WO2009049113A1 - Pipéridinylhydroxyéthylpipéridines utilisables en tant que modulateurs des récepteurs aux chimiokines - Google Patents

Pipéridinylhydroxyéthylpipéridines utilisables en tant que modulateurs des récepteurs aux chimiokines Download PDF

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Publication number
WO2009049113A1
WO2009049113A1 PCT/US2008/079447 US2008079447W WO2009049113A1 WO 2009049113 A1 WO2009049113 A1 WO 2009049113A1 US 2008079447 W US2008079447 W US 2008079447W WO 2009049113 A1 WO2009049113 A1 WO 2009049113A1
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alkyl
mmol
methyl
compound
pharmaceutically acceptable
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PCT/US2008/079447
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English (en)
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Clark A. Sehon
Gren Z. Wang
Andrew Q. Viet
Jing Zhang
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Glaxo Group Limited
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Priority to EP08838205A priority Critical patent/EP2211618A1/fr
Priority to JP2010529064A priority patent/JP2011500590A/ja
Publication of WO2009049113A1 publication Critical patent/WO2009049113A1/fr

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    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a class of piperidinylhydroxyethylpiperidines that are modulators of chemokine receptors, particularly as CCR2 antagonists and their methods of use.
  • CCR2 is a chemokine receptor that is expressed on a cell surface of monocytes and some other blood leukocytes. CCR2 binds to the monocyte chemo tactic protein MCP-I, and other CC chemokines, which are produced at sites of inflammation and infection.
  • each R 1 is independently -NR y -SO 2 -Ci-C 6 -alkyl, -NR -C(O)-N(R 1 1 ⁇ U X) 2 , -NR -C(O)-OR*, halo, Ci-Ce-alkyl, CF 3 , cyano, Ci-C 6 -alkoxy, OH, or -(Y) q -N(R 10 ) 2 ;
  • R 2 is H, Ci-C 6 -alkyl, -C(O)-C,-C 6 -alkyl, or -SO 2 R 11 ;
  • R 3 is H, halo, HO-C r C 6 -alkyl, C,-C 6 -alkyl, or CF 3 ;
  • R 4 and R 5 are each independently H, C r C 6 -alkyl, OH, HO-Ci-C 6 -alkyl, COOH, or Q-
  • R 6 is H, C,-C 6 -alkyl, OH, C t -C 6 -alkoxy, or HO-C r C 6 -a]kyl;
  • R 7 is H, OH, F, Cl, CN, CF 3 , Ci.C 6 -alkyl, hydroxy-C,-C 6 -alkyl, or Ci.C 6 -alkoxy;
  • each R 8 is independently halo, HO-Ci -C ⁇ -alkyl, Q-C ⁇ -alkyl, cyano, trifluoromethyl, Ci-C ⁇ -alkoxy, or Ci-C6-alkylthio;
  • each R 9 is independently H or Ci-C ⁇ -alkyl
  • each R 10 is independently H, -Ci-C ⁇ -alkyl, or acetyl, or, together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocycloalkyl ring;
  • R 1 ' is C , -C 6 -alkyl or phenyl-(R s ) n ; PU62673
  • Y is -SO 2 - or -C(O)-;
  • each m is independently O, 1, 2, or 3;
  • each n is independently 0, 1, 2, or 3;
  • q is 0 or 1 ;
  • the present invention is a composition that comprises a) the compound of Formula 1 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.
  • the invention provides a method of treating a disease comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, endometriosis, or diabetes.
  • the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, endometriosis, or diabetes.
  • the present invention relates to a compound of the following formula:
  • R 1 is chloro, fluoro, methyl, trifluoromethyl, cyano, or methoxy;
  • R 2 and R 3 are each independently H or methyl; and
  • R 4 is H.
  • the compound of the present invention is represented by the following formula:
  • the compound of the present invention is represented by either of the following formulae:
  • the compound of the present invention is represented by either of the following formulae:
  • Ci-C ⁇ -alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, n-propyl, n- butyl, rt-pentyl, w-hexyl, isobutyl, isopropyl, /-butyl, and 1,1-dimethylpropyl.
  • Ci-C 6 -alkoxy examples include methoxy, ethoxy, n-propoxy, prop-2-oxy, «-butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop-2-oxy, «-pentoxy and n-hexyloxy.
  • Q-C ⁇ -alkylthio examples include methylthio, ethylthio, w-propylthio, prop-2-thio, w-butylthio, but-2-thio, 2-methylprop-l-thio, and 2-methylprop-2-thio.
  • R 10 and R 1 ' together with the nitrogen atom to which they are attached, may form a 5- to 6-membered heterocycloaliphatic ring, examples of which include pyrrolidinyl, morpholino, thiomorpholino, dihydropyridazinyl, piperidinyl, and piperazinyl.
  • PU62673
  • halo refers to fluoro, chloro, or bromo.
  • a compound of Formula (I) or “the compound of Formula (I)” refers to one or more compounds according to Formula (I).
  • the compound of Formula (I) may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the incorporated solvent are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • Compounds of the present invention contain at least one chiral center and therefore may be present as racemic mixtures or as enantiomers.
  • the present invention includes all such racemic mixtures and enantiomers.
  • the present invention includes compounds as well as their pharmaceutically acceptable salts. Accordingly, the word “or” in the context of "a compound or a pharmaceutically acceptable salt thereof is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication.
  • pharmaceutically acceptable salts of the compounds according to Formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and m are as defined above.
  • the compound of Formula (II) is a racemate, even where R 6 and R 7 are H, due to the asymmetric carbon atom of the epoxide ring.
  • This racemate may be resolved with (S,S)- Co(Salen) or (R, R)-Co(Salen) prior to reaction with the compound of Formula (HI).
  • A is a protecting group such as Boc or Cbz, to form a compound of Formula VI:
  • Compounds of the Formula (VI) can be converted to compounds of the Formula (I) by those skilled in the art of synthetic chemistry using standard reaction conditions. For example, after the protecting group A is converted to H, the corresponding compound can be reacted with a suitable cinnamic acid or a phenyl isocyanate to form a compound of Formula (I).
  • Compounds of Formula (V) can be prepared, for example, by epoxidation of the corresponding aldehyde in the presence of (CFb ⁇ SOI and NaH in DMSO.
  • intermediate of Formula (IX) can be prepared by contacting indole of Formula (VII) with the protected piperidinone of Formula (VIII) in the presence of phosphoric acid and acetic acid to form a deprotected tetrahydropiperazinyl indole, followed by reprotection with (Boc) 2 ⁇ in a suitable solvent, such as THF or acetone.
  • a suitable solvent such as THF or acetone.
  • a 3' trans-hydroxylated piperidinyl intermediate can be prepared from the compound of Formula (IX) as shown in Scheme 2:
  • the indole of Formula (VII) can be prepared by a number of methods including those outlined in Schemes 5-8.
  • 3'-Alkoxylated piperidine intermediates can be prepared as shown in Scheme 12, where the alkyl group is methyl.
  • DMAP refers to A- dimethylaminopyridine.
  • Suitable protecting groups for amines include acyl type protecting groups such as formyl, trifluoroacetyl, acetyl groups; aromatic urethane type protecting groups such as benzyloxycarbonyl (Cbz) and substituted Cbz groups; aliphatic urethane protecting groups such as 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, and cyclohexyloxycarbonyl groups; and alkyl type protecting groups such as benzyl, trityl, and chlorotrityl groups.
  • acyl type protecting groups such as formyl, trifluoroacetyl, acetyl groups
  • aromatic urethane type protecting groups such as benzyloxycarbonyl (Cbz) and substituted Cbz groups
  • aliphatic urethane protecting groups such as 9-fluorenylmethoxycarbony
  • Suitable acids include inorganic and organic acids; examples of suitable inorganic acids include hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids; examples of suitable organic acids include tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, methanesulfonic, ethanesulfonic, stearic, benzenesulfonic, bromobenzenesulfonic, and /j-toluenesulfonic acids.
  • Suitable bases include NaH, potassiu ⁇ W-butoxide, sodium hydroxide, and potassium hydroxide.
  • the compounds of Formula (I) contain at least one asymmetric carbon atom. Racemates as well as individual stereoisomers (enantiomers and diastereomers) of the compounds of Formula (1) are included within the scope of the present invention. PU62673
  • the invention provides method of treating atherosclerosis comprising administering the compound of formula (I), or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • a compound of the invention may be administered as the pure chemical, it is generally preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
  • the carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers, diluents or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may contain conventional excipients including binding agents, fillers, lubricants, disintegrants, and wetting agents such as those well known in the art.
  • the tablets may be coated according to methods well known in the art.
  • pKi (corresponding to the antilogarithm of Ki) is used instead of Ki.
  • the present invention is a compound of Formula I having a pKi of at least 6.5 as derived from the assay method set out below.
  • CHO cells expressing the human CCR-2 receptor were grown in DMEM Fl 2 media supplemented with 10% foetal calf serum, 2mM L-glutamine, G418 at 37°C 5% CO 2 .
  • Confluent cells were harvested using Hanks buffered salt solution (HBSS, Ca 2+ , Mg 2+ free) containing 0.6mM EDTA. The resulting cell suspension was centrifuged at 30Og at 4°C for 10 min, cell pellet resuspended in 100ml HBSS+EDTA and respun at 30Og for 5 min.
  • HBSS Hanks buffered salt solution
  • the resulting cell pellet was resuspended in 5OmM HEPES containing 10OmM leupeptin, 25 ⁇ g/ml bacitracin, ImM EDTA, ImM PMSF and 2 ⁇ M pepstain A, at pH7.4.
  • the suspension was homogenised using an ice cold blender and centrifuged at 500g for 20mins. The supernatant is withdrawn and spun at 4800Og for 30mins. This cell pellet is PU62673
  • membranes are thawed and resuspended in assay buffer (2OmM HEPES, 10 mM MgCl 2 , 100 mM NaCl, pH7.4, containing lmg/ml saponin, 1OmM GDP) to give final concentration of 5 ⁇ g/well.
  • assay buffer 2OmM HEPES, 10 mM MgCl 2 , 100 mM NaCl, pH7.4, containing lmg/ml saponin, 1OmM GDP
  • LEADseeker SPA beads (0.25 mg/well) for 30 min at room temperature whilst mixing.
  • Assay plates containing 0.5 ⁇ L of various test compounds (30 ⁇ M-30pM) in 100% DMSO as 1 1 point, four fold dilutions across a 384 well plate are used in the assay which have been prepared on a Biomek FX.
  • the plate also contains 16 wells of DMSO and 16 wells of a high concentration of a standard antagonist to produce high and low controls in the experiment.
  • 15 ⁇ L of bead and membrane mix are added with, 15 ⁇ L [ 35 S] GTPgS (0.2 nM final assay concentration) and 15 ⁇ L of an EC 80 (40 nM) of MCP-I .
  • This concentration of MCP-I has been pre-determined from agonist curves run against this receptor. All additions are made using a multidrop. Plates are then sealed and centrifuged for 5 min at 300 rpm before they are left to incubate at room temperature for 3 h. After this time they are read on a Viewlux imaging system. For data handling the high and low controls wells are used to normalise the data which is then fitted using a 4 parameter kit in Excel.
  • the assay described above is believed to have an effective limit of detection of a pKi in the region of 5.0-5.5. Accordingly, a compound exhibiting a pKi value within this range from such an assay may indeed have a reasonable affinity for the receptor, but equally it may also have a lower affinity, including a considerably lower affinity.
  • Mass spectra were obtained using either a Waters ZQ mass spectrometer or Micromass Platform 2 mass spectrometer and use electro-spray ionisoation to observe either MH+ or
  • Table 1 is a table of substituted indoles that were prepared in accordance with the specified scheme. All other indoles used in the Examples were commercially available. PU62673
  • (S,S)-Co-salen catalyst (206 mg, 0.3 mmol) ((S,S)-(+)-N,N'-Bis(3,5-di-tert- butylsalicylidene)-l,2-cyclohexanediamino cobalt (II)) was dissolved in toluene (2 mL) in an open air flask. Glacial acetic acid (39 uL) was added and the reaction stirred at room temperature for 1 hour. The reaction was then concentrated to a brown solid which was placed under high vacuum overnight.
  • Trimethylsulfoxonium iodide (1.65 g, 7.5 mmol) was added in two portions to a solution of NaH (300 mg, 7.5 mmol) in anhydrous DMSO (10 mL) at room temperature. The resulting mixture was stirred for 1 hour, whereupon a solution of phenylmethyl 4-formyl- 1-piperidinecarboxylate (1.2 g, 5.0 mmol) in anhydrous DMSO (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then poured into cold water (100 mL), and extracted with Et 2 O (2 x 100 mL). The extracts were combined, washed with water, brine, and dried (Na 2 SO 4 ). The solvent was removed in vacuo to give the title compound (0.95 g, 3.6 mmol, 72%) as a colorless oil. MS (ES) m/e 262 [M+H] + .
  • the crude material was purified by reverse phase high pressure liquid chromatography ( ⁇ PLC, YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 20 to 55% over 10 minute, UV detection at 214 nm) to give a white solid material as a TFA salt (57 mg, 0.087 mmol, 15%). MS(ES) m/e 544 [M+ ⁇ ]+.
  • Table 2 illustrates other compounds prepared by methods as indicated. PU62673

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Abstract

La présente invention a trait à un composé de formule suivante ou à un sel, acceptable sur le plan pharmaceutique, de celui-ci, où R1 à R8 et X, m et n sont tels que définis. Les composés et compositions de la présente invention se révèlent utiles dans le cadre du traitement de l'athérosclérose.
PCT/US2008/079447 2007-10-11 2008-10-10 Pipéridinylhydroxyéthylpipéridines utilisables en tant que modulateurs des récepteurs aux chimiokines WO2009049113A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP08838205A EP2211618A1 (fr) 2007-10-11 2008-10-10 Pipéridinylhydroxyéthylpipéridines utilisables en tant que modulateurs des récepteurs aux chimiokines
JP2010529064A JP2011500590A (ja) 2007-10-11 2008-10-10 ケモカイン受容体のモジュレータとしてのピペリジニルヒドロキシエチルピペリジン誘導体

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US97916107P 2007-10-11 2007-10-11
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7723350B2 (en) 2007-06-20 2010-05-25 Glaxo Group Limited Spiroindolines as modulators of chemokine receptors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054974A2 (fr) * 2002-12-13 2004-07-01 Smithkline Beecham Corporation Antagonistes de ccr5 utiles comme agents therapeutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054974A2 (fr) * 2002-12-13 2004-07-01 Smithkline Beecham Corporation Antagonistes de ccr5 utiles comme agents therapeutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SONG ET AL.: "Three-dimensional quantitative structure-activity relationship analyses of piperidine based CCR5 receptor antagonists.", BIOORG MED CHEM, vol. 12, no. 2, 2004, pages 489 - 499, XP008133148 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7723350B2 (en) 2007-06-20 2010-05-25 Glaxo Group Limited Spiroindolines as modulators of chemokine receptors
US8431590B2 (en) 2007-06-20 2013-04-30 Glaxo Group Limited Spiroindolines as modulators of chemokine receptors

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