CAS: 870823-12-4; Mk-0893

该化合物是一种复杂的有机化合物,其特点是多功能结构,包括一个丙烯酸环,一个苯甲基组和一个乙型亚麻黄碱.这种化合物展示了制药剂的典型特性,可能包括防炎或止痛效应,因为有烟和芳香系统存在.二氯苯和甲基丙烯基苯基组的存在表明,它可能具有显著的亲脂性,影响其溶性及生物利用率. (S)配置表明的立体化学化学学可能在其生物活动中发挥关键作用,因为立体异构体可能呈现不同的药性特征. 此外,复合分子相互作用,如氢结合和欧元堆叠合剂,可能影响其整个化学化合物的结合性.

结构式图片

物理性质

MSDS等安全信息

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    tert-butyl N-{4-[(1R)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate (6-methoxy-2-naphthalene)boronic acid tert-butyl N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate ethyl 4-{(1S)1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoate

    合成工艺路线路线简述

    • 156641-98-4 + 870822-98-3 = 870823-12-4
      反应条件:1.1 Reagents: Triethylamine Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: 1,2-Dimethoxyethane; 10 Min,100 °C1.2 Reagents: Acetonitrile,Trifluoroacetic Acid,Water1.3 Reagents: Trifluoroacetic Acid Solvents: Dichloromethane; 30 Min,Rt
      标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-Yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
      作者:Xiong,Yusheng; Et Al
      参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(13) 页码:6137-6148]

      870823-08-8 + 58620-93-2 = 870823-12-4
      反应条件:1.1 Reagents: Sodium Hydroxide Solvents: Methanol,1,4-Dioxane,Water; 1 H,10 °C1.2 Reagents: Hydrochloric Acid Solvents: Water; Acidified1.3 Reagents: Diisopropylethylamine,Pybop Solvents: Dimethylformamide; Overnight,Rt1.4 Reagents: Water; 30 Min,60 °C2.1 Reagents: Triethylamine Solvents: Tetrahydrofuran; 1 H,-78 °C -> 0 °C2.2 Reagents: Ethyl Acetate,Water3.1 Reagents: Triethylamine Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: 1,2-Dimethoxyethane; 10 Min,100 °C3.2 Reagents: Acetonitrile,Trifluoroacetic Acid,Water3.3 Reagents: Trifluoroacetic Acid Solvents: Dichloromethane; 30 Min,Rt
      标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-Yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
      作者:Xiong,Yusheng; Et Al
      参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(13) 页码:6137-6148]

      870822-87-0 = 870823-12-4
      反应条件:1.1 Reagents: P-Toluenesulfonic Acid Monohydrate,Sodium Cyanoborohydride Solvents: Tetrahydrofuran; 10 H,Rt1.2 Reagents: Sodium Hydroxide Solvents: Dimethyl Carbonate,Water; 1 H,Rt2.1 Solvents: Ethanol,Heptane3.1 Reagents: Trifluoroacetic Acid,Triisopropylsilane Solvents: Dichloromethane; 1 H,Rt3.2 Reagents: Hydrochloric Acid Solvents: Water; Rt4.1 Solvents: Acetic Acid; 4 H,Reflux5.1 Reagents: Sodium Hydroxide Solvents: Methanol,1,4-Dioxane,Water; 1 H,10 °C5.2 Reagents: Hydrochloric Acid Solvents: Water; Acidified5.3 Reagents: Diisopropylethylamine,Pybop Solvents: Dimethylformamide; Overnight,Rt5.4 Reagents: Water; 30 Min,60 °C6.1 Reagents: Triethylamine Solvents: Tetrahydrofuran; 1 H,-78 °C -> 0 °C6.2 Reagents: Ethyl Acetate,Water7.1 Reagents: Triethylamine Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: 1,2-Dimethoxyethane; 10 Min,100 °C7.2 Reagents: Acetonitrile,Trifluoroacetic Acid,Water7.3 Reagents: Trifluoroacetic Acid Solvents: Dichloromethane; 30 Min,Rt
      标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-Yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
      作者:Xiong,Yusheng; Et Al
      参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(13) 页码:6137-6148]

      1383937-87-8 + 358-23-6 = 870823-12-4
      反应条件:1.1 Reagents: Triethylamine Solvents: Tetrahydrofuran; 1 H,-78 °C -> 0 °C1.2 Reagents: Ethyl Acetate,Water2.1 Reagents: Triethylamine Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: 1,2-Dimethoxyethane; 10 Min,100 °C2.2 Reagents: Acetonitrile,Trifluoroacetic Acid,Water2.3 Reagents: Trifluoroacetic Acid Solvents: Dichloromethane; 30 Min,Rt
      标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-Yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
      作者:Xiong,Yusheng; Et Al
      参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(13) 页码:6137-6148]

      172168-01-3 + 875558-57-9 = 870823-12-4
      反应条件:1.1 Solvents: Acetic Acid; 4 H,Reflux2.1 Reagents: Sodium Hydroxide Solvents: Methanol,1,4-Dioxane,Water; 1 H,10 °C2.2 Reagents: Hydrochloric Acid Solvents: Water; Acidified2.3 Reagents: Diisopropylethylamine,Pybop Solvents: Dimethylformamide; Overnight,Rt2.4 Reagents: Water; 30 Min,60 °C3.1 Reagents: Triethylamine Solvents: Tetrahydrofuran; 1 H,-78 °C -> 0 °C3.2 Reagents: Ethyl Acetate,Water4.1 Reagents: Triethylamine Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: 1,2-Dimethoxyethane; 10 Min,100 °C4.2 Reagents: Acetonitrile,Trifluoroacetic Acid,Water4.3 Reagents: Trifluoroacetic Acid Solvents: Dichloromethane; 30 Min,Rt
      标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-Yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
      作者:Xiong,Yusheng; Et Al
      参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(13) 页码:6137-6148]

      870822-89-2 = 870823-12-4
      反应条件:1.1 Reagents: Trifluoroacetic Acid,Triisopropylsilane Solvents: Dichloromethane; 1 H,Rt1.2 Reagents: Hydrochloric Acid Solvents: Water; Rt2.1 Solvents: Acetic Acid; 4 H,Reflux3.1 Reagents: Sodium Hydroxide Solvents: Methanol,1,4-Dioxane,Water; 1 H,10 °C3.2 Reagents: Hydrochloric Acid Solvents: Water; Acidified3.3 Reagents: Diisopropylethylamine,Pybop Solvents: Dimethylformamide; Overnight,Rt3.4 Reagents: Water; 30 Min,60 °C4.1 Reagents: Triethylamine Solvents: Tetrahydrofuran; 1 H,-78 °C -> 0 °C4.2 Reagents: Ethyl Acetate,Water5.1 Reagents: Triethylamine Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: 1,2-Dimethoxyethane; 10 Min,100 °C5.2 Reagents: Acetonitrile,Trifluoroacetic Acid,Water5.3 Reagents: Trifluoroacetic Acid Solvents: Dichloromethane; 30 Min,Rt
      标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-Yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
      作者:Xiong,Yusheng; Et Al
      参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(13) 页码:6137-6148]

      870822-88-1 = 870823-12-4
      反应条件:1.1 Solvents: Ethanol,Heptane2.1 Reagents: Trifluoroacetic Acid,Triisopropylsilane Solvents: Dichloromethane; 1 H,Rt2.2 Reagents: Hydrochloric Acid Solvents: Water; Rt3.1 Solvents: Acetic Acid; 4 H,Reflux4.1 Reagents: Sodium Hydroxide Solvents: Methanol,1,4-Dioxane,Water; 1 H,10 °C4.2 Reagents: Hydrochloric Acid Solvents: Water; Acidified4.3 Reagents: Diisopropylethylamine,Pybop Solvents: Dimethylformamide; Overnight,Rt4.4 Reagents: Water; 30 Min,60 °C5.1 Reagents: Triethylamine Solvents: Tetrahydrofuran; 1 H,-78 °C -> 0 °C5.2 Reagents: Ethyl Acetate,Water6.1 Reagents: Triethylamine Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: 1,2-Dimethoxyethane; 10 Min,100 °C6.2 Reagents: Acetonitrile,Trifluoroacetic Acid,Water6.3 Reagents: Trifluoroacetic Acid Solvents: Dichloromethane; 30 Min,Rt
      标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-Yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
      作者:Xiong,Yusheng; Et Al
      参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(13) 页码:6137-6148
    📜3-(3,5-二氯苯基)-3-氧代-丙酸乙酯置于四(三苯基膦)钯,溶剂黄146,三乙胺,三氟乙酸,Sodium Hydroxide体系中,用 四氢呋喃,1,4-二氧六环,甲醇,乙二醇二甲醚,二氯甲烷 作为反应溶剂,化学反应 9.17H,反应生成 N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-Beta-丙氨酸
    参考文献:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
    标题:Discovery Of A Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)Carbonyl]-β-Alanine (Mk-0893) For The Treatment Of Type Ii Diabetes
    摘要:A Potent,Selective Glucagon Receptor Antagonist 9M,N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-Methoxynaphthalen-2-yl)-1H-Pyrazol-1-Yl]Ethyl}Phenyl)-Carbonyl]-Beta-Alanine,Was Discovered By Optimization Of A Previously Identified Lead. Compound 9M Is A Reversible And Competitive Antagonist With High Binding Affinity (Ic50 Of 6.6 Nm) And Functional Camp Activity (Ic50 Of 15.7 Nm). It Is Selective For Glucagon Receptor Relative To Other Family B Gpcrs,Showing Ic50 Values Of 1020 Nm For Gipr,9200 Nm For Pac1,And >10000 Nm For Glp-1R,Vpac1,And Vpac2. Compound 9M Blunted Glucagon-Induced Glucose Elevation In Hgcgr Mice And Rhesus Monkeys. It Also Lowered Ambient Glucose Levels In Both Acute And Chronic Mouse Models: In Hgcgr Ob/ob Mice It Reduced Glucose (Auc 0-6 H) By 32% And 39% At 3 And 10 Mpk Single Doses,Respectively. In Hgcgr Mice On A High Fat Diet,Compound 9M At 3,And 10 Mpk Po In Feed Lowered Blood Glucose Levels By 89% And 94% At Day 10,Respectively,Relative To The Difference Between The Vehicle Control And Lean Hgcgr Mice. On The Basis Of Its Favorable Biological And Dmpk Properties,Compound 9M (Mk-0893) Was Selected For Further Preclinical And Clinical Evaluations.
    DOI:10.1021/jm300579Z

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    专利信息


    专利号:US-9969686-B2
    优先权日:2014-08-05
    标 题 :Synthesis of diindolylmethanes and indolo[3,2-b]carbazoles, compounds formed thereby, and pharmaceutical compositions containing them
    发明人：TANG WEIPING; LI XIAOXUN; SHU DONGXU; WINSTON-MCPHERSON GABRIELLE N
    权利人:WISCONSIN ALUMNI RES FOUND
    摘要:Described is a method to make diindolylmethanes and indolyl/pyrrolylmethanes, The method includes the steps of contacting an ether comprising an arylpropargyl moiety and an amine-protected, substituted or unsubstituted aniline moiety with a substituted or unsubstituted indol or a substituted or unsubstituted pyrrole, in the presence of a metal-containing catalyst, for a time and at a temperature to cause an annulation/arylation cascade reaction that yields a diindolylmethane or a indolyl/pyrrolylmethane. The resulting compounds are effective to modulate activity of arylhydrocarbon receptors, to inhibit activity of PCSK9, and to stimulate secretion of glucagon-like peptide 1 in mammals.

    专利号:US-2011301143-A1
    优先权日:2009-02-23
    标题 :Heterocyclic derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
    发明人：ISABEL ELISE; LACHANCE NICOLAS; LECLERC JEAN-PHILIPPE; LEGER SERGE; OBALLA RENATA M; POWELL DAVID; RAMTOHUL YEEMAN K; ROY PATRICK; TRANMER GEOFFREY K; ASPIOTIS RENEE; LI LIANHAI; MARTINS EVELYN
    权利人:ISABEL ELISE; LACHANCE NICOLAS; LECLERC JEAN-PHILIPPE; LEGER SERGE; OBALLA RENATA M; POWELL DAVID; RAMTOHUL YEEMAN K; ROY PATRICK; TRANMER GEOFFREY K; ASPIOTIS RENEE; LI LIANHAI; MARTINS EVELYN
    摘要:Heterocyclic compounds of structural formula (I), or a pharmaceutically acceptable salt thereof, wherein W is a R1— substituted heteroaryl, R1 is an heteroaryl ring substituted with an ester or carboxylic acid containing radical, X-T is N—CR5R6, Câ•?CR5 or CR13—CR5R6, Y is a bond or —C(O)—, a and b represent an integer selected from 1 to 4, and Ar is an optionally substituted phenyl or naphtyl, are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) The heterocyclic compounds are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, atherosclerosis, obesity, diabetes, neurological disease, Metabolic Syndrome, insulin resistance, cancer, liver steatosis, and non-alcoholic steatohepatitis.

    专利号:US-2011183958-A1
    优先权日:2008-10-17
    标 题 :Azetidine derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
    发明人：POWELL DAVID; TRANMER GEOFFREY K
    权利人:MERCK FROSST CANADA LTD
    摘要:Azetidine derivatives of structural formula I are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD). The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease; atherosclerosis; obesity; diabetes; neurological disease; Metabolic Syndrome; insulin resistance; cancer; liver steatosis; and non-alcoholic steatohepatitis.

    专利号:US-2012010186-A1
    优先权日:2009-03-23
    标题:Heterocyclic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase
    发明人：LACHANCE NICOLAS; LEGER SERGE; OBALLA RENATA M; POWELL DAVID; TRANMER GEOFFREY K; MARTINS EVELYN; GAREAU YVES
    权利人:LACHANCE NICOLAS; LEGER SERGE; OBALLA RENATA M; POWELL DAVID; TRANMER GEOFFREY K; MARTINS EVELYN; GAREAU YVES; MERCK FROSST CANADA LTD
    摘要:Heterocyclic compounds of structural formula I are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD). The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease; atherosclerosis; obesity; diabetes; neurological disease; Metabolic Syndrome; insulin resistance; cancer, liver steatosis; and non-alcoholic steatohepatitis.

    专利号:US-2011152295-A1
    优先权日:2008-09-08
    标 题:Heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase
    发明人：LECLERC JEAN-PHILIPPE; LI CHUN SING; RAMTOHUL YEEMAN K
    权利人:LECLERC JEAN-PHILIPPE; LI CHUN SING; RAMTOHUL YEEMAN K
    摘要:Heteroaromatic compounds of structural formula I are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; and liver steatosis.

    专利号:US-2011166152-A1
    优先权日:2008-10-02
    标题 :Heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase
    发明人：LECLERC JEAN-PHILIPPE; LI CHUN SING; RAMTOHUL YEEMAN K
    权利人:LECLERC JEAN-PHILIPPE; LI CHUN SING; RAMTOHUL YEEMAN K
    摘要:Heteroaromatic compounds of structural formula (I) are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD). The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; Type 2 diabetes; insulin resistance; hyperglycemia; Metabolic Syndrome; neurological disease; cancer; and liver steatosis.

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    主要参考文献


    1: Guan HP, Yang X, Lu K, Wang SP, Castro-Perez JM, Previs S, Wright M, Shah V, Herath K, Xie D, Szeto D, Forrest G, Xiao JC, Palyha O, Sun LP, Andryuk PJ, Engel SS, Xiong Y, Lin S, Kelley DE, Erion MD, Davis HR, Wang L. Glucagon receptor antagonism induces increased cholesterol absorption. J Lipid Res. 2015 Nov;56(11):2183-95. doi: 10.1194/jlr.M060897. Epub 2015 Sep 15.
    2: Lin S, Zhang F, Jiang G, Qureshi SA, Yang X, Chicchi GG, Tota L, Bansal A, Brady E, Trujillo M, Salituro G, Miller C, Tata JR, Zhang BB, Parmee ER. A novel series of indazole-/indole-based glucagon receptor antagonists. Bioorg Med Chem Lett. 2015 Oct 1;25(19):4143-7. doi: 10.1016/j.bmcl.2015.08.015. Epub 2015 Aug 8. doi: 10.1186/1471-2105-15-S16-S13. Epub 2014 Dec 8.
    4: Xiong Y, Guo J, Candelore MR, Liang R, Miller C, Dallas-Yang Q, Jiang G, McCann PE, Qureshi SA, Tong X, Xu SS, Shang J, Vincent SH, Tota LM, Wright MJ, Yang X, Zhang BB, Tata JR, Parmee ER. Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbo nyl]-β-alanine (MK-0893) for the treatment of type II diabetes. J Med Chem. 2012 Jul 12;55(13):6137-48. doi: 10.1021/jm300579z. Epub 2012 Jun 28. doi: 10.1371/journal.pone.0049572. Epub 2012 Nov 19.

    合成参考文献


    摘要:S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
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