WO2004063192A1 - Derives de d'imidazolyl pyrimidine utilises comme modulateurs du recepteur de il-8 - Google Patents

Derives de d'imidazolyl pyrimidine utilises comme modulateurs du recepteur de il-8 Download PDF

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WO2004063192A1
WO2004063192A1 PCT/US2004/000469 US2004000469W WO2004063192A1 WO 2004063192 A1 WO2004063192 A1 WO 2004063192A1 US 2004000469 W US2004000469 W US 2004000469W WO 2004063192 A1 WO2004063192 A1 WO 2004063192A1
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alkyl
alkoxy
heterocycloalkyl
trifluoromethyl
compound
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PCT/US2004/000469
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English (en)
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Jaap Van Der Louw
Michael H. J. Ohlmeyer
Adolph C. Bohnstedt
Koc-Kan Ho
Douglas S. Auld
Steven G. Kultgen
Andrew Laird Roughton
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Pharmacopeia Drug Discovery, Inc.
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    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to chemical compounds containing the imidazolyl-2-pyrimidine nucleus, a process for the preparation of the compounds, pharmaceutical compositions containing the same, as well as the use of the compounds for the manufacture of a medicament for treating or preventing IL-8 (CXCL8) receptor mediated disorders.
  • Chemokines are pro-inflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors. By interaction with their respective G-protein-coupled receptor (GPCR) chemokines have a profound influence on the selective recruitment of specific cell types in several inflammatory diseases.
  • GPCR G-protein-coupled receptor
  • Chemokines are members of the cytokine superfamily. They generally have low molecular weights ranging from 7 to 15 kDa and stimulate the recruitment of well defined leukocyte subtypes. Chemokines are secondary pro-inflammatory mediators that are induced by primary pro-inflammatory mediators like IL-1 and TNF. Chemokines are divided into two large families (CXC and CC) according to the organisation of the first two of four conserved cysteines in the primary molecular structure.
  • CXC chemokines are mediated through four cell surface receptors, CXCR1 to CXCR4, which are G protein-coupled receptors (GPCRs).
  • GPCRs G protein-coupled receptors
  • IL-8 signals through CXCR1 and CXCR2 (IL-8 receptors).
  • Pharmacological distinction between both receptors is possible since GRO, ENA78, and NAP-2 only bind CXCR2, whereas IL-8 binds both CXCR1 and CXCR2.
  • This two-receptor system does not exist in rodents. Rodents appear to possess only the CXCR2 homologue, which is designated IL-8Rh (IL-8 receptor homologue).
  • mice that lack the murine IL-8Rh resembles that of patients with leukocyte adhesion deficiency, i.e. neutrophils that fail to infiltrate tissues (Cacalano G et al., Science 265;682-684, 1994).
  • CXCR2 was especially regarded as a chemokine receptor inducing neutrophil activation. More recently it became clear that CXCR2 also functions on monocytes, macrophages, and T cells. Strong, recently collected, data suggest a crucial role of CXCR2 in both atherosclerosis and rheumatoid arthritis.
  • IL-8 and CXCR2 are important for monocyte infiltration into the vascular wall.
  • Expression of IL-8 is induced by Ox-LDL in monocytes and is expressed in atherosclerotic plaques.
  • IL-8 and CXCR2 signalling have been shown to be associated with atherosclerosis in vivo.
  • Boisvert et al. JCI 101;353-363, 1998) showed that atherosclerosis susceptible mice (LDL-R-deficient) that were lethally irradiated and transplanted with bone marrow from mice that lack the mIL-8Rh develop less severe lesions compared to mice that receive normal bone marrow.
  • mice Lesion area from these mice were reduced by a factor 2.5 and contained significantly less macrophages as compared to control recipients (Boisvert WA et ai, 1CI 101;353-363, 1998). Thus, there seems to be a role for a CXCR2 homologue in the recruitment of monocytes/macrophages.
  • KC/GRO- ⁇ and MIP-2 are endogenous ligands for mIL-8Rh.
  • KC/GRO- ⁇ expression was generally abundant in atherosclerotic lesions of LDLR knock-out mice (Boisvert WA et al, CI 101 ;353-363, 1998).
  • the role of CXCR2 in atherosclerosis was further underscored by researchers from SmithKline Beecham.
  • the current concept of rheumatoid arthritis deals with the assumption that inflammation and joint destruction are the net results of complex cell-cell interactions.
  • the driving force is supposed to be the (false) recognition of self-peptides by CD 4 + T cells on the surface of various types of antigen presenting cells.
  • Released lymphokines activate monocytes/macrophages, which respond with an increase in their cytokine (e.g. TNF ⁇ , IL-1), chemokine (e.g IL-8) and enzyme (e.g. MMFs) output.
  • cytokine e.g. TNF ⁇ , IL-1
  • chemokine e.g IL-8
  • enzyme e.g. MMFs
  • MMPs adhesion molecules
  • chemotactic factors e.g. IL-8
  • T cells T cells
  • monocytes and neutrophils T cells
  • IL-8 chemotactic factors
  • IL-8 production can be achieved by simple contact with synovial fluid taken from rheumatoid arthritis patients and, without the interference of soluble mediators, by direct contact with activated T cells (Koch et al., J. Immunol., 147, 2187-2195, 1991; Rodenburg et al, Ann Rheum. Dis., 58, 648-652, 1999).
  • Pro-inflammatory cytokines like TNF ⁇ , IL-1 and IL-17, which are all prominantly present in synovial fluid of arthritis patients, induce high levels of IL-8 as well as GRO ⁇ production by synovial chondrocytes and fibroblasts (Pulsatelli et al, J. RheumatoL, 26, 1992-2000, 1999).
  • Chemokine such as, but not limited to IL-8, Gro-alpha (CXCL1), Gro-beta (CXCL2), Gro-gamma (CXCL3), NAP-2 or ENA-78 (CXCL5)
  • mediated diseases include psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, idiopathic pulmonary fibrosis, imTammatory bowel disease, adult respiratory distress syndrome (ARDS), Crohn's disease, stroke, meconium aspiration syndrome, cardiac and renal reperfusion injury, glomerulonephritis, graft vs.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, sulfonamide, cyano, OH and nitro;
  • R 5 is H or (l-6C)alkyk
  • R 6 is H, (l-6C)alkyl or (l-6C)alkoxy
  • R 7 is H or (l-6C)alkyl
  • R 8 is (l-6C)alkyl, optionally substituted with (l-6C)alkoxy;
  • R 9 is -(CH 2 ) n R 10 , wherein n is 1, 2 or 3 and R 10 is selected from (l-4C)alkoxy, (1-
  • the compounds of the present invention are useful for treating or preventing IL-8 receptor mediated disorders, such as atherosclerosis, inflammation, rheumatoid arthritis and related disorders.
  • IL-8 receptor mediated disorders refers to any and all disease states in which chemokines play a role (vide supra).
  • Preferred compounds according to the invention are compounds having the structure II
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, trifluoromethoxy, halogen and nitro;
  • R 5 is H;
  • R 6 is (l-6C)alkyl;
  • R 7 is H; and
  • R 8 is (l-6C)alkyl.
  • R 9 is -(CH 2 ) n R 10 , wherein n is 2 or 3 and R 10 is selected from (l-4C)alkoxy, trifluoromethyl, cyclopentyl, cyclohexyl, phenyl substituted with (l-4C)alkoxy, and -NR ⁇ R 12 , wherein one of R 11 and R 12 is (l-4C)alkoxy, the other being (l-4C)alkyl, or R 9 is -(CH 2 ) 3 (2-7C)heterocycloalkyl or -(CH 2 ) 2 CHR 13 R 14 , wherein
  • (l-4C)alkyl and (l-6C)alkyl mean a branched or unbranched alkyl group having 1 to 4 or 1 to 6 carbon atoms, respectively, such as methyl, ethyl, isopropyl, t-butyl and the like.
  • (l-4C)alkoxy means an alkoxy group having 1-4 carbon atoms, the alkyl moiety of which having the meaning as previously defined.
  • (3-5C)alkylene means an unbranched alkylene group having 3 to 5 carbon atoms, respectively, such as propylene.
  • (3-8C)cycloalkyl means a cycloalkyi group having 3-8 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo-octyl. Cyclopentyl and cyclohexyl are preferred cycloalkyi groups.
  • (2-7C)heterocycloalkyl means a cyclic group having 2 or 7 carbon atoms and further containing one or two heteroatoms selected from O, S or N, such as tetrahydrofuranyl, tetrahydropyranyl and morpholinyl.
  • halogen means fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine and chlorine.
  • substituted means: substituted by one or more substituent.
  • Compounds according to formula I may suitably prepared as described in the following. The synthesis is started with 2,4-dichloropyrimidine or 4,6-dichloro-2- methylsulfanylpyrimidine. Substituents on the pyrimidine ring are introduced under basic conditions. Regioisomers can be separated by column cliromatography. In the final two steps the alcohol is oxidised to the carboxylic acid and the in situ formed active ester of the carboxylic acid is condensed with a range of amines to form the desired amides.
  • Benzofuranylimidazole building blocks used in the current invention are prepared from the corresponding phenols.
  • the phenol is converted to a 2-formyl-benzofuran.
  • Subsequent ether formation using 2-bromo-l, 1-diethoxyethane and cyclisation under acidic conditions yields the benzofuran-2-carbaldehyde.
  • the aldehyde is reacted with p-tolylsulfonyl isocyanide (TosMIC), followed by heating in methanolic ammonia to give the imidazole.
  • a further embodiment of this invention is a process for preparing a compound of formula I, comprising the introduction of the chiral centre using enantiomer pure aminoalcohol (e.g. leucinol), which after modifications on the pyrimidine ring, is oxidised to the corresponding carboxylic acid followed by amide formation. By using this synthetic sequence, racemisation of the chiral centre is avoided.
  • the compounds of the invention which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, ⁇ propionic acid, glycolic acid, maleic acid, maionic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
  • an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, ⁇ propionic acid, glycolic acid, maleic acid, maionic acid, methanesulphonic acid, fumaric acid, succ
  • the compounds of this invention possess one or more chiral carbon atoms, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers.
  • Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. For diastereomers straight phase or reversed phase columns may be used.
  • the compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0.001-100 mg per kg body weight, preferably 0.01-10 mg. per kg body weight.
  • the oral administration is generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray.
  • dosage units e.g. tablets
  • conventional additives such as fillers, colorants, polymeric binders and the like
  • any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
  • Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
  • Benzofuranylimidazoles used in the current invention were prepared from the corresponding phenols (Scheme 2).
  • the phenol was converted to a 2-formyl-benzofuran Chem.Pharm.Bull.,1983, 31, 1751; Tetrahedron Lett., 1992, 33, 2179).
  • Subsequent ether formation using 2-bromo-l,l-diethoxyethane and cyclisation under acidic conditions yielded the benzofuran-2-carbaldehyde.
  • the aldehyde was reacted with p-totylsulfonyl isocyanide (TosMIC), followed by heating in methanolic ammonia to give the imidazole.
  • TosMIC p-totylsulfonyl isocyanide
  • DCM Silica gel chromatography
  • (2S)-2- ⁇ 6-Butyl-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazoH-yl]-pyrimidin-4- ylamino ⁇ -4-methyl-pentanoic acid A suspension of 2- ⁇ 6-butyl-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazol-l-yl]- pyrimidin-4-ylamino ⁇ -4-methyl-pentan-l-ol (647 mg), iodobenzene diacetate (990 mg) and TEMPO (40 mg) in dioxane/water (120 ml/40 ml) was stirred for 41 hours at room temperature.
  • N-(3-aminopropyl)-N,O-dimethylhydroxylamine was synthesized in 2 steps by alkylation of N,O-dimethyIhydroxylamine with N-(3-bromopropyl)phthalimide (Scheme 4) followed by removal of the phthalimide protecting group with hydrazine (J. Org. Chem., 1978, 43, 2320).
  • Scheme 4 The procedures to prepare 2-[3-(methoxymethylamino)propyl]isoindole-l,3-dione are shown below.
  • Triethylamine (2.1 mL, 15 mM) and methanesulfonyl chloride (0.85 mL, 11 mM) were added dropwise to a cold (-5 to -10 °C) solution of 2-(tetrahydro-furan-3-yl)-ethanol (1.14 g, 10 mM) in dichloromethane (15 mL).
  • the reaction was stirred for 20 min at this temperature then, water (10 mL) was added and the reaction was stirred an additional 10 min, the aqueous phase was extracted with dichloromethane (3 x 20 mL). The combined organics were washed with 50 % aqueous HCI, sat.
  • Freshly prepared sodium methoxide (from the reaction of 0.165 g, 7.2 mM sodium with anhydrous methanol (1 mL)) was added dropwise via double ended needle to a cooled (0 °C) solution of tetrahydrofuran-3-carboxaldehyde (0.72 g, 7.2 mM, obtained from dichloromethane extraction of commercially available tetrahydrofuran-3-carboxaIdehyde in water (50 %, 2 mL)) and mtromethane (0.39 mL, 7.2 mM) in methanol (1 mL). The reaction mixture was stirred at 0 °C for 30 min, Et 2 O was added and the resulting precipitate was collected via filtration.
  • Tabel 1 shown below, lists representative compounds prepared according to the above described methodes.
  • the oxyalkyl substituents were introduced using the potassium salt of the corresponding alcohol and 4,6-dichloro-2-methylsulfanyl-pyrimidine as the starting compound, followed by aminoalcohol introduction, oxidation of the methylsulfanyl group to the corresponding methylsulfonyl group, substitution of the methylsulfonyl group, oxidation of the alcohol to the corresponding carboxylic acid and amide formation using TBTU.
  • Ki values of compounds of formula I were measured by means of IL-8 displacement.
  • [ 125 I]- LL8 human recombinant was obtained from NEN-New England Nuclear, Boston, Mass. with a specific activity of 2200 Ci/mmol. All other chemicals were of analytical grade.
  • High levels of recombinant CXCR2 receptors were expressed in Chinese hamster ovary cells as described previously (Holmes, et al., Science 253; 1278 1991).
  • the Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour et al., J. Biol. Chem. 249; 2195-2205 1974), using a homogenization buffer of 20 mM HEPES and 10 mM EDTA adjusted to pH 8.0.
  • Microscint20 scintillation liquid Packard Bioscience cat #3013621
  • AML-193 cells (ATCC: CRL-9589, Rockwell MD) were maintained in suspension at a concentration of 3xl0 5 cells/mL in culture medium (Iscove modified Dulbecco medium (Life Technologies # 21980-065) containing 5 ⁇ g/mL transferrin and insulin, 1 % (v/v) of penicilline/streptomycine solution (Sigma), 5 ⁇ g/mL GM-CSF (R&D systems # 215-GM) and 10 % fetal calf serum (FCS) (v/v).
  • culture medium Iscove modified Dulbecco medium (Life Technologies # 21980-065) containing 5 ⁇ g/mL transferrin and insulin, 1 % (v/v) of penicilline/streptomycine solution (Sigma), 5 ⁇ g/mL GM-CSF (R&D systems # 215-GM) and 10 % fetal calf serum (FCS) (v/v).
  • AML-193 cells were stimulated to differentiate with all-trans-retinoic acid (ATRA) in the concentration of lxl 0 "7 M during 3-4 days.
  • Cells were harvested and washed in Krebs buffer (120 mM NaCL 4.75 mM KCL, 1 mM KH 2 PO 4, 1.44 mM MgSO 4 .7H 2 O, 1.1 mM CaCl 2 .2H 2 O, 5 mM NaHCO 3 , 11 mM glucose, 25 mM Hepes adjusted to pH 7.4).
  • the cell suspension was centrifuged at 25000 N/kg at room temperature for 6 min. The supernatant was siphoned off and The pellet was resuspended in Krebs buffer in order to obtain a suspension containing lxl0 7 cells/mL.
  • Human neutrophils were obtained from free-flowing blood from healthy volunteers. Blood was collected in 0.1 volume sodium citrate dihydrate in water (38 g/L) and diluted 5 times with medium (RPMI 1640 solution (Life Technologies #32404-014), 2 mM L-glutamine (Sigma #G7513) and 0.01 volume of penicilline/streptomycine solution (Sigma #P0781) + 0.1 % bovine serum albumin (Sigma #A-9418)). The neutrophils were separated by the Ficoll Paque technique. In different tubes containing 20 ml Ficoll Paque (Amersham-Pharmacia #17-1440- 03) 30 ml bloodcells were pipetted.
  • the tubes were centrifuged at 25000 N/kg for 60 minutes at room temperature.
  • the plasma and the lymphocytes layers were siphoned off.
  • the red pellet was collected and adjusted to approximately 100 ml with medium in a sterile flask.
  • An equal volume of Dextran solution (3 % w/w Dextran T500 (Amersham-Pharmacia #115977) in NaCl 0.9 %) was added and mixed with the cells.
  • the mixture was divided into two graduated- glasses of 250 ml and the air bubles were removed. After an incubation of 30 minutes at room temperature the upper-layer containing neurophils was siphoned off and 30 ml was pipetted into Falcon tubes.
  • the cells were centrifuged at 20000 N/kg for 6 minutes at 4° C.
  • the supernatant was siphoned off.
  • the pellet was shaken free from the bottom and 20 ml ice-cold NaCl 0.2 % was added and the suspension was mixed for exactly 30 sec.
  • the red cells were lysed and the cell suspension was neutralised by adding 20 ml ice-cold NaCl 1.6 %.
  • the cells were centrifuged again at 20000 N/kg for 6 min. at 4° C.
  • the supernatant was siphoned off and the white pellet was resuspended in medium in order to obtain a suspension containing lxl0 7 cells/ml.
  • the assay was performed in a 96 well plate. Each reaction contained 40 ⁇ L celsuspension in Krebs buffer (total volume 250 ⁇ L). In addition, drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between 0.1 nM and 10 ⁇ M. The assay was initiated by addition of 50 ⁇ l agonist solution (final concentrations 2 nM IL-8 (R&D systems # 618-IL) or 10 nM Gro-alpha (R&D systems # 275-GR)) to each well automatically by Victor 2 Wallac 1420 multilabel HTS counter (PerkinElmer) equipped with a dispenser.
  • 50 ⁇ l agonist solution final concentrations 2 nM IL-8 (R&D systems # 618-IL) or 10 nM Gro-alpha (R&D systems # 275-GR)

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Abstract

L'invention concerne des composés représentés par la formule I, dans laquelle R1, R2, R3 et R4 sont chacun indépendamment choisis dans le groupe constitué de H, alkyle (1-4C), alcoxy (1-4C), trifluorométhyle, trifluorométhoxy, halogène, amino, sulfonamide, cyano, OH et nitro; R5 représente H ou alkyle (1-6C); R6 représente H, alkyle (1-6C) ou alcoxy (1-6C); R7 représente H ou alkyle (1-6C); R8 représente alkyle (1-6C), éventuellement substitué par alcoxy (1-6C); R9 représente -(CH2)nR10, où n vaut 1, 2 ou 3 et R10 est choisi dans le groupe constitué d'alcoxy (1-4C), alkylthio (1-4C), trifluorométhyle, cycloalkyle (3-8C), phényle éventuellement substitué par alcoxy (1-4C), -NR11R12 et -O(CH2)2NR11R12, où R11 ou R12 représente alcoxy (1-4C) tandis que l'autre représente H ou alkyle (1-4C), ou R9 représente -CH2(2-7C)hétérocycloalkyle, à la condition que lorsque au moins un hétéroatome de la fraction hétérocycloalkyle représente azote, la distance entre cette azote et l'azote de 'NHR9' est d'au moins trois atomes de carbone, ou R9 représente -(CH2)3(2-7C)hétérocycloalkyle ou -(CH2)2CHR13R14, où R13 et R14 conjointement avec l'atome de carbone auquel ils sont fixés, représentent hétérocycloalkyle (2-7C); et X représente O, S ou NH; ou un sel pharmaceutiquement acceptable de ces derniers. Les composés selon l'invention sont des modulateurs du récepteur de Il-8, notamment des inhibiteurs du récepteur de Il-8 ; ils peuvent être utilisés dans le traitement ou la prévention des affections médiées par le récepteur de Il-8, telles que l'athérosclérose, les inflammations, la polyarthrite rhumatoïde et les affections associées.
PCT/US2004/000469 2003-01-10 2004-01-09 Derives de d'imidazolyl pyrimidine utilises comme modulateurs du recepteur de il-8 WO2004063192A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004062609A2 (fr) * 2003-01-10 2004-07-29 Pharmacopeia, Inc. Derives de pyrimidine utilises comme antagonistes des recepteurs de l'il-8
WO2008076705A1 (fr) * 2006-12-21 2008-06-26 Eli Lilly And Company Composés imidazolidinonyl aminopyrimidine pour le traitement du cancer
WO2008076704A1 (fr) * 2006-12-21 2008-06-26 Eli Lilly And Company Composés imidazolidinonyl aminopyrimidine pour le traitement du cancer
WO2009000651A1 (fr) * 2007-06-22 2008-12-31 Saltigo Gmbh Procédé de fabrication de 2-phénoxyacétals et des 2-phénoxycarbaldéhydes correspondants
US8063035B2 (en) 2007-05-16 2011-11-22 Eli Lilly And Company Triazolyl aminopyrimidine compounds
US8114872B2 (en) 2007-05-16 2012-02-14 Eli Lilly And Company Triazolyl aminopyrimidine compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014081A1 (fr) * 1992-01-13 1993-07-22 Smithkline Beecham Corporation Derives imidazole et leur utilisation comme inhibiteurs de cytokine
WO1998021957A1 (fr) * 1996-11-20 1998-05-28 Merck & Co., Inc. Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation
US5837719A (en) * 1995-08-10 1998-11-17 Merck & Co., Inc. 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use
US6080763A (en) * 1997-11-03 2000-06-27 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds and their use as anti-inflammatory agents
US6174901B1 (en) * 1998-12-18 2001-01-16 Amgen Inc. Substituted pyridine and pyridazine compounds and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014081A1 (fr) * 1992-01-13 1993-07-22 Smithkline Beecham Corporation Derives imidazole et leur utilisation comme inhibiteurs de cytokine
US5837719A (en) * 1995-08-10 1998-11-17 Merck & Co., Inc. 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use
WO1998021957A1 (fr) * 1996-11-20 1998-05-28 Merck & Co., Inc. Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation
US6080763A (en) * 1997-11-03 2000-06-27 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds and their use as anti-inflammatory agents
US6174901B1 (en) * 1998-12-18 2001-01-16 Amgen Inc. Substituted pyridine and pyridazine compounds and methods of use

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7037916B2 (en) 1999-07-15 2006-05-02 Pharmacopeia Drug Discovery, Inc. Pyrimidine derivatives as IL-8 receptor antagonists
WO2004062609A2 (fr) * 2003-01-10 2004-07-29 Pharmacopeia, Inc. Derives de pyrimidine utilises comme antagonistes des recepteurs de l'il-8
WO2004062609A3 (fr) * 2003-01-10 2004-11-25 Pharmacopeia Inc Derives de pyrimidine utilises comme antagonistes des recepteurs de l'il-8
KR101080594B1 (ko) 2006-12-21 2011-11-04 일라이 릴리 앤드 캄파니 암의 치료를 위한 이미다졸리디노닐 아미노피리미딘 화합물
WO2008076704A1 (fr) * 2006-12-21 2008-06-26 Eli Lilly And Company Composés imidazolidinonyl aminopyrimidine pour le traitement du cancer
WO2008076705A1 (fr) * 2006-12-21 2008-06-26 Eli Lilly And Company Composés imidazolidinonyl aminopyrimidine pour le traitement du cancer
US8063212B2 (en) 2006-12-21 2011-11-22 Eli Lilly And Company Imidazolidinonyl aminopyrimidine compounds for the treatment of cancer
KR101088291B1 (ko) 2006-12-21 2011-11-30 일라이 릴리 앤드 캄파니 암의 치료를 위한 이미다졸리디노닐 아미노피리미딘 화합물
US8101628B2 (en) 2006-12-21 2012-01-24 Eli Lilly And Company Imidazolidinonyl aminopyrimidine compounds for the treatment of cancer
EA016177B1 (ru) * 2006-12-21 2012-02-28 Эли Лилли Энд Компани Соединения имидазолидинониламинопиримидина для лечения рака
EA016178B1 (ru) * 2006-12-21 2012-02-28 Эли Лилли Энд Компани Соединения имидазолидинониламинопиримидина
CN101563342B (zh) * 2006-12-21 2012-09-05 伊莱利利公司 用于治疗癌症的咪唑啉酮基氨基嘧啶化合物
US8063035B2 (en) 2007-05-16 2011-11-22 Eli Lilly And Company Triazolyl aminopyrimidine compounds
US8114872B2 (en) 2007-05-16 2012-02-14 Eli Lilly And Company Triazolyl aminopyrimidine compounds
WO2009000651A1 (fr) * 2007-06-22 2008-12-31 Saltigo Gmbh Procédé de fabrication de 2-phénoxyacétals et des 2-phénoxycarbaldéhydes correspondants

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