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Chemical Structure| 90098-04-7 Chemical Structure| 90098-04-7
Chemical Structure| 90098-04-7

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Rebamipide

CAS No.: 90098-04-7

,99%

Rebamipide is an endogenous prostaglandin inducer, oxygen free radical scavenger, and cholecystokinin type 1 receptor inhibitor (IC50 = 37.7 μM), used for gastric mucosal protection and in the treatment of gastritis, gastric ulcers, and gastric cancer.

Synonyms: OPC12759;Proamipide

4.5 *For Research Use Only !

99%98%
Cat. No.: A2670852 Purity: 99%

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    Product Citations

    Product Citations

    Faisal Aziz ; Kanamata Reddy ; Virneliz Fernandez Vega , et al.

    Abstract: The suppressor of T cell receptor signaling (Sts) proteins are negative regulators of immune signaling. Genetic inactivation of these proteins leads to significant resistance to infection. From a 590,000 compound high-throughput screen, we identified the 2-(1H)-quinolinone derivative, , as a putative inhibitor of Sts activity. , and a small library of derivatives, are competitive, selective inhibitors of Sts-1 with IC50 values from low to submicromolar. SAR analysis indicates that the , the acid, and the moieties are all essential for activity. A crystal structure confirmed the SAR and reveals key interactions between this class of compound and the . Although has poor cell permeability, we demonstrated that a liposomal preparation can inactivate the activity of Sts-1 in cells. These studies demonstrate that Sts-1 enzyme activity can be pharmacologically inactivated and provide foundational tools and insights for the development of immune-enhancing therapies that target the Sts proteins.

    Product Details of [ 90098-04-7 ]

    CAS No. :90098-04-7
    Formula : C19H15ClN2O4
    M.W : 370.78
    SMILES Code : O=C(O)C(NC(C1=CC=C(Cl)C=C1)=O)CC2=CC(NC3=C2C=CC=C3)=O
    Synonyms :
    OPC12759;Proamipide
    MDL No. :MFCD00866895
    InChI Key :ALLWOAVDORUJLA-UHFFFAOYSA-N
    Pubchem ID :5042

    Safety of [ 90098-04-7 ]

    GHS Pictogram:
    Signal Word:Danger
    Hazard Statements:H301
    Precautionary Statements:P264-P270-P301+P310+P330-P405-P501
    Class:6.1
    UN#:2811
    Packing Group:

    Calculated chemistry of [ 90098-04-7 ] Show Less

    Physicochemical Properties

    Num. heavy atoms 26
    Num. arom. heavy atoms 16
    Fraction Csp3 0.11
    Num. rotatable bonds 6
    Num. H-bond acceptors 4.0
    Num. H-bond donors 3.0
    Molar Refractivity 98.45
    TPSA ?

    Topological Polar Surface Area: Calculated from
    Ertl P. et al. 2000 J. Med. Chem.

    99.26 Ų

    Lipophilicity

    Log Po/w (iLOGP)?

    iLOGP: in-house physics-based method implemented from
    Daina A et al. 2014 J. Chem. Inf. Model.

    2.25
    Log Po/w (XLOGP3)?

    XLOGP3: Atomistic and knowledge-based method calculated by
    XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

    2.38
    Log Po/w (WLOGP)?

    WLOGP: Atomistic method implemented from
    Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

    2.61
    Log Po/w (MLOGP)?

    MLOGP: Topological method implemented from
    Moriguchi I. et al. 1992 Chem. Pharm. Bull.
    Moriguchi I. et al. 1994 Chem. Pharm. Bull.
    Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

    2.51
    Log Po/w (SILICOS-IT)?

    SILICOS-IT: Hybrid fragmental/topological method calculated by
    FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

    3.76
    Consensus Log Po/w?

    Consensus Log Po/w: Average of all five predictions

    2.7

    Water Solubility

    Log S (ESOL):?

    ESOL: Topological method implemented from
    Delaney JS. 2004 J. Chem. Inf. Model.

    -3.7
    Solubility 0.0744 mg/ml ; 0.000201 mol/l
    Class?

    Solubility class: Log S scale
    Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

    Soluble
    Log S (Ali)?

    Ali: Topological method implemented from
    Ali J. et al. 2012 J. Chem. Inf. Model.

    -4.11
    Solubility 0.0291 mg/ml ; 0.0000785 mol/l
    Class?

    Solubility class: Log S scale
    Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

    Moderately soluble
    Log S (SILICOS-IT)?

    SILICOS-IT: Fragmental method calculated by
    FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

    -6.51
    Solubility 0.000114 mg/ml ; 0.000000306 mol/l
    Class?

    Solubility class: Log S scale
    Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

    Poorly soluble

    Pharmacokinetics

    GI absorption?

    Gatrointestinal absorption: according to the white of the BOILED-Egg

    High
    BBB permeant?

    BBB permeation: according to the yolk of the BOILED-Egg

    No
    P-gp substrate?

    P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
    and tested on 415 molecules (test set)
    10-fold CV: ACC=0.72 / AUC=0.77
    External: ACC=0.88 / AUC=0.94

    No
    CYP1A2 inhibitor?

    Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
    and tested on 3000 molecules (test set)
    10-fold CV: ACC=0.83 / AUC=0.90
    External: ACC=0.84 / AUC=0.91

    No
    CYP2C19 inhibitor?

    Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
    and tested on 3000 molecules (test set)
    10-fold CV: ACC=0.80 / AUC=0.86
    External: ACC=0.80 / AUC=0.87

    No
    CYP2C9 inhibitor?

    Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
    and tested on 2075 molecules (test set)
    10-fold CV: ACC=0.78 / AUC=0.85
    External: ACC=0.71 / AUC=0.81

    Yes
    CYP2D6 inhibitor?

    Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
    and tested on 1068 molecules (test set)
    10-fold CV: ACC=0.79 / AUC=0.85
    External: ACC=0.81 / AUC=0.87

    No
    CYP3A4 inhibitor?

    Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
    and tested on 2579 molecules (test set)
    10-fold CV: ACC=0.77 / AUC=0.85
    External: ACC=0.78 / AUC=0.86

    No
    Log Kp (skin permeation)?

    Skin permeation: QSPR model implemented from
    Potts RO and Guy RH. 1992 Pharm. Res.

    -6.87 cm/s

    Druglikeness

    Lipinski?

    Lipinski (Pfizer) filter: implemented from
    Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
    MW ≤ 500
    MLOGP ≤ 4.15
    N or O ≤ 10
    NH or OH ≤ 5

    0.0
    Ghose?

    Ghose filter: implemented from
    Ghose AK. et al. 1999 J. Comb. Chem.
    160 ≤ MW ≤ 480
    -0.4 ≤ WLOGP ≤ 5.6
    40 ≤ MR ≤ 130
    20 ≤ atoms ≤ 70

    None
    Veber?

    Veber (GSK) filter: implemented from
    Veber DF. et al. 2002 J. Med. Chem.
    Rotatable bonds ≤ 10
    TPSA ≤ 140

    0.0
    Egan?

    Egan (Pharmacia) filter: implemented from
    Egan WJ. et al. 2000 J. Med. Chem.
    WLOGP ≤ 5.88
    TPSA ≤ 131.6

    0.0
    Muegge?

    Muegge (Bayer) filter: implemented from
    Muegge I. et al. 2001 J. Med. Chem.
    200 ≤ MW ≤ 600
    -2 ≤ XLOGP ≤ 5
    TPSA ≤ 150
    Num. rings ≤ 7
    Num. carbon > 4
    Num. heteroatoms > 1
    Num. rotatable bonds ≤ 15
    H-bond acc. ≤ 10
    H-bond don. ≤ 5

    0.0
    Bioavailability Score?

    Abbott Bioavailability Score: Probability of F > 10% in rat
    implemented from
    Martin YC. 2005 J. Med. Chem.

    0.56

    Medicinal Chemistry

    PAINS?

    Pan Assay Interference Structures: implemented from
    Baell JB. & Holloway GA. 2010 J. Med. Chem.

    0.0 alert
    Brenk?

    Structural Alert: implemented from
    Brenk R. et al. 2008 ChemMedChem

    0.0 alert: heavy_metal
    Leadlikeness?

    Leadlikeness: implemented from
    Teague SJ. 1999 Angew. Chem. Int. Ed.
    250 ≤ MW ≤ 350
    XLOGP ≤ 3.5
    Num. rotatable bonds ≤ 7

    No; 1 violation:MW<1.0
    Synthetic accessibility?

    Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
    based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
    trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

    2.76

    Application In Synthesis [ 90098-04-7 ]

    * All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

    • Downstream synthetic route of [ 90098-04-7 ]

    [ 90098-04-7 ] Synthesis Path-Downstream   1~2

    • 2
    • [ 64-17-5 ]
    • [ 4876-10-2 ]
    • [ 81918-01-6 ]
    • [ 90098-04-7 ]
    YieldReaction ConditionsOperation in experiment
    7.18 g (92.17%) With hydrogenchloride; sodium hydroxide; sodium ethanolate; In water; EXAMPLE 9 Synthesis of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic Acid 100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96percent) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 2.71 g of sodium hydroxide (93percent) was dissolved in 30 ml of purified water and this aqueous solution was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 2 hours to complete the reaction. The ethyl alcohol was removed through vacuum concentration, and purified water and 1N HCl were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with DMF and water to yield 7.18 g (92.17percent) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid. The data of melting point and 1H NMR were the same as those in Example 4.
    7.17 g (92.04%) With hydrogenchloride; potassium hydroxide; sodium ethanolate; EXAMPLE 13 Synthesis of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic Acid 100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96percent) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 3.93 g of potassium hydroxide (90percent) was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 4 hours to complete the reaction. The concentrated hydrochloric acid were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with DMF and water to yield 7.17 g (92.04percent) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid. The data of melting point and 1H NMR were the same as those in Example 4.
    7.08 g (90.88%) With hydrogenchloride; potassium hydroxide; sodium ethanolate; In water; EXAMPLE 11 Synthesis of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic Acid 100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96percent) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, -ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 3.93 g of potassium hydroxide (90percent) was dissolved in 30 ml of purified water and this aqueous solution was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 2 hours to complete the reaction. The ethyl alcohol was removed through vacuum concentration, and purified water and 1N HCl were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with DMF and water to yield 7.08 g (90.88percent) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid. The data of melting point and 1H NMR were the same as those in Example 4.
    7.15 g (91.78%) With hydrogenchloride; sodium hydroxide; sodium ethanolate; EXAMPLE 12 Synthesis of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic Acid 100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96percent) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 2.71 g of sodium hydroxide (93percent) was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 4 hours to complete the reaction. The concentrated hydrochloric acid were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with DMF and water to yield 7.15 g (91.78percent) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid. The data of melting point and 1H NMR were the same as those in Example 4.
    6.7 g (86.0%) With hydrogenchloride; sodium hydroxide; sodium ethanolate; In water; EXAMPLE 10 Synthesis of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic Acid 100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96percent) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 2.71 g of sodium hydroxide (93percent) was dissolved in 30 ml of purified water and this aqueous solution was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 2 hours to complete the reaction. The ethyl alcohol was removed through vacuum concentration, and purified water and 1N HCl were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with methanol and potassium hydroxide to yield 6.7 g (86.0percent) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid. The data of melting point and 1H NMR were the same as those in Example 4.

     

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