WO2009041790A1 - Nouveau dérivé 2,4,5-trisubtitué-1,3-thiazole et sel pharmaceutiquement acceptable, procédé de préparation et agent thérapeutique utilisé contre une maladie inflammatoire induite par une activité spc contenant le dérivé 2,4,5-trisubstitué-1,3-thiazole comme principe actif - Google Patents

Nouveau dérivé 2,4,5-trisubtitué-1,3-thiazole et sel pharmaceutiquement acceptable, procédé de préparation et agent thérapeutique utilisé contre une maladie inflammatoire induite par une activité spc contenant le dérivé 2,4,5-trisubstitué-1,3-thiazole comme principe actif Download PDF

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WO2009041790A1
WO2009041790A1 PCT/KR2008/005726 KR2008005726W WO2009041790A1 WO 2009041790 A1 WO2009041790 A1 WO 2009041790A1 KR 2008005726 W KR2008005726 W KR 2008005726W WO 2009041790 A1 WO2009041790 A1 WO 2009041790A1
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chemical formula
phenyl
trisubstiuted
substituted
thiazole
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PCT/KR2008/005726
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English (en)
Inventor
Young-Dae Gong
Heeyeong Cho
Moon-Kook Jeon
Taeho Lee
Gildon Choi
Jae-Yang Kong
Dae Young Jeong
Soon-Hee Hwang
Jung Ju Kim
Chang-Hoon Lee
Jaeyoung Ko
Minsoo Noh
Eun Sil Han
Hyoung June Kim
Hyuk Kim
Jun-Won Yun
Joo Hyun Moh
Do Hoon Kim
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Korea Research Institute Of Chemical Technology
Amorepacific Corporation
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Application filed by Korea Research Institute Of Chemical Technology, Amorepacific Corporation filed Critical Korea Research Institute Of Chemical Technology
Publication of WO2009041790A1 publication Critical patent/WO2009041790A1/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
    • C07D277/32—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 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • 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
    • C07D277/32—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 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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]
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

  • Example embodiments of the present invention relate to a 2,4,5- trisubstiuted-thiazole derivative, a pharmaceutically acceptable salt thereof, a method for preparation thereof, and a therapeutic agent for inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the same as an effective ingredient, more particularly, to a 2,4,5-trisubstiuted-thiazole derivative as a novel compound exhibiting inhibition activity against SPC receptor, a pharmaceutically acceptable salt thereof, and pharmaceutical composition for treating inflammatory disease containing the derivative or the pharmaceutically acceptable salt thereof as an effective ingredient.
  • SPC sphingosylphosphorylcholine
  • SPC Sphingosylphosphorylcholine
  • SlP structurally similar sphingosine-1-phosphate
  • LPA lysophosphatidic acid
  • SPC is produced from sphingomyelin, a component of the cell membrane, by the action of the enzyme sphingomyelin deacylase [Higuchi K, Biocheni. J., 2000, 350, 747-56].
  • SPC is known to be deeply associated with growth and proliferation of various types of cells [Desai , Biochem. Biophys. Res. Comniun. , 1991, 181, 361-366], angiogenesis [Boguslawski , Biochem. Biophys. Res. Commun., 2000, 272, 603-609], apoptosis [Jeon ES, Biochem. Biophys. Acta., 2005, 1734(1); 25-33], and the like.
  • a typical example of SPC-related diseases is atopic dermatitis.
  • Atopic dermatitis results in reduced antibacterial activity due to decreased lipid content in the stratum corneum and reduced resistance to external stimulants because of reduced barrier capability. As a result, it causes inflammatory reactions and itching. Since the itching may lead to secondary infections, the hyperimmune response may result in a vicious cycle.
  • SPC may be not only the direct cause of skin barrier function disorder characteristic of the atopic dermatitis, but also the cause of secondary inflammatory responses.
  • the control of the production of SPC may lead to the development of a new therapeutic agent for skin inflammatory disease.
  • the inventors of the present invention have researched to develop novel compounds that can be used as pharmaceutical composition for treating inflammatory disease. They designed and synthesized a 2,4,5-trisubstiuted- 1,3-thiazole derivative, which has not yet been reported to exhibit inhibition activity against SPC receptor. Through experiments using human- derived endothelial cells and mice, they confirmed that the 2,4,5- trisubstiuted-1,3-thiazole derivative has superior antiinflamatory effect and completed the present invention. [Disclosure] [Technical Problem]
  • the present invention provides a 2,4,5-trisubstiuted-1,3- thiazole derivative prepared through an organic synthesis technique and a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of the 2,4,5- trisubstiuted-1,3-thiazole derivative or the pharmaceutically acceptable salt thereof as an effective ingredient of a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor.
  • SPC sphingosylphosphorylcholine
  • the present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof: [Chemical Formula 1]
  • R is heteroaryl, phenyl or substituted phenyl, the substituted phenyl being substituted by 1-4 substituents selected from the group
  • R is amide having
  • the present invention further provides a method for preparation of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 using an organic synthesis technique.
  • the present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the 2,4,5- trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
  • SPC sphingosylphosphorylcholine
  • the present invention further provides a pharmaceutical composition containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient for preventing scarring after injury and promoting wound healing.
  • the present invention further provides a modulator of chemotaxis- mediated symptoms containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
  • the present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative prepared using an organic synthesis technique and a pharmaceutically acceptable salt thereof, which exhibits superior inhibition activity against sphingosylphosphorylcholine (SPC) receptor in an animal model experiment using human-derived endothelial cells and mice.
  • SPC sphingosylphosphorylcholine
  • the present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of SPC receptor.
  • the present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof:
  • R is the same as defined above, and may be a substituent selected from the followings:
  • R 2 is the same as defined above, and may be a substituent selected from the followings:
  • R 3 is the same as defined above, and may be a substituent selected from the followings:
  • R 1 may be selected from the group consisting of
  • R 2 may be amide having C 1 -C 5
  • arylalkyl C 5 -C 10 heteroarylalkyl , phenyl or substituted phenyl; and R 3 may be
  • phenyl substituted by phenyl, C 1 -C 5 linear, branched or cyclic alkyl, or heteroarylamide, the phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C 1 -C 5 alkyl, C 1 -C 10 alkoxy and C 1 - C 10 haloalkyl .
  • the present invention further provides a method for the preparation of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1.
  • the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 of the present invention may be prepared by an organic synthesis technique, according to the following Scheme 1:
  • R 1 , R 2 and R 3 are the same as defined above.
  • the method for the preparation of the 2,4,5-trisubstiuted- 1,3-thiazole derivative represented by Chemical Formula 1 comprises: reacting methylcyanocarbonimidodithionate represented by Chemical Formula 2 with a 2-haloacetophenone derivative to synthesize a 4-amino-1,3- thiazole represented by Chemical Formula 3 in which the substituent R 1 is introduced; reacting the 4-amino group of the compound represented by Chemical Formula 3 with chlorocarboxylic acid to synthesize a 4-N-acyl-1,3-thiazole represented by Chemical Formula 4 in which the substituent R2 is introduced; oxidizing the sulfanyl group of the compound represented by Chemical Formula 4 with m-chloroperbenzoic acid (m-CPBA) to synthesize a 2-sulfonyl-4- N-acyl-1,3-thiazole represented by Chemical Formula 5; and reacting the compound represented by Chemical Formula 5 with a primary or secondary amine to synthesize the 2,4,5-tri
  • dimethylformamide (DMF), acetone, methanol or ethanol is used as solvent.
  • DMF may be used.
  • the substituent R1 and a base may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy.
  • the base may be N,N- diisopropylethylamine, triethylamine (Et3N), sodium methoxide (NaOMe), sodium ethoxide (NaOEt), or the like.
  • the substituent R is the same as defined above, and may be an alkyl halide.
  • acetonitrile MeCN
  • dichloromethane CH2C12
  • a base and the substituent R2 may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy.
  • the base may be pyridine, triethylamine, or the like.
  • the substituent R substituent is the same as defined above, and may be a chlorocarboxylic acid.
  • dichloromethane is used as solvent.
  • tn-CPBA or hydrogen peroxide may be used in an amount of about 4 equivalents, respectively. Preferably, they may be used in an amount of about 2.5 equivalents, respectively, considering economy.
  • dioxane or dichloromethane is used, and the substituent R3 and a base are used for the addition reaction to obtain the wanted 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical
  • the base and the substituent R 3 may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy.
  • 3 base may be pyridine, triethylamine, or the like.
  • the substituent R substituent is the same as defined above, and may be a primary or secondary amine.
  • Structural analysis of the reaction intermediates represented by Chemical Formulas 3, 4 and 5 may be carried out by NMR or mass spectroscopy after separation and purification.
  • the present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the 2,4,5- trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
  • SPC sphingosylphosphorylcholine
  • the pharmaceutical composition for treating inflammatory disease may comprise N- ⁇ 5-benzoyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]thiazoyl-4- yl ⁇ pivalamide (Compound No. 1-76, see Table 1 below) or N- ⁇ 5-benzoyl-2-[2- (piperidin-1-yl)ethylamido]thiazoyl-4-yl ⁇ -4-fluorobenzamide (Compound No. 1- 94, see Table 1) of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1, as an effective ingredient.
  • the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention was confirmed to have an antagonistic effect in selective cell proliferation induced by SPC (see Table 2). Therefore, it may be effective for atopic dermatitis or other skin disease caused by excessive cell division and proliferation induced by SPC. Further, because excessive cell division and proliferation during wound healing may result in scars through inflammatory response, the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention, which inhibits the excessive cell division and proliferation, may be used to prevent unwanted scarring. In addition, it may be used to facilitate wound healing after injury.
  • the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention reduced ear edema and inhibited MPO activity, comparable to hydrocortisone which is commonly used to treat inflammation (see Table 4). Accordingly, the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention may be effective in treating inflammation, itching, skin infections, etc. associated with atopic dermatitis or other disease, and may be useful as a pharmaceutical composition for preventing scarring after injury and promoting wound healing.
  • the present invention provides a modulator of chemotaxis- mediated symptoms containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
  • Chemotaxis is the phenomenon in which endothelial cells or immune cells are attracted by specific materials such as cytokines or chemokines. By this, immune cells move to inflamed area or endothelial cells migrate to result in angiogenesis.
  • the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention was confirmed to be able to strongly inhibit the migration of endothelial cells or immune cells induced by SPC (see Table 3).
  • a modulator of chemotaxis-mediated symptoms comprising the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an effective ingredient may inhibit angiogenesis caused by the migration of endothelial cells and may control the amplification of immune response to antigens from outside.
  • the modulator of chemotaxis-mediated symptoms may comprise N- ⁇ 5- benzoyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]thiazoyl-4-yl ⁇ pivalamide (Compound No. 1-76) of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 as an effective ingredient.
  • chemotaxis-mediated symptoms that can be controlled by the modulator of chemotaxis-mediated symptoms according to the present invention may include inflammation, itching and skin infection associated with atopic dermatitis or other disease.
  • the pharmaceutically acceptable salt according to the present invention may be one that can be prepared by a method commonly used in the related art.
  • a pharmaceutically acceptable acid salt may be prepared using an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium bisulfate, phosphoric acid, carbonic acid, etc.
  • a metal salt may be prepared using an alkali metal ion such as sodium, potassium, etc., or other pharmaceutically acceptable salt may be prepared using an ammonium ion.
  • a commonly used non-toxic pharmaceutically acceptable carrier, modifier or excipient may be added to the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition in oral or parenteral preparation forms common in the pharmaceutical field, e.g. tablet, capsule, troche, liquid, suspension, etc.
  • the administration dose of the compound of the present invention may vary depending on the age, body weight and sex of the patient, administration route, physical conditions and severity of disease. For an adult patient weighing 70 kg, a usual dosage may be 0.01-1,000 mg/day. Depending on the physician' s or pharmacist' s decision, it may be administered once or several times a day at predetermined intervals.
  • Step 1 Conversion of potassium (E)-methylcyanocarbonimidodithionate (Chemical Formula 2) to 4-amino-1,3-thiazole
  • Step 4 Addition of amine to 2-sulfonyl-4-N-acetyl-1,3-thiazole (Chemical Formula 5-1)
  • 2-Sulfonyl-4-N-acetyl-1,3-thiazole (50 mg, 0.15 mmol) represented by Chemical Formula 5-1 was dissolved in 5 mL of dioxane. After adding diethylamine (Et2NH; 0.031 mL, 0.30 mmol) and triethylamine (0.056 mL, 0.40 mmol), reaction was carried out at room temperature for 12 hours while stirring. Then, the reaction mixture was dissolved in 20 mL of EtOAc and washed with 20 mL of brine. After drying the organic layer using Na2S04, the reaction mixture was filtered and concentrated.
  • Et2NH diethylamine
  • EtOAc 0.031 mL, 0.30 mmol
  • triethylamine 0.056 mL, 0.40 mmol
  • IxIO 5 normally lxl0 4 ⁇ 10 6
  • NIH 3T3 cells American Type Culture Collection
  • Manassas, VA, USA were cultured on a culture plate. Then, they were cultured in an RPMI medium free of bovine serum for 24 hours until serum starvation. After treating with the compounds prepared in Examples or with FTY720 (fingolimod) , an agonist of sphingosine-1-phosphate (SlP), as control compound at concentrations of 0.001 ⁇ M, 0.01 ⁇ M, 0.1 ⁇ M and 1 ⁇ M, the cells were cultured for 30 minutes. Then, after adding SPC (Biomol , Plymouth Meeting, PA, USA) at a concentration of 7 ⁇ M, the cells were cultured for 24 hours at 37 ° C .
  • SPC Biomol , Plymouth Meeting, PA, USA
  • Proliferation rate (%) 100 (SPC treated group) - (SPC non - treated group)
  • the compounds of the present invention prepared in Examples exhibited antagonistic effect against selective cell proliferation induced by SPC. Because inflammatory response due to excessive cell division and proliferation during wound healing after injury results in scars, the material which inhibits cell division and proliferation may be used to prevent unwanted scarring. And, the material which enhances cell division and proliferation may be used to promote wound healing after injury. Especially, the compounds of Examples 1-1 and 1-76 inhibited the cell division and proliferation induced by SPC in a dose-dependent manner. It is to be noted that FTY720, an agonist of SlP, which has a chemical structure similar to that of SPC and shares some of membrane receptors, did not inhibit the cell division and proliferation induced by SPC.
  • the inhibition of cell division and proliferation is due to the inherent structural activity of the compound of the present invention, and the compound of the present invention may be used to prevent scarring caused by inflammatory response due to excessive cell division and proliferation during wound healing after injury.
  • a 25 x 80 mm polycarbonate membrane (Neuro Probe, Inc.) having 8 ⁇ m pores was immersed in 0.01% gelatin, 0.1% acetic acid solution. After coating overnight, the membrane was allowed to be dried at room temperature.
  • Human umbilical vein endothelial cells cultured in a complete EBM-2 medium containing 2% fetal bovine serum (FBS) were cultivated for 4 hours in a EBM-2 medium (Cambrex, Catalog No. CC-3121) without containing bovine serum until serum starvation, and harvested with trypsin/EDTA solution.
  • the HUVECs were suspended in a EBM-2 medium containing 0.1% bovine serum albumin (BSA), transferred to a si Iicone-coated Eppendorf tube, and treated with the test compound of Example 1-78 at concentrations of 0, 0.1, 1 and 10 ⁇ g/mL, at 37°C for 30 minutes.
  • BSA bovine serum albumin
  • Example 1-76 strongly inhibited the chemotactic cell migration induced by SPC. This suggests that, by inhibiting the migration of endothelial cells or immune cells, the compound may control the process of angiogenesis in tumors or amplification of immune response to antigens from outside.
  • TPA Tetradecanoyl phorbol acetate
  • TPA myeloperoxidase
  • Example 1-76 As seen from Table 4, the compound of Example 1-76 was superior in inhibiting ear edema caused by TPA-induced inflammatory response and MPO activity, comparable to hydrocortisone, which is commonly used as antiinflammatory drug. This result signifies that the compound of Example 1- 76 inhibited the infiltration of neutrophils at the inflammation area.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
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Abstract

L'invention concerne un dérivé 2,4,5-trisubstitué-l,3-thiazole représenté par la formule chimique 1 suivante, un sel pharmaceutiquement acceptable dudit dérivé, son procédé de préparation et son utilisation comme principe actif dans un agent thérapeutique utilisé contre une maladie inflammatoire induite par la sphingosylphosphorylcholine (SPC). Le dérivé 2,4,5-trisubstitué-l,3-thiazole de l'invention présente de manière confirmée une activité inhibitrice supérieure contre le récepteur de la SPC dans une expérience animale dans laquelle sont utilisées des cellules endothéliales humaines et des souris. Une composition pharmaceutique pour le traitement d'une maladie inflammatoire, contenant ledit dérivé 2,4,5-trisubstitué-l,3-thiazole ou un sel pharmaceutiquement acceptable de celui-ci comme principe actif, peut ainsi être utilisée pour traiter l'inflammation, les démangeaisons ou les infections cutanées associées à une dermatite atopique ou une autre maladie induite par le récepteur de la SPC.
PCT/KR2008/005726 2007-09-27 2008-09-26 Nouveau dérivé 2,4,5-trisubtitué-1,3-thiazole et sel pharmaceutiquement acceptable, procédé de préparation et agent thérapeutique utilisé contre une maladie inflammatoire induite par une activité spc contenant le dérivé 2,4,5-trisubstitué-1,3-thiazole comme principe actif WO2009041790A1 (fr)

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KR10-2007-0097553 2007-09-27
KR1020070097553A KR100903974B1 (ko) 2007-09-27 2007-09-27 2,4,5-삼중치환-1,3-티아졸 유도체 및 약제학적으로 허용가능한 그의 염, 그의 제조방법 및 그를 유효성분으로함유하는 ｓｐｃ 수용체 활성으로 유발되는 염증관련 질환치료제

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021214019A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101051078B1 (ko) 2008-12-05 2011-07-21 한국화학연구원 염증관련 질환치료제용 2,4-이중치환-5-아미노카르보닐-1,3-티아졸 유도체, 그의 제조방법 및 그를 유효성분으로 함유하는 ｓｐｃ 수용체 활성으로 유발되는 염증관련질환 치료제

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006078287A2 (fr) * 2004-05-06 2006-07-27 Plexxikon, Inc. Inhibiteurs de pde4b

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006078287A2 (fr) * 2004-05-06 2006-07-27 Plexxikon, Inc. Inhibiteurs de pde4b

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HIRAI, KENTARO ET AL.: "Heterocyclic Cation System. 14. Synthesis of Thieno[3,2- e][1,4]diazepine, Thiazolo[4,5-e][1,4]diazepine, and s-Triazolo[3,4-c]thiazolo[4,5- e][1,4]diazepine derivatives.", J. ORG. CHEM., vol. 45, no. 2, 1980, pages 253 - 260 *
LEE, ILL YOUNG ET AL.: "Traceless solid-phase synthesis of2,4,5-trisubstituted thiazoles.", SYNLETT., vol. 16, 2005, pages 2483 - 2485 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021214019A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
WO2021214020A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
US11964953B2 (en) 2020-04-24 2024-04-23 Bayer Aktiengesellschaft Substituted aminothiazoles as DGKzeta inhibitors for immune activation

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