, for example, lactose, glucose, raff ⁇ nose, 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 semi-solid 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 therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • 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 (including pharmaceutically acceptable salts) 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 17, 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 signalling pathways
  • 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 with a modulator of chemokihe receptor function such as an antagonist of CCRl , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and s CCRl 1 (for the C-C family); CXCRl , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-
  • the present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the I 0 collagenases, and the gelatinases, as well as aggrecanase; for example coUagenase-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.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5- lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2- alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as
  • Zeneca ZD-2138 the compound SB-210661 ; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
  • the present invention further relates to the combination of a compound of the invention 2 5 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-yls 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.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected
  • the present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention and an alpha- 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 hydrochloride, oxymetazoline hydrochlor
  • the present invention further relates to the combination of a compound of the invention and an anticholinergic agent including muscarinic receptor (Ml , M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml muscarinic receptor
  • M2 muscarinic receptor
  • 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 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 and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • anti-IgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • 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 together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine
  • the present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • 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 pentoxyfylline
  • the present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an 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-dopa, ropini
  • the present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agents, paracetamol, or a non-steroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agents for example an opioid or derivative thereof
  • paracetamol for example an opioid or derivative thereof
  • non-steroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kina
  • -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
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM- CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.subl.
  • 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
  • inhibitor of transcription factor activation such as NFkB, API, or STATS
  • GR-receptor a non-steroidal glucocorticoid receptor
  • the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined and one or more agents independently selected from: • a non-steroidal glucocorticoid receptor (GR-receptor) agonist; • a selective ⁇ 2 adrenoceptor agonist (such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol);
  • GR-receptor non-steroidal glucocorticoid receptor
  • a selective ⁇ 2 adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol,
  • a phosphodiesterase inhibitor such as a PDE4 inhibitor
  • a protease inhibitor such as a neutrophil elastase or matrix metalloprotease MMP- 12 inhibitor
  • a modulator of chemokine receptor function such as a CCRl receptor antagonist
  • an inhibitor of kinase function (such as the kinases p38 or IKK).
  • the invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is
  • GR-receptor a non-steroidal glucocorticoid receptor
  • the invention provides a kit comprising a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is • a non-steroidal glucocorticoid receptor (GR-receptor) agonist; 53
  • the compound was synthesized according to General Method A using Intermediate A and Imidazol-1-yl-acetic acid.
  • Membranes from CHO-Kl cells transfected with human recombinant chemokine CCR8 receptor (ES-136-M) were purchased from Euroscreen. Membrane preparations are stored at -7O 0 C in 7.5mM tris(hydroxymethyl)aminomethane hydrochloride (Tris-Cl; pH 7.5), 12.5 mM magnesium chloride (MgCl 2 ), 0.3 mM ethylenediamine tetraacetic acid (EDTA), ImM ethylene glycol bis(beta-amino-ethylether)N,N,N',N'-tetraacetic acid (EGTA) and 250 mM sucrose until used.
  • Tris-Cl tris(hydroxymethyl)aminomethane hydrochloride
  • MgCl 2 magnesium chloride
  • EDTA ethylenediamine tetraacetic acid
  • EGTA ImM ethylene glycol bis(beta-amino-ethylether)N,N
  • SPA Wheat Germ Agglutinin Scintillation Proximity Assay
  • a 10-point dose-response curve (final concentrations 50 ⁇ M, 16.7 ⁇ M, 5.6 ⁇ M, 1.9 ⁇ M, 0.62 ⁇ M, 0.21 ⁇ M, 0.069 ⁇ M, 0.023 ⁇ M) was prepared by diluting compounds by serial dilution 1:3 in dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • l ⁇ l from the DMSO solutions of compounds was transferred into each well, l ⁇ l of DMSO was added to the blank control wells and 1 ⁇ l unlabeled CCLl (300 nM) was added to background control wells. 50 ⁇ l of the Scintillation
  • SPA Proximity Assay
  • the compounds of the Examples have an IC 50 of less than 2 ⁇ M.
  • the results obtained for a representative selection of the compounds of the Examples are shown in Table 1 below.

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Abstract

La présente invention porte sur des composés de formule (I), dans laquelle n, R1, R2, R3 et R4 sont tels que définis dans la description, sur un procédé pour leur préparation, sur des compositions pharmaceutiques le contenant et sur leur utilisation en thérapie.
PCT/GB2008/000490 2007-02-15 2008-02-13 Dérivés de pipéridine et leur utilisation pour le traitement de maladies à médiation par ccr8 WO2008099165A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2344479A2 (fr) * 2008-09-23 2011-07-20 Georgetown University Dérivés de 1,2-benzisothiazolinone et d'isoindolinone
US9428472B2 (en) 2011-08-16 2016-08-30 Georgetown University Methods of treating bacterial infections with 1,2-benzisothiazolinone and isoindolinone derivatives
WO2017066705A1 (fr) * 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Composés, compositions et méthodes d'utilisation contre des granules de stress

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037271A2 (fr) * 2001-10-30 2003-05-08 Millennium Pharmaceuticals,Inc. Composes, compositions pharmaceutiques et methodes d'utilisation
WO2004032856A2 (fr) * 2002-10-07 2004-04-22 Smithkline Beecham Corporation Composes
WO2004058709A1 (fr) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Inhibiteurs du ccr8
WO2005040167A1 (fr) * 2003-10-23 2005-05-06 Astrazeneca Ab Nouveaux diazaspiroalcanes et leur utilisation dans le traitement de maladies induites par ccr8

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037271A2 (fr) * 2001-10-30 2003-05-08 Millennium Pharmaceuticals,Inc. Composes, compositions pharmaceutiques et methodes d'utilisation
WO2004032856A2 (fr) * 2002-10-07 2004-04-22 Smithkline Beecham Corporation Composes
WO2004058709A1 (fr) * 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Inhibiteurs du ccr8
WO2005040167A1 (fr) * 2003-10-23 2005-05-06 Astrazeneca Ab Nouveaux diazaspiroalcanes et leur utilisation dans le traitement de maladies induites par ccr8

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2344479A2 (fr) * 2008-09-23 2011-07-20 Georgetown University Dérivés de 1,2-benzisothiazolinone et d'isoindolinone
EP2344479A4 (fr) * 2008-09-23 2012-05-30 Univ Georgetown Dérivés de 1,2-benzisothiazolinone et d'isoindolinone
US9040715B2 (en) 2008-09-23 2015-05-26 Georgetown University 1,2-benzisothiazolinone and isoindolinone derivatives
US9428472B2 (en) 2011-08-16 2016-08-30 Georgetown University Methods of treating bacterial infections with 1,2-benzisothiazolinone and isoindolinone derivatives
WO2017066705A1 (fr) * 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Composés, compositions et méthodes d'utilisation contre des granules de stress

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