WO2014114603A1 - Composés thiazole substitués - Google Patents

Composés thiazole substitués Download PDF

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Publication number
WO2014114603A1
WO2014114603A1 PCT/EP2014/051054 EP2014051054W WO2014114603A1 WO 2014114603 A1 WO2014114603 A1 WO 2014114603A1 EP 2014051054 W EP2014051054 W EP 2014051054W WO 2014114603 A1 WO2014114603 A1 WO 2014114603A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
naphthalene
amino
thiazol
carbonyl
Prior art date
Application number
PCT/EP2014/051054
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English (en)
Inventor
Ronald Charles Hawley
Stephen M. Lynch
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Filing date
Publication date
Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2014114603A1 publication Critical patent/WO2014114603A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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 organic compounds useful for therapy and/or prophylaxis in a mammal of an inflammatory disease or disorder, and in particular to substituted thiazole compounds for the treatment of rheumatoid arthritis, lupus and irritable bowel disease (IBD), their manufacture, pharmaceutical compositions containing them and their use as LMP7 inhibitors.
  • IBD irritable bowel disease
  • LMP7 is an essential component of the immunoproteasome, mainly expressed in immune cells such as T/B lymphocytes and monocytes, as well as non-immune cells that have exposed to inflammatory cytokines, including IFN- ⁇ and TNFa.
  • Immunoproteasome plays an essential role in generation of antigenic peptide repertoire and shaping MHC class I restricted CD8+ T cell response. Moebius J. et al. European Journal of Immunology. 2010; Basler, M. et al. Journal of Immunology. 2004. 3925-34. Emerging data suggested that LMP7 also regulate inflammatory cytokine production and immune cell functions beyond the regulation of MHC class I mediated antigen presentation.
  • a small molecule LMP7 inhibitor, PR-957 has been shown to potently block Thl/17 differentiation, B cell effector functions and production of inflammatory cytokines (IL-6, TNF-a, IL-23).
  • IL-6 IL-6
  • TNF-a IL-6
  • IL-23 inflammatory cytokines
  • LMP7 blockade with PR-957 has been demonstrated to produce therapeutic benefits in several preclinical autoimmune disease models.
  • PR-957 was demonstrated to significantly decrease disease score in mouse CAIA and CIA arthritis models, with hallmarks of significantly reduced inflammation and bone erosion. Muchamuel T. et al. Natural Medicine. 2009. 15, 781-787.
  • PR-957 reduced plasma cells numbers and levels of anti-dsDNA IgG in MRL/lpr lupus-prone mice model, and prevented disease progression in these mice.
  • LMP7 activity is closely related to the functions of B/T lymphocytes and production of inflammatory cytokines, all of which are clinically validated targets/pathways in the pathogenesis of rheumatoid arthritis, lupus and IBD.
  • existing data have provided strong rationale for targeting LMP7 for autoimmune disease indications. Due to potential liability with long term usage of a covalent inhibitor in chronic diseases like autoimmunity, a covalent reversible or non-covalent small molecule LMP7 inhibitor is highly desired for autoimmune disease indications.
  • R 1 is Ci-7 alkyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, benzothiazolyl, furanyl,
  • R and R' is hydrogen or Ci_7 alkyl and the other is hydrogen, C 1-7 alkyl, C 3 -6
  • cycloalkyl substituted or unsubstituted phenyl, phenyl-Ci-7 alkyl, furanyl, pyranyl, tetrahydropyranyl or R and R' taken together form cyclopropyl or cyclobutyl .
  • the invention also provides for pharmaceutical compositions comprising the compounds, methods of using the compounds and methods of preparing the compounds.
  • moiety refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule.
  • R variables of formula I refer to moieties that are attached to the core structure of formula I by a covalent bond.
  • substituted refers to the fact that at least one of the hydrogen atoms of that moiety is replaced by another substituent or moiety.
  • C 1-7 alkyl substituted by halogen refers to the fact that one or more hydrogen atoms of a C 1-7 alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).
  • alkyl refers to an aliphatic straight-chain or branched-chain saturated
  • hydrocarbon moiety having 1 to 20 carbon atoms.
  • the alkyl has 1 to 10 carbon atoms.
  • C 1-7 alkyl refers to an alkyl moiety having 1 to 7 carbon atoms. In particular embodiments the C 1-7 alkyl has 1 to 4 carbon atoms and in other particular embodiments the C 1-7 alkyl has 1 to 3 carbon atoms. Examples of C 1-7 alkyls include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • alkoxy denotes a group of the formula -O-R', wherein R' is an alkyl group, and "Ci-7 alkoxy” wherein the alkyl group is C 1-7 alkyl.
  • alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy, most particularly methoxy.
  • Aryl means a monovalent cyclic aromatic hydrocarbon moiety having a mono-, bi- or tricyclic aromatic ring.
  • the aryl group can be optionally substituted as defined herein.
  • Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,
  • diphenylsulfidyl diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,
  • ethylenedioxyphenyl and the like, including partially hydrogenated derivatives thereof, each being optionally substituted.
  • Particular aryl is phenyl.
  • Phenyl-Ci-7 alkyl means a C 1-7 alkyl moiety which is substituted with a phenyl group.
  • halo refers to a substituent fluoro, chloro, bromo, or iodo. Particular halogen is chloro
  • hydrogen refers to the moiety of a hydrogen atom (-H) and not H 2 .
  • a compound of the formula or “a compound of formula” or “compounds of the formula” or “compounds of formula” refers to any compound selected from the genus of compounds as defined by the formula (including any
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, N-acetylcystein and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid
  • salts may be prepared by the addition of an inorganic base or an organic base to the free acid.
  • Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polyamine resins and the like.
  • the compounds of the present invention can be present in the form of pharmaceutically acceptable salts.
  • the compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula I to be used as prodrugs).
  • the compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be effected in the course of the manufacturing process or can take place as a consequence of hygroscopic properties of an initially anhydrous compound of formula I
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers” and fall within the scope of the invention. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more
  • enantiomers asymmetric centers that are non-superimposable mirror images of each other are termed "enantiomers.”
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • a therapeutically effective amount of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated.
  • a daily dosage of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded when indicated.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration it may be given as continuous infusion.
  • pharmaceutically acceptable carrier is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any
  • compositions of the invention are conventional media or agent incompatible with the active compound, use thereof in the compositions of the invention is contemplated.
  • Supplementary active compounds can also be incorporated into the compositions.
  • Useful pharmaceutical carriers for the preparation of the compositions hereof can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like.
  • the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile.
  • Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • the compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
  • Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
  • an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt or ester thereof is administered via any of the usual and acceptable methods known in the art, either singly or in combination.
  • the compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions.
  • buccal cavity e.g., buccal cavity
  • parenterally e.g., intramuscularly, intravenously, or subcutaneously
  • rectally e.g., by suppositories or washings
  • transdermally e.g., skin electroporation
  • the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.
  • the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.
  • R 1 is Ci-7 alkyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, benzothiazolyl, furanyl, pyranyl, dioxothiophenyl or phenyl optionally substituted with halogen, -SO 2 CH 3 or cyano, and one of R and R' is hydrogen or Ci_7 alkyl and the other is hydrogen, C 1-7 alkyl, C 3 -6 cycloalkyl, substituted or unsubstituted phenyl, phenyl-Ci-7 alkyl, furanyl, pyranyl,
  • the invention provides for compounds of formula (I) wherein R is Ci-7 alkyl.
  • the invention provides for compounds of formula (I) wherein R 1 is cyclobutyl, cyclopropyl, cyclopentyl or cyclohexyl. In another embodiment, the invention provides for compounds of formula (I) wherein R 1 is benzothiazolyl, furanyl, pyranyl or dioxothiophenyl.
  • the invention provides for compounds of formula (I) wherein R 1 is phenyl or phenyl substituted with halogen.
  • the invention provides for compounds of formula (I) wherein R 1 is phenyl.
  • the invention provides for compounds of formula (I) wherein R 1 is phenyl substituted with halogen, -SO 2 CH 3 or cyano.
  • the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen or C 1-7 alkyl and the other is hydrogen, C 1-7 alkyl, C 3 -6 cycloalkyl, substituted or unsubstituted phenyl, phenyl-Ci-7 alkyl, furanyl, pyranyl or R and R' taken together form cyclopropyl or cyclobutyl.
  • the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen or C 1-7 alkyl and the other is phenyl or phenyl substituted with halogen or Ci-7 alkoxy.
  • the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen and the other is hydrogen, C 1-7 alkyl, C 3 -6 cycloalkyl, substituted or unsubstituted phenyl, phenyl-Ci-7 alkyl, furanyl, pyranyl, tetrahydropyranyl or R and R' taken together form cyclopropyl or cyclobutyl.
  • the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen and the other is hydrogen, C 1-7 alkyl, phenyl or phenyl substituted with halogen or C 1-7 alkoxy, or R and R' taken together form cyclopropyl or cyclobutyl.
  • the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen and the other is C 1-7 alkyl, phenyl or phenyl substituted with halogen or Ci-7 alkoxy. In another embodiment, the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen or C 1-7 alkyl and the other is phenyl or phenyl substituted with halogen or C 1-7 alkoxy.
  • the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen or C 1-7 alkyl and the other is hydrogen, C 1-7 alkyl, C 3 -6 cycloalkyl, phenyl optionally mono- or disubstituted with halogen or C 1-7 alkoxy, phenyl-Ci-7 alkyl, tetrahydropyranyl or R and R' taken together form cyclopropyl or cyclobutyl.
  • the invention provides for compounds of formula (I) wherein one of R and R' is hydrogen and the other is hydrogen, C 1-7 alkyl, C 3 -6 cycloalkyl, phenyl optionally mono- or disubstituted with halogen or C 1-7 alkoxy, phenyl-Ci-7 alkyl, tetrahydropyranyl, or R and R' taken together form cyclopropyl or cyclobutyl.
  • the invention provides for compounds of formula (I) wherein the compound is:
  • the invention provides for a pharmaceutical composition, comprising a therapeutically effective amount of a compound according to formula (I) and a pharmaceutically acceptable carrier.
  • the invention provides for a compound according to formula (I) for use as a therapeutically active substance.
  • the invention provides for the use of a compound according to formula (I) for the treatment or prophylaxis of an inflammatory disease or disorder. In another embodiment, the invention provides for the use of a compound according to formula (I) for the preparation of a medicament for the treatment or prophylaxis of an inflammatory disease or disorder.
  • the invention provides for a compound according to formula (I) for the treatment or prophylaxis of an inflammatory disease or disorder.
  • the invention provides for a method for treating an inflammatory disease or disorder selected from rheumatoid arthritis, lupus and irritable bowel disease (IBD), comprising the step of administering a therapeutically effective amount of a compound according to formula (I) to a subject in need thereof.
  • an inflammatory disease or disorder selected from rheumatoid arthritis, lupus and irritable bowel disease (IBD)
  • the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser 's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15;
  • the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 °C.
  • the tetralone 1 can be condensed with carbon disulfide under basic conditions and the reaction quenched with iodomethane to provide dithiane 2.
  • Ketone reduction followed by Lewis acid mediated dehydration and methanolysis gives the ester 3.
  • Saponification gives acid 4 which can be converted to the amide 5 using oxalyl chloride followed by aqueous ammonium hydroxide.
  • Treatment with Lawesson's reagent provides the thioamide 6, which can be reacted with bromide 7 with gentle heating to afford thiazole 8.
  • the bromide functionality of 8 can be carbonylated with molybdenum hexacarbonyl and Herrmann's catalyst in the presence of water to afford acid 9.
  • dihydronaphthalene 8 can be oxidized with DDQ to afford naphthalene 10.
  • Treatment with t-BuLi at low temperature and quenching of the intermediate organolithium with carbon dioxide gives rise to acid 11.
  • the acid 11 can be also prepared according to Scheme 2.
  • the mono-carboxylic acid 13 can be formed through low temperature transmetallation of 2,7-dibromonaphthalene (12) and quenching of the intermediate organolithium with carbon dioxide.
  • the acid can be then converted to the amide 14 using oxalyl chloride followed by aqueous ammonium hydroxide.
  • Treatment with Lawesson's reagent provides the thioamide 15, which can be reacted with bromide 7 with gentle heating to afford thiazole 10.
  • the bromide functionality of 10 can be carbonylated with molybdenum hexacarbonyl and Herrmann's catalyst in the presence of water or an alcoholic solvent to form acid 11 or ester 16, respectively. In the case that ester 16 can be formed, subsequent hydrolysis with lithium hydroxide provides acid 11.
  • Scheme 3
  • Acid chloride 18 can be prepared from acid 17 using oxalyl chloride. Treatment with trimethylsilyldiazomethane results in the in situ formation of diazo ketone 19 which can be quenched with hydrobromic acid in acetic acid to isolate the bromoketone 7 in good yield and purity. Alternatively, ketone 20 can be treated with bromine in methanol to provide bromoketone 7.
  • the acid 11 can be also prepared according to Scheme 4.
  • the mono-carboxylic acid 13 can be esterified with acidic methanol to provide 21.
  • the bromide can be converted to the borane pinacol ester 22 using bis(pinacolato)diboron under palladium catalysis. Suzuki coupling with appropriately substituted bromothiazole 23 results in ester 16a. Saponification gives the acid 11.
  • Suzuki coupling of 22 with 2,4-dibromothiazole (24) provids ester 25 in a regioselective manner.
  • Subsequent Suzuki coupling with appropriately substituted boronic acid results in 16a.
  • the acid 11 can be also prepared according to Scheme 5.
  • Bromide 21 can be converted to nitrile 26 with zinc cyanide under palladium catalysis.
  • Treatment with ammonium sulfide gives rise to thioamide 27 which can be reacted with bromide 7 with gentle heating to afford thiazole 16a. Saponification gives the acid 11.
  • the compounds of the present invention can be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art. All reactions involving air-sensitive reagents were performed under an inert atmosphere. Reagents were used as received from commercial suppliers unless otherwise noted.
  • Step 7 ⁇ r7-(4-Phenyl-thiazol-2-yl)-naphthalene-2-carbonyll -amino I -acetic acid
  • Step 2 (3,4-Dichloro-phenyl)- ⁇ r7-(4-phenyl-thiazol-2-yl)-naphthalene-2-carbonyll- amino ⁇ -acetic acid
  • Step 1 2-(tetrahydro-2H-pyran-4-yl)acetate hydrochloride for methyl 2-amino-2-(4- chlorophenyl)acetate hydrochloride in Step 1. Additionally, Step 1 was conducted at 65°C under conventional heating for 20 h instead of microwave heating at 120°C for 2 h.
  • LC/MS: (M+H) + 473; 1H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.83 (br.
  • the Cell-Based Proteasome subunit activity/selectivity assay can be a panel of 5
  • This cell -based proteasome activity assay can be similar to previous Ramos cell -based assay as of the substrates, but using human PBMCs in the context of complete RPMI with 10 % FBS as reaction buffer.
  • This assay can be designed to assess the level of cellular penetration of test compounds in primary human cells. The following procedure can be followed: Fresh isolated PBMC from healthy donor were plated at lxlO 5 cells/well in 100 ⁇ of complete RPMI with 10% FBS in V bottom 96 plates. Added 1 ⁇ of 100X 4-fold serial diluted compounds /well and incubated for 1 hr. The highest compound concentration tested can be 20 ⁇ (100X working stock start with 2 mM). Spun down the cells @ 2000rpm for 5 min.
  • the cells Removed all supernatant. Then resuspended the cells in 25 ⁇ DPBS and transferred the cells to a fresh half-area plate (PerkinElmer Cat 6005569).
  • the final reaction volume can be 50 ⁇ , including 25 ⁇ cell suspension, 0.5 ⁇ ⁇ inhibitor or DMSO, 25 ⁇ substrate mix containing 0.025% digitonin, 20 uM substrate (Substrate: (PAL) 2 Rhl l0, (LLE) 2 Rhl lO, (KQL) 2 Rhl l0, (WLA) 2 Rhl l0, or (ANW) 2 Rhl l0)/in 10% FBS and 0.5M sucrose mixture. Shaked for one minute (@ 700 rpm). Incubated for 2 hrs, then read the plates with Envision plate reader using 500 nm excitation/519 nm emission.
  • PBMCs were isolated from whole blood as follows: Blood can be collected in a sterile environment in heparinized tubes. Blood can be diluted with an equal volume PBS/2% FCS and 30 ml of this mixture can be added to ACCUSPIN tubes containing 15 ml Histopaque-1077 already centrifuged at 800g for 30 seconds and warmed up at room temperature. The tubes were then centrifuged at 800 g for 20 minutes at room temperature with no brake. The mononuclear band, just above the polyethylene frit, can be removed by Pasteur pipet.
  • CpG Type A Invivogen, Cat # tlrl- 2216; ODN 2216
  • CpG Type A Invivogen, Cat # tlrl- 2216; ODN 2216
  • PBMC viability of cells remaining in the well can be measured with ATPlite luminescence assay (Perkin-Elmer) per the manufacturer's instructions.
  • Luminescence can be measured on the Perkin-Elmer Envision, using the luminescence filter.
  • IP 10 level can be measured with CXCL10/IP10 AlphaLISA kit (Perkin-Elmer) per the manufacturer's instructions, except halving all volumes. Fluorescence can be measured on the Envision Multilabel plate reader, using the AlphaScreen standard settings. Results:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) ainsi que leurs sels pharmaceutiquement acceptables. La présente invention concerne également des procédés de fabrication et d'utilisation des composés de formule (I), ainsi que des compositions pharmaceutiques contenant lesdits composés. Les composés de formule (I) sont des inhibiteurs de LMP7 et peuvent être utiles pour le traitement de maladies inflammatoires et troubles associés tels que, par exemple, la polyarthrite rhumatoïde, le lupus et le syndrome du côlon irritable.
PCT/EP2014/051054 2013-01-24 2014-01-20 Composés thiazole substitués WO2014114603A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106402A1 (fr) * 2002-06-12 2003-12-24 Bayer Aktiengesellschaft Derives de 2-naphtamide
EP1676834A1 (fr) * 2004-12-30 2006-07-05 Sanofi-Aventis Deutschland GmbH Dérivés de carboxamide bicycliqués et fusionnés utiles comme des inhibiteurs de CXCR2 pour traiter l'inflammation
WO2008000407A1 (fr) * 2006-06-28 2008-01-03 Sanofi-Aventis Inhibiteurs de cxcr2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106402A1 (fr) * 2002-06-12 2003-12-24 Bayer Aktiengesellschaft Derives de 2-naphtamide
EP1676834A1 (fr) * 2004-12-30 2006-07-05 Sanofi-Aventis Deutschland GmbH Dérivés de carboxamide bicycliqués et fusionnés utiles comme des inhibiteurs de CXCR2 pour traiter l'inflammation
WO2008000407A1 (fr) * 2006-06-28 2008-01-03 Sanofi-Aventis Inhibiteurs de cxcr2

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Fieser and Fieser's Reagents for Organic Synthesis", vol. 1-15, 1991, WILEY & SONS
"Organic Reactions", vol. 1-40, 1991, WILEY & SONS
"Rodd's Chemistry of Carbon Compounds", vol. 1-5, 1989, ELSEVIER SCIENCE PUBLISHERS
BASLER M. ET AL., JOURNAL OF IMMUNOLOGY, 2010, pages 634 - 41
BASLER, M. ET AL., JOURNAL OF IMMUNOLOGY, 2004, pages 3925 - 34
ICHIKAWA HT ET AL., ARTHRITIS & RHEUMATISM, vol. 64, 2012, pages 493 - 503
MOEBIUS J. ET AL., EUROPEAN JOURNAL OF IMMUNOLOGY, 2010
MUCHAMUEL T. ET AL., NATURAL MEDICINE, vol. 15, 2009, pages 781 - 787
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