US20050239801A1 - Novel compounds - Google Patents

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US20050239801A1
US20050239801A1 US11/157,742 US15774205A US2005239801A1 US 20050239801 A1 US20050239801 A1 US 20050239801A1 US 15774205 A US15774205 A US 15774205A US 2005239801 A1 US2005239801 A1 US 2005239801A1
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Prior art keywords
phenyl
hydroxy
propoxy
phenoxy
piperidin
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US11/157,742
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Tomas Eriksson
Krister Henriksson
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AstraZeneca AB
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AstraZeneca AB
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Priority claimed from SE0002330A external-priority patent/SE0002330D0/en
Priority claimed from SE0003980A external-priority patent/SE0003980D0/en
Priority claimed from PCT/SE2001/001378 external-priority patent/WO2001098272A1/en
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to US11/157,742 priority Critical patent/US20050239801A1/en
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ERIKSSON, TOMAS, HENRIKSSON, KRISTER
Publication of US20050239801A1 publication Critical patent/US20050239801A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies. such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 ka proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys.(C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • 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 but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, 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 MP-1 ⁇ .
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
  • G protein-coupled receptors among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
  • an alkyl or alkenyl substituent group or an alkyl or alkenyl moiety in a substituent group may be linear or branched.
  • R 15 it should be noted that the unsaturated 5- to 10-membered heterocyclic ring system may be aliphatic or aromatic.
  • the integer m is preferably 1 or 2.
  • Each R 1 independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl), C 1 -C 6 , preferably C 1 -C 4 , alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C 1 -C 6 , preferably C 1 -C 4 , alkoxycarbonyl (e.g.
  • C 1 -C 6 preferably C 1 -C 4 , haloalkyl (e.g. trifluoromethyl), C 1 -C 6 , preferably C 1 -C 4 , haloalkoxy (e.g. trifluoromethoxy), —NR 9 R 10 , C 3 -C 6 cycloalkylamino (e.g. cyclopropylarnio, cyclobutylamino, cyclopentylamino or cyclohexylamino), C 1 -C 6 , preferably C 1 -C 4 , alkylthio (e.g.
  • C 1 -C 6 preferably C 1 -C 4 , alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C 1 -C 6 , preferably C 1 -C 4 , alkylcarbonylanino (e.g.
  • sulphonauido C 1 -C 6 , preferably C 1 -C 4 , alkylsulphonyl (e.g. methylsulphonyl ethylsulphonyl, n-propylsulphonyl isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR 11 R 12 , —NR 13 C(O)—(NH) p R 14 , phenyl or C 1 -C 6 , preferably C 1 -C 4 , alkyl (e.g.
  • each R 1 independently represents halogen (particularly chlorine or fluorine), cyano, nitro, C 1 -C 6 alkoxy (especially methoxy), C 1 -C 6 alkylcarbonyl (especially methylcarbonyl) or C 1 -C 6 alkylcarbonylamino (particularly methylcarbonylamino).
  • Each R 1 especially represents halogen or cyano
  • X represents an oxygen atom or a CH 2 or NH group.
  • Y, Z 1 and Z 2 include: Y Z 1 Z 2 CH CH 2 bond CH bond CH 2 CH CH 2 CH 2 CH (CH 2 ) 2 bond N CH 2 CH 2
  • Q preferably represents an oxygen atom.
  • Each R 3 independently represents a C 1 -C 6 , preferably C 1 -C 4 , alkyl (e.g. methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hecyl), C 1 -C 6 , preferably C 1 -C 4 , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), —CH 2 OH or carboxyl group. It is preferred that R 3 represents a methyl, methoxycarbonyl, ethoxycarbonyl —CH 2 OH or carboxyl group.
  • alkyl e.g. methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hecyl
  • R 4 , R 5 , R 6 and R 7 each independently represent a hydrogen atom or a C 1 -C 6 , preferably C 1 -C 4 , alkyl (e.g. methyl ethyl, n-propyl, isopropyl, n-butyl, isobutyl tert-butyl, n-pentyl or n-hexyl), or R 4 , R 5 , R 6 and R 7 together represent a C 1 -C 4 alkylene chain linking the two carbon atoms to which they are attached to form a 4 to 7-membered saturated carbocycle (e.g.
  • R 5 , R 6 and R 7 each represent a hydrogen atom and R 4 and R 8 together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle (preferably cyclopentyl).
  • R 8 represents a hydrogen atom, a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or is linked to R 4 as defined above.
  • alkyl group e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • R 9 and R 10 each independently represent a hydrogen atom or a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, teit-butyl, n-pentyl or n-hexyl), or R 9 and R 10 together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocycle.
  • alkyl group e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, teit-butyl, n-pentyl or n-hexyl
  • R 11 and R 12 each independently represent a hydrogen atom or a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a C 1 -C 6 , preferably C 1 -C 4 , alkoxycarbonyl substituent group.
  • alkyl group e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • R 13 represents a hydrogen atom or a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
  • alkyl group e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl.
  • R 14 represents a hydrogen atom, or a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl C 1 -C 6 , preferably C 1 -C 4 , alkoxy or C 1 -C 6 , preferably C 1 -C 4 , alkoxycarbonyl.
  • alkyl group e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • R 15 represents a group C 2 -C 6 , preferably C 2 -C 4 , alyl group (e.g. ethyl n-propyl, isopropyl, n-butyl, isobutyl tert-butyl or n-pentyl), C 2 -C 6 , preferably C 2 -C 4 , alkenyl C 3 -C 6 cycloalkyl (e.g. cyclobutyl or cyclopentyl), C 5 -C 6 cycloalkenyl, amntyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected.
  • alyl group e.g. ethyl n-propyl, isopropyl, n-butyl, isobutyl tert-butyl or n-pentyl
  • C 2 -C 6 preferably C
  • each group may be optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from nitro, hydroxyl, oxo, halogen (e.g: fluorine, chlorine, bromine or iodine), carboxyl, C 1 -C 6 , preferably C 1 -C 4 , alkyl (e.g. methyl ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl, n-pentyl or n-hexyl), C 1 -C 6 , preferably C 1 -C 4 , alkoxy (e.g.
  • C 1 -C 6 preferably C 1 -C 4 , alkylthio (e.g. methylthio or ethylthio), C 1 -C 6 , preferably C 1 -C 4 , alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C 1 -C 6 , preferably C 1 -C 4 , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), phenyl and —NHC(O)—R 17 .
  • alkylthio e.g. methylthio or ethylthio
  • C 1 -C 6 preferably C 1 -C 4 , alkylcarbonyl (e.g. methylcarbonyl,
  • the saturated or unsaturated 5- to 10-membered heterocyclic ring system may be monocyclic or polycyclic (e.g. bicyclic) and may comprise up to four heteroatoms independently selected from nitrogen, oxygen and sulphur.
  • ring systems that may be used include pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetraaolyl and pyridinyl.
  • Each R 16 independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C 1 -C 6 , preferably C 1 -C 4 , alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C 1 -C 6 , preferably C 1 -C 4 , alkoxycarbonyl (e.g.
  • C 1 -C 6 preferably C 1 -C 4 , haloalkyl (e.g. trifluoromethyl), C 1 -C 6 , preferably C 1 -C 4 , haloalkoxy(e.g. trifluoromethoxy), —NR 18 R 19 , C 3 -C 6 cycloalylamino (e.g. cyclopropylamino, cyclobutylamino., cyclopentylamino or cyclohexylamno), C 1 -C 6 , preferably C 1 -C 4 , alkylthio (e.g.
  • C 1 -C 6 preferably C 1 -C 4 , alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C 1 -C 6 , preferably C 1 -C 4 , alkylcarbonylamino (e.g.
  • sulphonamido C 1 -C 6 , preferably C 1 -C 4 , alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR 21 R 22 , —NR 23 C(O)—(NM) v R 24 , phenyl, or C 1 -C 6 , preferably C 1 -C 4 , alkyl (e.g.
  • each R 16 independently represents halogen (particularly chlorine or fluorine), cyano, C 1 -C 4 alkoxy (especially methoxy), C 1 -C 4 alkoxycarbonyl (especially methoxycarbonyl), C 1 -C 4 haloalkyl (especially trifluoromethyl), C 1 -C 4 akylcarbonyl (particularly methylcarbonyl), phenyl or C 1 -C 4 alkyl (e.g. methyl or tert-butyl).
  • Each R 16 is especially a halogen atom or methyl group.
  • R 17 represents a C 1 -C 6 , preferably C 1 -C 4 , all group (e.g. methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), amino or phenyl group.
  • R 18 and R 19 each independently represent a hydrogen atom or a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R 19 and R 20 together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated heterocycle.
  • R 20 and R 21 each independently represent a hydrogen atom or a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g.
  • R 23 represents a hydrogen atom, or a C 1 -C 6 , preferably C 1 -C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl, C 1 -C 6 , preferably C 1 -C 4 , alkoxy or C 1 -C 6 , preferably C 1 -C 4 , alkoxycarbonyl.
  • alkyl group e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl
  • Preferred compounds of the invention include:
  • the present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises reacting a compound of general formula or a salt thereof (e.g. an acid addition salt such as a hydrochloride salt), wherein m, n, t, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 16 , Q, Z 1 and Z 2 are as defined in formula (I), with a compound of general formula R 15 —CO 2 H (III) or chemically equivalent derivative thereof (e.g. acyl halide or anhydride derivative) wherein R 15 is as defined in formula (I);
  • a compound of general formula or a salt thereof e.g. an acid addition salt such as a hydrochloride salt
  • the process of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as an alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene), an amine (e.g. triethylamine or diisopropylethylamine) or acetonitrile at a temperature ot, for example, 15° C. or above, such as a temperature in the range from 20 to 120° C.
  • a solvent e.g. an organic solvent such as an alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene), an amine (e.g. triethylamine or diisopropylethylamine) or acetonitrile
  • a temperature ot for example, 15° C. or above, such as a temperature in the range from 20 to 120° C.
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orptolienesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orptolienesulphonate.
  • the compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially MIP-1 ⁇ chemokine receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of taplanted organs or tissues and Acquired Ilununodeficiency Syndrome (AIDS).
  • chemokine receptor especially MIP-1 ⁇ chemokine receptor
  • the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate 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 or solvate thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the invention also provides a method of treating an inflammatory disease 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 or solvate thereof, as hereinbefore defined.
  • the invention still further provides a method of treating an airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • the dosage administered will, of course, vary s with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula (I) may be in the range from 0.001 mg/kg to 30 mg/kg.
  • the compounds of formula (I) and pharmaceutically acceptable salts and solvates 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/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • 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 or solvate 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 or solvate thereof, as hereinbefore defined,,with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; 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 ad i:stion or by rectal administration in the form of suppositories or transdermally.
  • N-(2- ⁇ 3-[4-(3,4-chlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy ⁇ phenyl)-acetamide (1.418 g, 3.13 mmol, prepared by analogy to Example 1) was dissolved in 50 ml HCl (35%/aq, puriss) and refluxed overnight. The product precipitated and was filtered and dried to give 0.835 g (65%) of the title compound.
  • the product was diluted with 1000 uL dichloromethane and washed with with sat. NaHCO 3 /aq (800 uL), 1.8% HCl/aq(800 uL) and sat NaC])aq.
  • Pentanoic acid (2- ⁇ 3-[3-(4chloro-phenoxy)-pyrrolldin-1-yl]-2-hydroxy-propoxy ⁇ -phenyl)-amide
  • Pent-4-enoic acid (2- ⁇ 3-[3-(4-chloro-phenoxy)-pyrrolIdin-1-yl]-2-hydroxy-propoxy ⁇ -phenyl)-amide
  • Pentanoic acid (2- ⁇ 3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy ⁇ -phenyl)-amide
  • Pent-4-enoic acid (2- ⁇ 3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy ⁇ -phenyl)-amide
  • the compound (80 mg, 86%) was prepared from aniline intermediate 3 (60 mg, 0.159 mmol) and cyclopentanecarboxylic acid (18 ⁇ l, 0.159 mmol) as descnbed in Example 88.
  • the compound was prepared using an analogous method as in Example 88.
  • the compound was prepared using an analogous method as in Example 88.
  • the compound was prepared using an analogous method as in Example 88.
  • the compound was prepared using an analogous method as in Example 88.
  • the compound was prepared using an analogous method as in Example 88.
  • the assay measured the chemotactic response elicited by MIP-1 ⁇ chemokine in the human monocytic cell line TBP-1.
  • the compounds of the Examples were evaluated by their ability to depress the chemotactic response to a standard concentration of MP-lx chemokine.
  • THP-1 cells are routinely cultured in RPMI-1640 medium supplemented with 10% heat inactivated fetal calf serum and glutamax but without antibiotics. Optimal growth of the cells requires that they are passaged every 3 days and that the minimum subculture density is 4 ⁇ 10+5 cells/ml.
  • Cells were removed from the flask and washed by centrigation in RPMI+10%HEFCS+glutamax. The cells were then resuspended at 2 ⁇ 10+7 cells/mi in fresh medium (RPMI+10%HIFCS+glutamax) to which was added calcein-AM (5 ⁇ l of stock solution to 1 ml to give a final concentration of 5 ⁇ 10 ⁇ 6 M). After gentle mixing the cells were incubated at 37° C. in a CO 2 incubator for 30 minutes. The cells were th diluted to 50 ml with medium and washed twice by centrifigation at 400 ⁇ g.
  • Labelled cells were then resuspended at a cell concentration of 1 ⁇ 10+7 cells/ml and incubated with an equal volume of MIP-1 ⁇ antagonist (10 ⁇ 10 M to 10 ⁇ 6 M final concentration) for 30 minutes at 37° C. in a humidified CO 2 incubator.
  • Chemotaxis was performed using Neuroprobe 96-well chemotaxis plates employing 8 ⁇ M (filters (cat no. 101-8). Thirty microlitres of chemoattractant supplemented withy various concentrations of antagonists or vehicle were added to the lower wells of the plate in triplicate. The filter was then carefully positioned on top and then 25 ⁇ l of cells preincubated with the corresponding concentration of antagonist or vehicle were added to the surface of the filter. The plate was then incubated for 2 hours at 37° C. in a humidified CO 2 incubator. The cells remaining on the surface were then removed by adsorption and the whole plate was centrifuged at 2000 rpm for 10 minutes.
  • the filter was then removed and the cells that had migrated to the lower wells were quantified by the fluorescence of cell associated calcein-AM. Cell migration was then expressed in fluorescence units after subtraction of the reagent blank and values were standardized to % migration by comparing the fluorescence values with that of a known number of labelled cells. The effect of antagonists was calculated as % inhibition when the number of migrated cells were compared with vehicle.

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Abstract

The invention provides compounds of general formula (I) wherein m, n, Z1, Z2, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the specification, process for their preparation, pharmaceutical compositions containing them and their use in therapy.

Description

  • The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies. such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 ka proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys.(C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • 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).
  • The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MP-1β.
  • Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
  • In accordance with the present invention, there is therefore provided a compound of general formula
    Figure US20050239801A1-20051027-C00001
    wherein:
      • m is 0, 1, 2 or 3;
      • each R1 independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloakl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —NR9R10, C3-C6 cycloalkylano, C1pk -C 6 alkylthio, C1-C6 akylcarbonyl, C1-C6 allcarbonylamio, sulphonamido (—SO2NH2), C1-C6 alkylsuiphonyl, —C(O)NR11R, —NR13 C(O)—pR14, phenyl, or C1-C6 alkyl optionally substituted by carboxyl or C1-C6 alkoxycarbonyl;
      • p is 0 or 1;
      • X represents an oxygen atom or a CH2, OCH2, CH2O, CH2NH, NH, carbonyl or sulphonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen atom or a CH2O, CH2NH or NH group, then Y represents a CH group;
      • Z1 represents a bond or a group (CH2)q where q is 1 or 2;
      • Z2 represents a bond or a group CH2, with the proviso that Z1 and Z1 do not both simultaneously represent a bond;
      • Q represents an oxygen or sulphur atom or a group CH2 or NH;
      • R2 represents a group
        Figure US20050239801A1-20051027-C00002
      • n is 0, 1 or 2;
      • each R3 independently represents a C1-C6 alkyl, C1-C6 alkoxycarbonyl, —CH2OH or carboxyl group;
      • R4, R5, R6 and R7 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R4, R5, R6 and R7 together represent a C1-C4 alkylene chain linking the two carbon atoms to which they are attached to form a 4 to 7-membered satrn carbocycle, or R5, R6 and R7 each represent a hydrogen atom and R4 and R8 together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
      • R8represents a hydrogen atom, a C1-C6 alkyl group or is linked to R4 as defined above;
      • R9 and R10 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R9 and R10 together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated heterocycle;
      • R11 and R12 each independently represent a hydrogen atom or a C1-C6 alkyl group optionally substituted by C1-C6 alkoxycarbonyl;
      • R13represents a hydrogen atom or a C1-C6 alkyl group;
      • R14 represents a hydrogen atom, or a C1-C6 alkyl group optionally substituted by carboxyl, C1-C6 alkoxy or C1-C6 alkoxycarbonyl;
      • R15 represents a group C2-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, adamantyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, wherein each group may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenyl and —NHC(O)—R17 with the proviso that R15 does not represent an unsubstituted 1-pyrrolidinyl, an unsubstituted 1-piperidinyl or an unsubstituted 1-hexamethyleneiminyl (1-homopiperidinyl) group;
      • t is 0, 1, 2 or 3;
      • each R16 independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —NR18R19, C3-C6 cycloalkylammo, C1-C6allylthio, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonylamino, sulphonamido (—SO2NH2), C1-C6 alkylsuphonyl, —C(O)NR20R21, —NR22C(O)(NH)vR23, phenyl, or C1-C6 alkyl optionally substituted by carboxyl or C1-C6 alkoxycarbonyl;
      • R17 represents a C1-C6 alkyl, amino (—NH2) or phenyl group;
      • R18 and R19 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R18 and R19 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
      • R20 and R21 each independently represent a hydrogen atom or a C1-C6 alkyl group optionally substituted by C1-C6 alkoxycarbonyl;
      • v is 0 or 1;
      • R22 represents a hydrogen atom or a C1-C6 alkyl group; and
      • R23 represents a hydrogen atom, or a C1-C6 alkyl group optionally substituted by carboxyl, C1-C6 alkoxy or C1-C6 alkoxycarbonyl;
        or a pharmaceutically acceptable salt or solvate thereof.
  • In the context of the present specification, an alkyl or alkenyl substituent group or an alkyl or alkenyl moiety in a substituent group may be linear or branched. In the definition of R15, it should be noted that the unsaturated 5- to 10-membered heterocyclic ring system may be aliphatic or aromatic.
  • The integer m is preferably 1 or 2.
  • Each R1 independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl), C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C1-C6, preferably C1-C4, haloalkyl (e.g. trifluoromethyl), C1-C6, preferably C1-C4, haloalkoxy (e.g. trifluoromethoxy), —NR9R10, C3-C6 cycloalkylamino (e.g. cyclopropylarnio, cyclobutylamino, cyclopentylamino or cyclohexylamino), C1-C6, preferably C1-C4, alkylthio (e.g. methylthio or ethylthio), C1-C6, preferably C1-C4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-C6, preferably C1-C4, alkylcarbonylanino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonauido, C1-C6, preferably C1-C4, alkylsulphonyl (e.g. methylsulphonyl ethylsulphonyl, n-propylsulphonyl isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR11R12, —NR13C(O)—(NH)pR14, phenyl or C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or C1-C6, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).
  • Most preferably, each R1 independently represents halogen (particularly chlorine or fluorine), cyano, nitro, C1-C6 alkoxy (especially methoxy), C1-C6 alkylcarbonyl (especially methylcarbonyl) or C1-C6 alkylcarbonylamino (particularly methylcarbonylamino). Each R1 especially represents halogen or cyano
  • Preferably X represents an oxygen atom or a CH2 or NH group.
  • Preferred combinations of Y, Z1 and Z2 include:
    Y Z1 Z2
    CH CH2 bond
    CH bond CH2
    CH CH2 CH2
    CH (CH2)2 bond
    N CH2 CH2
  • Q preferably represents an oxygen atom.
  • Each R3 independently represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hecyl), C1-C6, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), —CH2OH or carboxyl group. It is preferred that R3 represents a methyl, methoxycarbonyl, ethoxycarbonyl —CH2OH or carboxyl group.
  • R4, R5, R6 and R7 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl (e.g. methyl ethyl, n-propyl, isopropyl, n-butyl, isobutyl tert-butyl, n-pentyl or n-hexyl), or R4, R5, R6 and R7 together represent a C1-C4 alkylene chain linking the two carbon atoms to which they are attached to form a 4 to 7-membered saturated carbocycle (e.g. cyclohexyl or preferably cyclopentyl), or R5, R6 and R7 each represent a hydrogen atom and R4 and R8 together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle (preferably cyclopentyl).
  • R8 represents a hydrogen atom, a C1-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or is linked to R4 as defined above.
  • R9 and R10 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, teit-butyl, n-pentyl or n-hexyl), or R9 and R10 together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocycle.
  • R11 and R12 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a C1-C6, preferably C1-C4, alkoxycarbonyl substituent group.
  • R13 represents a hydrogen atom or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
  • R14 represents a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl C1-C6, preferably C1-C4, alkoxy or C1-C6, preferably C1-C4, alkoxycarbonyl.
  • R15 represents a group C2-C6, preferably C2-C4, alyl group (e.g. ethyl n-propyl, isopropyl, n-butyl, isobutyl tert-butyl or n-pentyl), C2-C6, preferably C2-C4, alkenyl C3-C6 cycloalkyl (e.g. cyclobutyl or cyclopentyl), C5-C6 cycloalkenyl, amntyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected. from nitrogen, oxygen and sulphur, wherein each group may be optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from nitro, hydroxyl, oxo, halogen (e.g: fluorine, chlorine, bromine or iodine), carboxyl, C1-C6, preferably C1-C4, alkyl (e.g. methyl ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl, n-pentyl or n-hexyl), C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6, preferably C1-C4, alkylthio (e.g. methylthio or ethylthio), C1-C6, preferably C1-C4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-C6, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), phenyl and —NHC(O)—R17.
  • The saturated or unsaturated 5- to 10-membered heterocyclic ring system may be monocyclic or polycyclic (e.g. bicyclic) and may comprise up to four heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of ring systems that may be used include pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetraaolyl and pyridinyl.
  • Each R16 independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C1-C6, preferably C1-C4, haloalkyl (e.g. trifluoromethyl), C1-C6, preferably C1-C4, haloalkoxy(e.g. trifluoromethoxy), —NR18R19, C3-C6 cycloalylamino (e.g. cyclopropylamino, cyclobutylamino., cyclopentylamino or cyclohexylamno), C1-C6, preferably C1-C4, alkylthio (e.g. methylthio orethylthio), C1-C6, preferably C1-C4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-C6, preferably C1-C4, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido, C1-C6, preferably C1-C4, alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR21R22, —NR23C(O)—(NM)vR24, phenyl, or C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl n-pentyl or n-hexyl) optionally substituted by carboxyl or C1-C6, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).
  • Preferably, each R16 independently represents halogen (particularly chlorine or fluorine), cyano, C1-C4 alkoxy (especially methoxy), C1-C4 alkoxycarbonyl (especially methoxycarbonyl), C1-C4 haloalkyl (especially trifluoromethyl), C1-C4 akylcarbonyl (particularly methylcarbonyl), phenyl or C1-C4 alkyl (e.g. methyl or tert-butyl). Each R16 is especially a halogen atom or methyl group.
  • R17 represents a C1-C6, preferably C1-C4, all group (e.g. methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), amino or phenyl group.
  • R18 and R19 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R19 and R20 together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated heterocycle. R20 and R21 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl ethyl, n-propyl, isopropyl, n-butyl isobutyl tert-butyl n-pentyl or n-hexyl) optionally substituted by a C1-C6, preferably C1-C4, alkoxyCarbonyl substituent group.
      • R22 represents a hydrogen atom or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
  • R23 represents a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl, C1-C6, preferably C1-C4, alkoxy or C1-C6, preferably C1-C4, alkoxycarbonyl.
  • Preferred compounds of the invention include:
    • N-(5-Chloro-2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy})-phenyl)-isobutramide,
    • Thiophene-2-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-[(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)methyl]-benzamide,
    • Pyrazine-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Cyclohexanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-phthalamic acid methyl ester,
    • N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydrpxy-butyramide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-acetamide,
    • 4-Acetylamino-N-(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,
    • 1-Acetyl-piperidine-4-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide,
    • 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,
    • 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,
    • Adamantane-1-carboxylic acid (2-{3-[34-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide,
    • 5-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • 1-Acetyl-pyrrolidine-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • 5-Oxo-pyrrolidine-2-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • 1H-Indole-6-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Cyclobutanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,
    • Pentanoic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Pent-4-enoic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Cyclopentanecarboxylic acid (2-{3-[3(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Cyclopropanecarboxylic acid (2-{3-[3-(chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,
    • N2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfinyl-acetamide,
    • 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,
    • N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide,
    • 5-Oxo-hexanoic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Hexanoic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • 2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,
    • 3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,
    • (4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazlidine-carboxamide ditrifluoroacetate,
    • Thiophene-2-carboxylic acid (2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,
    • N-(2-{3-[4(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,
    • Pyridine-2-carboxylic acid (2-{3-[4-(3,4dichloro-phenoxypiperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,
    • Cyclohexanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,
    • 5-Methyl-thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Cyclobutanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,
    • Pentanoic acid (2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Pentenoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • Cyclopentanecarboxylic acid (2-{3-[4-(3 ,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
    • N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,
    • N2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifluoroacetamide hydrochloride,
    • 4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)3-methyl-butyric acid,
    • N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic acid,
    • Furan-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 1H-Pyrrole-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Thiophene-2-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Cyclopentanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 5-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4methyl-phenyl)-amide,
    • 3-Chloro-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 5-Methyl-isoxazole-4-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • [1,2,3]Thiadiazole-4-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidn-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 3-Methyl-furan-2-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Cyclopent-1-enecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 2-Methyl-furan-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-methyl-phenyl)-amide,
    • 3-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 5-Nitro-1H-pyrazole-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}4-methyl-phenyl)-amide,
    • Thiophene-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Cyclobutanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Furan-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 1H-Pyrrole-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Thiophene-2-carboxylic acid (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 3-Chloro-thiophene-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 5-Methyl-isoxazole-4-carboxylic acid (2-{3-[3-(4-fuoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 3-Methyl-furan-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Cyclopent-1-enecarboxylic acid (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 2-Methyl-furan-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 3-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 5-Chloro-thiophene-2-carboxylic acid (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Thiophene-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • 2,5-Dimethyl-furan-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Cyclobutanecarboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • Furan-3-carboxylic acid (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
    • N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-2-carboxamide,
    • N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-3-thiophenecarboxamide,
    • N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxamide, compound with trifluoroacetic acid,
    • N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-thiophenecarboxamide,
    • N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-2-furancarboxamide,
    • N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrole-2-carboxamide,
    • N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-3-carboxamide,
    • N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-furancarboxamide,
    • N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxamide, compound with trifluoracetic acid,
    • N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,
    • N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,
    • N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,
    • N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide, and
    • N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.
  • The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises reacting a compound of general formula
    Figure US20050239801A1-20051027-C00003
    or a salt thereof (e.g. an acid addition salt such as a hydrochloride salt), wherein m, n, t, R1, R3, R4, R5, R6, R7, R8, R16, Q, Z1 and Z2 are as defined in formula (I), with a compound of general formula
    R15—CO2H  (III)
    or chemically equivalent derivative thereof (e.g. acyl halide or anhydride derivative) wherein R15 is as defined in formula (I);
      • and optionally thereafter forming a pharmaceutically acceptable salt or solvate of the compound of formula (I) obtained.
  • The process of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as an alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene), an amine (e.g. triethylamine or diisopropylethylamine) or acetonitrile at a temperature ot, for example, 15° C. or above, such as a temperature in the range from 20 to 120° C.
  • Compounds of formulae (II) and (III) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
  • It will be appreciated by those skilled in the art that in the process of the present invention certain functional groups such as hydroxyl or amino groups in the staring reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
  • The protection and deprotection of functional groups is descnbed in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
  • The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orptolienesulphonate.
  • Compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention.
  • The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially MIP-1α chemokine receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of taplanted organs or tissues and Acquired Ilununodeficiency Syndrome (AIDS).
  • Examples of these conditions are:
      • (1) (the respiratory tract) airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthmn (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, iinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
      • (2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis;
      • (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, eiydiemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
      • (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
      • (5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;
      • (6) (allograft rejection) acute and chronic following, for example, tnsplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease;
      • (7) cancers, especially non-sraill cell lung cancer (NSCLC) and squamous sarcoma;
      • (8) diseases in which angiogenesis is associated with raised chemokine levels (e.g. NSCLC); and
      • (9) cystic fibrosis, stroke, re-perfusion injury in the heart, brain, peripheral limbs and sepsis.
  • Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly.
  • The invention also provides a method of treating an inflammatory disease 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 or solvate thereof, as hereinbefore defined.
  • The invention still further provides a method of treating an airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • For the above-mentioned therapeutic uses the dosage administered will, of course, vary s with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (I) may be in the range from 0.001 mg/kg to 30 mg/kg.
  • The compounds of formula (I) and pharmaceutically acceptable salts and solvates 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/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate 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 or solvate thereof, as hereinbefore defined,,with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; 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 ad i:stion or by rectal administration in the form of suppositories or transdermally.
  • The invention will now be further explained by reference to the following illustrative examples, in which 1H NMR spectra were recorded on Varian Unity Inova 400. The central solvent peak of chloroform-d (δH 7.27 ppm) were used as internal standard Low resolution mass spectra and accurate mass determination were recorded on a Hewlett-Packard 1100 LC-MS system equipped with APCI/ESI ionisation chambers. All solvents and commercial reagents were laboratory grade and used as received. The nomenclature used for the compounds was generated with ACDUAC Name Pro. The following abbreviations are used in the examples:
  • NMP: 1-Methyl-2-pyrrolidinone
  • DIMA: N,N-Diisopropylethylanine
  • HBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • HoBT: 1-Hydroxybenzotriazole
  • THF: Tetrahydrofuran
    • EXAMPLE 1 N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide
  • a) N-(5-Chloro-2-hydroxy-phenyl)-isobutyramide
  • In a flask was added 4-chloro-2-aminophenol (1.2 g, 8.39 mmole) and water (25 ml). The suspension was vigorously stirred and isobutyric anhydride (1.6 ml, 10.5 inmole) was added. The mixture was heated to 60° C. for 30 minutes under vigorous stirring. The emulsion was cooled, and a precipitate was formed, which was collected through filtration. The solid was washed twice with water on the filter and was finally dried to give 1.4 g (78%) of the sub-title compound as a white solid.
  • 1H-NMR (400 MHz DMSO-d6) δ: 10.11 (1H, s); 9.12 (1H, s); 7.94 (1H, d, J2.5 Hz); 6.95 (1H, dd, J 8.7 2.6 Hz); 6.84 (1H, d, J8.5 Hz); 2.79 (1H, p, J6.7 Hz); 1.08 (6H, d, J6.8 Hz)
  • b) N-(5-Chloro-2-oxiranylmethoxy-phenyl)-isobutyramide
  • In a vial was added the compound obtained in a) (0.4 g, 1.87 mmole), epibromohydrin (0.28 g, 2.06 mmole), K2CO3 (0.5 g, 3.7 mnmole) and DMF (2 ml). The vial was sealed and heated with stirrng (2 hours, 60° C.). The mixture was then partitioned between EtOAc and water, and the organic phase was washed twice with water and once with brine, and was finally evaporated to give a brown solid. The crude epoxide was purified on silica, to give 0.22 g (44%) of the sub-title compound as a white solid.
  • c) In a vial was added the compound obtained in b) (0.026 g, 0.13 mmole), 3-(4-chlorophenoxy)-pyrrolidine (0.035 g, 0.13 mmole) in ethanol (2 ml). The vial was sealed and heated with stirring at 75° C. for 3 hours. The solution was allowed to cool, and the solvent was evaporated. The crude product was purified on silica, and the pure fractions were collected. The title compound was lyophilized as the hydrochloride, giving 0.055 g (84%) as a white solid. The compound was a mixture of four stereoisomers, which had an effect on the NMR-spectra.
  • 1H-NMR (400 MHz, DMSO-d6) δ: 10.84-10.34 (1H, m); 9.12 (1H, s); 8.09 (1H, s); 7.36 (2H, dd, J 9.2 1.3 Hz); 7.11-7.00 (3H, m); 7.00 (211 d, J 8.8 Hz); 6.22-6.06 (1H, m); 5.22-5.10 (1H, m); 4.34 (1H, bs); 4.08-3.96 (1.5H, m); 3.95-3.87 (1H, m); 3.83-3.66 (1.5H m); 3.61-3.23 (3H, m); 2.86 (1H, sept, J6.6 Hz); 2.64-2.51 (½H, m); 2.36-2.14 (1H, m); 2.14-2.00 (½H, m); 1.08 (6H, d, J 6.7 Hz) APCI-MS: m/z 467.2 [MH+]
  • Aniline Intermediate 1
  • 1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol dihydrochloride
  • N-(2-{3-[4-(3,4-chlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)-acetamide (1.418 g, 3.13 mmol, prepared by analogy to Example 1) was dissolved in 50 ml HCl (35%/aq, puriss) and refluxed overnight. The product precipitated and was filtered and dried to give 0.835 g (65%) of the title compound.
  • APCI-MS m/z: 411, 413 [MH+]1H NMR (400 Mz, CDCl3): δ 8.39-3.31 (m, 2H), 7.31(d, 1H), 7.01-6.98(m, 3E), 6.94-6.91(m, 1H), 6.75(dd, 1H), 4.31(m, 1), 4.12-4.02 (m, 2H), 3.92(dd, 1H), 2.90(m, 1H), 2.69(m, 1H), 2.62-2.51(m, 2H), 2.46(dd, 1H), 2.34(m, 1H), 2.18(s, 3H), 2.04-1.93(m, 2H), 1.89-1.77(m, 2H).
  • Aniline Intermediate 2
  • 1-[(2-aminophenyl)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol dihydrochloride
  • Prepared according to the method described in Aniline Intermediate 1.
  • APCI-MS m/z: 363, 365 [MH+]
  • The intermediate anilines 1 and 2 described above were used in the following examples.
    • EXAMPLE 2 Thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • To a solution of 80 uL 0.2M 2-thiophenecarboxylic acid in N were IBTU (80uL, 0.2M/NMP) ,HoBT (80 uL, 0.2M/NMP), DIEA (30 uL, 0.5M/NMP) and pyridine (30 uL, 0.5M/NMP) added and stirred for 30 minutes before 1-[(2-aminophenyl)oxy]-3-{3-[(4- chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol (75 uL, 0.2 M/NMP) was added. The mixture was stirred overnight at room temperature before it was concentrated under reduced pressure to dryness. The product was diluted with 1000 uL dichloromethane and washed with with sat. NaHCO3/aq (800 uL), 1.8% HCl/aq(800 uL) and sat NaC])aq.
  • The organic layer was concentrated under reduced pressure to dryness and used without further purification Yield 3.6 mg, 51%
  • APCI-MS m/z: 473.2 [MH+]1H NMR (400 MHz, CD3OD): δ 7.88-7.85 (d, 1H), 7.74-7.65 (m, 2H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 1H), 7.20-7.15 (m, 1H), 7.14-7.09 (dd, 1H), 7.06-7.00 (m, 1H), 6.96-6.91 (m, 2H), 5.18-5.12 (m, 1H), 4.39-4.30 (m, 1H), 4.19-3.24 (m, 9H), 2.66-2.11 (m, 3H)
  • The following Examples 3 to 53 were prepared by methods analogous to the method descnbed in Example 2.
    • EXAMPLE 3 N-[(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide
  • APCI-MS m/z: 524.3 [MH+]
    • EXAMPLE 4 Pyrazine-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}phenyl)-amide
  • APCI-MS m/z: 469.2 [MH+]
    • EXAMPLE 5 Cyclohexanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 473.3 [MH+]
    • EXAMPLE 6 N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-phthalamic acid methyl ester
  • APCI-MS m/z: 525.2 [MH+]
    • EXAMPLE 7 N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide
  • APCI-MS m/z: 449.2 [MH+]
    • EXAMPLE 8 N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-acetamide
  • APCI-MS m/z: 463.2 [MH+]
    • EXAMPLE 9 4-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide
  • APCI-MS m/z: 490.3 [MH+]
    • EXAMPLE 10 1-Acetyl-piperidine-4-carboxylic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 516.3 [MH+]
    • EXAMPLE 11 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide
  • APCI-MS m/z: 497.2 [MH+]
    • EXAMPLE 12 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide
  • APCI-MS m/z: 504.3 [MH+]
    • EXAMPLE 13 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide
  • APCI-MS m/z: 506.2 [MH+]
    • EXAMPLE 14 Adamantane-1-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 525.3 [MH+]
    • EXAMPLE 15 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide
  • APCI-MS m/z: 552.3 [MH+]
    • EXAMPLE 16 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide
  • APCI-MS m/z: 497.2
    • EXAMPLE 17 5-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 487.2 [MH+]
    • EXAMPLE 18 1-Acetyl-pyrrolidine-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 502.3 [MH+]
    • EXAMPLE 19 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolIdin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 485.3 [MH+]
    • EXAMPLE 20 5-Oxo-pyrrolidine-2-carboxylic acid (2-{3-[3-(4-chlorophenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 474.2 [MH+]
    • EXAMPLE 21 1H-Indole-6-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 506.2 [MH+]
    • EXAMPLE 22 Cyclobutanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 445.3 [MH+]
    • EXAMPLE 23 N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide
  • APCI-MS m/z: 419.2 [MH+]
    • EXAMPLE 24 Pentanoic acid (2-{3-[3-(4chloro-phenoxy)-pyrrolldin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 447.3 [MH+]
    • EXAMPLE 25 Pent-4-enoic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolIdin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 445.3 [MH+]
    • EXAMPLE 26 Cyclopentanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 459.3 [MH+]
    • EXAMPLE 27 Cyclopropanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 431.2 [MH+]
    • EXAMPLE 28 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide
  • APCI-MS m/z: 433.3 [MH+]
    • EXAMPLE 29 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-acetamide
  • APCI-MS m/z: 451.2 [MH+]
    • EXAMPLE 30 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide
  • APCI-MS m/z: 476.2 [MH+]
    • EXAMPLE 31 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroy-propoxy}phenyl)-butyramide
  • APCI-MS m/z: 433.3 [MH+]
    • EXAMPLE 32 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide
  • APCI-MS m/z: 447.3 [MH+]
    • EXAMPLE 33 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide
  • APCI-MS m/z: 435.2 [MH+]
    • EXAMPLE 34 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide
  • APCI-MS m/z: 447.2 [MH+]
    • EXAMPLE 35 5-Oxo-hexanoic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 475.3 [MH+]
    • EXAMPLE 36 Hexanoic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 461.3 [MH+]
    • EXAMPLE 37 2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide
  • APCI-MS m/z: 501.2, 503.2 [MH+]
    • EXAMPLE 38 3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide
  • APCI-MS m/z: 501.2, 503.2 [MH+]
    • EXAMPLE 39 (4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazolidine-4-carboxamide ditrifluoroacetate
  • APCI-MS m/z: 478.2 [MH+]
    • EXAMPLE 40 Thiophene-2-carboxylic acid (2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 521.0, 523.0 [MH+]
    • EXAMPLE 41 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide
  • APCI-MS m/z: 515.2, 517.2[MH+]
    • EXAMPLE 42 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide
  • APCI-MS m/z: 516.2, 518.2 [MH+]
    • EXAMPLE 43 Pyridine-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy- propoxy}-phenyl)-amide
  • APCI-MS m/z: 516.2, 518.2 [MH+]
    • EXAMPLE 44 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide
  • APCI-MS m/z: 516.2, 518.2 [MH+]
    • EXAMPLE 45 Cyclohexanecarboxylic acid (2-{3-[4-(3,4-chloro-phenoxy)-piperldin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 521.3, 523.3 [MH+]
    • EXAMPLE 46 N-(2-{3-[4-(3,4-Dichlorophenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}phenyl)-3-hydroxy-butyramide
  • APCI-MS m/z: 497.2, 499.3 [MH+]
    • EXAMPLE 47 5-Methyl-thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 535.2, 537.2 [MH+]
    • EXAMPLE 48 Cyclobutanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 493.3, 495.2 [MH+]
    • EXAMPLE 49 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide
  • APCI-MS m/z: 467.2, 469.2 [MH+]
    • EXAMPLE 50 Pentanoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 495.3,497.3 [MH+]
    • EXAMPLE 51 Pent-4-enoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 493.3 ,495.2[MH+]
    • EXAMPLE 52 Cyclopentanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
  • APCI-MS m/z: 507.3, 509.3 [MH+]
    • EXAMPLE 53 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide
  • APCI-MS m/z: 495.3,497.3 [MH+]
    • EXAMPLE 54 N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifluoroacetamide hydrochloride
  • A mixture of 1-(2-aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol (10 mg, 0.022 mmol), dichloromethane (3 ml) and Triethyl amine was cooled in an ice bath A solution of Trifluoro acetic anhydride (3.5 μl, 0.025 mmol) in dichloromethane (2 ml) was then added and the mixture stirred at 0° C. until reaction completion. The mixture was diluted with dichloromethane, washed with 1M H2SO4, water, dried over natrium sulphate and concentrated to give an oil. The oil was treated with 1.0M ethereal HCl solution to give the product as solid (9 mg).
  • APCI-MS: m/z 459,460 [MH+]
    • EXAMPLE 55 4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyric acid
  • 1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol (75 uL, 0.2M/NMP) was mixed with 3-methyl glutaric anhydride (3 eq, 225 uL 0.2 M/NMP) to get a product containing both esther and amide. After evaporation of the mixture it was treated with 3 eq 0.5M LiOH in (TF/water 1:4) for two hours at 80° C. to hydrolyse the esther. The reaction mixture was diluted with more water (2 mL) and the desired product was extracted with 5×500 uL EtOAc which was evaporated to dryness.
  • APCI-MS m/z: 539.2, 541.2 [MH+]
    • EXAMPLE 56 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic acid
  • Prepared according to the method described in Example 55.
  • APCI-MS m/z: 511.2, 513.2 [MH+]
  • Aniline Intermediate 3
  • 1-(2-amino-5-methylphenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol
  • APCI-MS m/z: 377.2, 379.1 [MH+]
  • 1H NMR (400 MHz, CDCl3): δ 7.26-7.21 (m, 2H), 6.79-6.74 (m, 2H), 6.67-6.62 (m, 3H), 4.83-4.76 (m, 1H), 4.15-4.06 (m, 1H), 4.04-4.00 (d, 2H), 3.73-3.64 (s, 2H), 3.47-3.35 (s, 1H), 3.14-2.56 (m, 6H), 2.36-2.22(m, 4H), 2.05-1.95(m, 1H)
  • Aniline Intermediate 4
  • 1-(2-amino-5-methylphenoxy)-3-[3-(4-fluorophenoxy)-1-pyrrolidinyl]-2-propanol
  • APCI-MS m/z: 361.1 [MH+]
  • 1H NMR (400 MHz, CDCl3): δ 7.00-6.94 (m, 2H), 6.81-6.76 (m, 2H), 6.67-6.62(m, 3H), 4.81-4.74 (m, 1H), 4.15-4.06 (m, 1H), 4.03-3.99 (m, 2H), 3.88-3.36 (m, 3H), 3.12-2.56 (m, 6H), 2.33-2.23(m, 4H), 2.05-1.96(m, 1H)
  • The compounds of Examples 57 to 85 were prepared using one of the Aniline Intermediates 3 and 4.
    • EXAMPLE 57 Furan-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 471.5, 473.5 [MH+]
    • EXAMPLE 58 1H-Pyrrole-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 470.5, 472.5 [MH+]
    • EXAMPLE 59 Thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 487.5, 489.5 [MH+]
    • EXAMPLE 60 Cyclopentanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrilidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 473.6, 475.5 [MH+]
    • EXAMPLE 61 5-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolldin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 501.5, 503.5 [MH+]
    • EXAMPLE 62 3-Chloro-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 521.5, 532.5 [MH+]
    • EXAMPLE 63 5-Methyl-isoxazole-4-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 486.5, 488.6 [MH+]
    • EXAMPLE 64 [1,2,3]Thiadiazole-4-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 489.5, 491.5[MH+]
    • EXAMPLE 65 3-Methyl-furan-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 485.5, 487.6 [MH+]
    • EXAMPLE 66 Cyclopent-1-enecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 471.6, 473.6 [MH+]
    • EXAMPLE 67 2-Methyl-furan-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 485.6, 487.6 [MH+]
    • EXAMPLE 68 3-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 501.6, 503.5 [MH+]
    • EXAMPLE 69 5-Nitro-1H-pyrazole-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 516.5, 518.5 [MH+]
    • EXAMPLE 70 Thiophene-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 487.5, 489.5 [MH+]
    • EXAMPLE 71 Cyclobutanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 459.5, 461.5 [MH+]
    • EXAMPLE 72 Furan-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 455.5 [MH+]
    • EXAMPLE 73 1H-Pyrrole-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 454.6 [MH+]
    • EXAMPLE 74 Thiophene-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 471.5 [MH+]
    • EXAMPLE 75 3-Chloro-thiophene-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 505.5, 507.5 [MH+]
    • EXAMPLE 76 5-Methyl-isoxazole-4-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenylamide
  • APCI-MS m/z: 470.5 [MH+]
    • EXAMPLE 77 3-Methyl-furan-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 469.6 [MH+]
    • EXAMPLE 78 Cyclopent-1-enecarboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 455.6 [MH+]
    • EXAMPLE 79 2-Methyl-furan-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 469.6 [MH+]
    • EXAMPLE 80 3-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 485.5 [MH+]
    • EXAMPLE 81 5-Chloro-thiophene-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 505.5, 507.5 [MH+]
    • EXAMPLE 82 Thiophene-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 471.5 [MH+]
    • EXAMPLE 83 2,5-Dimethyl-furan-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 483.6 [MH+]
    • EXAMPLE 84 Cyclobutanecarboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 443.6 [MH+]
    • EXAMPLE 85 Furan-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
  • APCI-MS m/z: 455.5 [M+H+]
    • EXAMPLE 86 N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-2-carboxamlde
  • APCI-MS: m/z 454.1 [M+H+]
    • EXAMPLE 87 N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-3-thiophenecarboxamide
  • APCI-MS: m/z 471.1 [M+H+]
    • EXAMPLE 88 N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxamide, compound with trifluoroacetic acid
  • Aniline intermediate 3 (60 mg, 0.159 mmol), 2-thiophenecarboxylic acid (20.4 mg, 0.159 mmol) and HATU (72 mg, 0.191 mmol) were stirred in dichloromethane (2 ml).
  • Diisopropylethylamine was added to pH 8. The mixture was stirred overnight and then concentrated. The residue was purified on silica (dichloromethane/methanol 98/2) followed by purificaton on C18 (2 g Isolute, acetonitfile/water 20/80 to 35/65 with 0.5% trifluoroacetic acid) to give the title compound (75 mg, 79%).
  • 1H-NMR (400 MHz, MeOD): δ 7.86 (m, 1H), 7.72 (m, 1H), 7.50 (m, 1H), 7.29 (m, 3H), 7.16 (m, 2H), 7.07 (m, 1H), 6.91 (m, 2H), 5.10 (m, 1H), 3.82-4.17 (m, 4H), 3.24-3.69 (m, 4H), 2.13-2.64 (m, 2H), 1.38 (m, 3H). MS-APCI+: m/z 487 [MH+]
    • EXAMPLE 89 N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-thiophenecarboxamiide
  • APCI MS APCI-MS: m/z 471.1 [M+H+]
    • EXAMPLE 90 N-{2-[(3-{3-[(4-chlorophenyl)oxyl-1-pyrroldinyl}-2-hydroxpropyl)oxy]phenyl}-2-furancarboxamide
  • APCI-MS: m/z 456.9 [M+H+]
    • EXAMPLE 91 N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrole-2-carboxamide
  • APCI-MS: m/z 456.1 [M+H+]
    • EXAMPLE 92 N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-3-carboxamide
  • APCI-MS: m/z 470.0 [M+H+]
    • EXAMPLE 93 N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-furancarboxamide
  • APCI-MS: m/z 4551 M+H+]
    • EXAMPLE 94 N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxamide, compound with trinfluoracetic acid
  • The compound (80 mg, 86%) was prepared from aniline intermediate 3 (60 mg, 0.159 mmol) and cyclopentanecarboxylic acid (18 μl, 0.159 mmol) as descnbed in Example 88.
  • 1H-NMR (400 MHz, MeOD): δ 7.59 (m, 1H), 7.29 (m, 2H), 7.19 (m, 1H), 7.09 (m, 1H), 6.97 (m, 3H), 5.17 (m, 1H), 3.86-4.23 (m, 4H), 3.35-3.73 (m, 4H), 2.86 (m, 1H), 1.45 (bs, 3H).
  • MS-APCI+: m/z 473 [MH+]
    • EXAMPLE 95 N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide
  • The compound was prepared using an analogous method as in Example 88.
  • APCI-MS: m/z 465 [MH+]
    • EXAMPLE 96 N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide
  • The compound was prepared using an analogous method as in Example 88.
  • APCI-MS: m/z 472 [MH+]
    • EXAMPLE 97 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide
  • The compound was prepared using an analogous method as in Example 88.
  • APCI-MS: m/z 529 [MH+]
    • EXAMPLE 98 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide
  • The compound was prepared using an analogous method as in Example 88.
  • APCI-MS: m/z 481 [MH+]
    • EXAMPLE 99 N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide
  • The compound was prepared using an analogous method as in Example 88.
  • APCI-MS: m/z 528 [MH+]
  • THP-1 Chemotaxis Assay
  • Introduction
  • The assay measured the chemotactic response elicited by MIP-1α chemokine in the human monocytic cell line TBP-1. The compounds of the Examples were evaluated by their ability to depress the chemotactic response to a standard concentration of MP-lx chemokine.
  • Methods
  • Culture of THP-1 cells
  • Cells were thawed rapidly at 37° C. from frozen aliquots and resuspended in a 25 cm flask containing 5 ml of RPI-1640 medium supplemented with Glutamax and 10% heat inactivated fetal calf serum without antibiotics (RPMI+10%HIFCS). At day 3 the medium is discarded and replaced with fresh medium
  • THP-1 cells are routinely cultured in RPMI-1640 medium supplemented with 10% heat inactivated fetal calf serum and glutamax but without antibiotics. Optimal growth of the cells requires that they are passaged every 3 days and that the minimum subculture density is 4×10+5 cells/ml.
  • Chemotaxis Assay
  • Cells were removed from the flask and washed by centrigation in RPMI+10%HEFCS+glutamax. The cells were then resuspended at 2×10+7 cells/mi in fresh medium (RPMI+10%HIFCS+glutamax) to which was added calcein-AM (5 μl of stock solution to 1 ml to give a final concentration of 5×10−6 M). After gentle mixing the cells were incubated at 37° C. in a CO2 incubator for 30 minutes. The cells were th diluted to 50 ml with medium and washed twice by centrifigation at 400 ×g. Labelled cells were then resuspended at a cell concentration of 1×10+7 cells/ml and incubated with an equal volume of MIP-1α antagonist (10−10M to 10−6M final concentration) for 30 minutes at 37° C. in a humidified CO2 incubator.
  • Chemotaxis was performed using Neuroprobe 96-well chemotaxis plates employing 8 μM (filters (cat no. 101-8). Thirty microlitres of chemoattractant supplemented withy various concentrations of antagonists or vehicle were added to the lower wells of the plate in triplicate. The filter was then carefully positioned on top and then 25 μl of cells preincubated with the corresponding concentration of antagonist or vehicle were added to the surface of the filter. The plate was then incubated for 2 hours at 37° C. in a humidified CO2 incubator. The cells remaining on the surface were then removed by adsorption and the whole plate was centrifuged at 2000 rpm for 10 minutes. The filter was then removed and the cells that had migrated to the lower wells were quantified by the fluorescence of cell associated calcein-AM. Cell migration was then expressed in fluorescence units after subtraction of the reagent blank and values were standardized to % migration by comparing the fluorescence values with that of a known number of labelled cells. The effect of antagonists was calculated as % inhibition when the number of migrated cells were compared with vehicle.

Claims (19)

1. A compound of general formula
Figure US20050239801A1-20051027-C00004
wherein:
m is 0, 1, 2 or 3;
each R1 independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —NR9R10, C3-C6 cycloalkylamino, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonylamino, sulphonamido, C1-C6 alkylsulphonyl, —C(O)NR11R12, —NR13C(O)—(NH)PR14, phenyl, or C1-C6 alkyl optionally substituted by carboxyl or C1-C6 alkoxycarbonyl;
p is 0 or 1;
X represents an oxygen atom or a CH2, OCH2, CH2O, CH2NH, NH, carbonyl or sulphonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen atom or a CH2O, CH2NH or NH group, then Y represents a CH group;
Z1 represents a group (CH2)q where q is 1 or 2;
Z2 represents a bond or a group CH2, with the proviso that when Z1 is CH2, Z2 is CH2, and when Z1 is (CH2)2. Z2 is a bond;
Q represents an oxygen or sulphur atom or a group CH2 or NH;
R represents a group
Figure US20050239801A1-20051027-C00005
n is 0, 1 or 2;
each R3 independently represents a C1-C6 alkyl, C1-C6 alkoxycarbonyl, —CH2OH or carboxyl group;
R4, R5, R6 and R7 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R4, R5, R6 and R7 together represent a C1-C4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or R5, R6 and R7 each represent a hydrogen atom and R4 and R8 together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R8 represents a hydrogen atom, a C1-C6 alkyl group or is linked to R4 as defined above;
R9 and R10 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
R11 and R12 each independently represent a hydrogen atom or a C1-C6 alkyl group optionally substituted by C1-C6 alkoxycarbonyl;
R13 represents a hydrogen atom or a C1-C6 alkyl group;
R14 represents a hydrogen atom, or a C1-C6 alkyl group optionally substituted by carboxyl, C1-C6 alkoxy or C1-C6 alkoxycarbonyl;
R15 represents a group C2-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, adamantyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, wherein each group may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenyl and —NHC(O)—R17, with the proviso that R15 does not represent an unsubstituted 1-pyrrolidinyl, an unsubstituted 1-piperidinyl or an unsubstituted 1-hexamethyleneiminyl group;
t is 0, 1, 2 or 3;
each R16 independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —NR18R19, C3-C6 cycloalkylamino, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonylamino, sulphonamido (—SO2NH2), C1-C6 alkylsulphonyl, —C(O)NR20R21, —NR22C(O)(NH)vR23, phenyl, or C1-C6 alkyl optionally substituted by carboxyl or C1-C6 alkoxycarbonyl;
R17 represents a C1-C6 alkyl, amino or phenyl group;
R18 and R19 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R18 and R19 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
R20 and R21 each independently represent a hydrogen atom or a C1-C6 alkyl group optionally substituted by C1-C6 alkoxycarbonyl;
v is 0 or 1;
R22 represents a hydrogen atom or a C1-C6 alkyl group; and
R23 represents a hydrogen atom, or a C1-C6 alkyl group optionally substituted by carboxyl, C1-C6 alkoxy or C1-C6 alkoxycarbonyl;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1, wherein X represents an oxygen atom or a CH2 or NH group.
3. A compound according to claim 1, wherein Y represents a CH group.
4. A compound according to claim 1, wherein Q represents an oxygen atom.
5. A compound according to claim 1, wherein R15 represents a group C2-C5 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, adamantyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, wherein each group may be optionally substituted by one, two or three substituents independently selected from hydroxyl, oxo, halogen, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, Cl-C6 alkoxycarbonyl, phenyl and —NHC(O)—R17.
6. A compound according to claim 5, wherein the saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, is pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, thiadiazolyl, isoxazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.
7. A compound according to claim 1, wherein each R16 independently represents halogen, cyano, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4haloalkyl, C1-C4 alkylcarbonyl, phenyl or C1-C4 alkyl.
8. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1 being selected from:
Thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,
Pyridine-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,
Cyclohexanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,
5-Methyl-thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
Cyclobutanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,
Pentanoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
Pent-4-enoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
Cyclopentanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,
4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyric acid,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic acid,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,
N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.
9. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises reacting a compound of general formula
Figure US20050239801A1-20051027-C00006
or a salt thereof, wherein m, n, t, R1, R3, R4, R5, R6, R7, R8, R16, Q, Z1 and Z2 are as defined in formula (I), with a compound of general formula

R15—CO2H  (III)
or chemically equivalent derivative thereof, wherein R15 is as defined in formula (I);
and optionally thereafter forming a pharmaceutically acceptable salt or solvate of the compound of formula (I) obtained.
10. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
11. A process for the preparation of a pharmaceutical composition as claimed in claim 10 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.
12-18. (canceled)
19. A method of treating an inflammatory disease 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 or solvate thereof, as claimed in claim 1.
20. A method of treating an airways disease 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 or solvate thereof, as claimed in claim 1.
21. A method of treating a human disease or condition in which modulation of chemokine receptor activity is beneficial, in a patient suffering from, or at risk of, said disease or condition, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.
22. A method of treating rheumatoid arthritis in a patient suffering from, or at risk of, rheumatoid arthritis, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.
23. A method of treating chronic obstructive pulmonary disease 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 or solvate thereof, as claimed in claim 1.
24. A method of treating asthma, in a patient suffering from, or at risk of, asthma, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.
25. A method of treating multiple sclerosis in a patient suffering from, or at risk of, multiple sclerosis, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.
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