N-cyclopentyl-5-(3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-enylamino)-N-(2-morpholinoethoxy)pentane-1-sulfonamide | 1202572-40-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: N-cyclopentyl-5-(3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-enylamino)-N-(2-morpholinoethoxy)pentane-1-sulfonamide
• 英文别名: N-cylopentyl-6-(3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-enylamino)-N-(2-morpholinoethoxy)pentane-1-sulfonamide；N-cyclopentyl-5-[[3,4-dioxo-2-(pyridin-4-ylamino)cyclobuten-1-yl]amino]-N-(2-morpholin-4-ylethoxy)pentane-1-sulfonamide
• CAS: 1202572-40-4
• 化学式: C₂₅H₃₇N₅O₆S
• 分子量: 535.665
• InChiKey: SYLNLBLOCCWBRD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  37
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  139
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  N-(2-氯乙基)吗啉盐酸盐 在 sodium hydride 、 sodium cyanoborohydride 、 一水合肼 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 28.25h， 生成 N-cyclopentyl-5-(3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-enylamino)-N-(2-morpholinoethoxy)pentane-1-sulfonamide
  参考文献：
  名称：

  Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship

  摘要：

  Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.

  DOI：

  10.1021/jm4009949

文献信息

• [EN] SQUARIC ACID DERIVATIVES AS INHIBITORS OF THE NICOTINAMIDE<br/>[FR] DÉRIVÉS DE L'ACIDE SQUARIQUE UTILISÉS COMME INHIBITEURS DU NICOTINAMIDE
  申请人：TOPOTARGET AS

  公开号：WO2009156421A1

  公开（公告）日：2009-12-30

  The present application discloses novel squaric acid derivatives of the formula A: from -C(=O)-, -S(=O)2-, -C(=S)- and -P(=O)(R5)-; B: -, -O-, -NR6- and -C(=O)-NR6-; D : -, -O-, -CR7R8- and -NR9; m=0-12; n = 0-12; m+n = 1-20; p=0-2; R1 : heteroaryl, aryl; R2 : H, C1-12-alkyl, C3-12-cycloalkyl, -[CH2CH2O]1-10-(C1-6-alkyl),C1-12-alkenyl, aryl, heterocyclyl, heteroaryl; R3 : C1-12-alkyl, C3-12-cycloalkyl, -[CH2CH2O]1-10-(C1-6-alkyl), C1-12-alkenyl, aryl, heterocyclyl, heteroaryl; or R2 and R3 : N-containing heterocyclic/heteroaromatic ring; R4 and R4* : H, C1-12-alkyl, C1-12-alkenyl; and pharmaceutically acceptable salts and prodrugs thereof, and their use in the treatment of diseases/conditions caused by an elevated level of NAMPRT (inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and CPOD, osteoarthritis, osteoporosis and fibrotic diseases; dermatosis; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, cachexia, inflammation associated with infection and viral infections, adult respiratory distress syndrome, ataxia telengiectasia).

  本申请公开了公式A的新颖方酸衍生物：来自-C(=O)-，-S(=O)2-，-C(=S)-和-P(=O)(R5)-；B：-，-O-，-NR6-和-C(=O)-NR6-；D：-，-O-，-CR7R8-和-NR9；m=0-12；n=0-12；m+n=1-20；p=0-2；R1：杂环烷基，芳基；R2：H，C1-12-烷基，C3-12-环烷基，-[CH2CH2O]1-10-(C1-6-烷基)，C1-12-烯基，芳基，杂环烷基，杂环芳基；R3：C1-12-烷基，C3-12-环烷基，-[CH2CH2O]1-10-(C1-6-烷基)，C1-12-烯基，芳基，杂环烷基，杂环芳基；或R2和R3：含氮杂环/杂芳环；R4和R4*：H，C1-12-烷基，C1-12-烯基；以及其药学上可接受的盐和前药，以及它们在治疗由NAMPRT水平升高引起的疾病/症状中的用途（炎症和组织修复紊乱，特别是类风湿关节炎，炎症性肠病，哮喘和CPOD，骨关节炎，骨质疏松症和纤维化疾病；皮肤病；自身免疫疾病，包括系统性红斑狼疮，多发性硬化，银屑病性关节炎，强直性脊柱炎，组织和器官排斥，阿尔茨海默病，中风，动脉粥样硬化，再狭窄，糖尿病，肾小球肾炎，癌症，虚弱，与感染和病毒感染相关的炎症，成人呼吸窘迫综合征，遗传性毛细血管扩张症）。
• SQUARIC ACID DERIVATIVES AS INHIBITORS OF THE NICOTINAMIDE
  申请人：Christensen Mette Knak

  公开号：US20120225847A1

  公开（公告）日：2012-09-06

  The present application discloses novel squaric acid derivatives of the formula A: from —C(═O)—, —S(═O) 2 —, —C(═S)— and —P(═O)(R 5 )—; B: -, —O—, —NR 6 — and —C(═O)—NR 6 —; D: -, —O—, —CR 7 R 8 — and —NR 9 ; m=0-12; n=0-12; m+n=1-20; p=0-2; R 1 : heteroaryl, aryl; R 2 : H, C 1-12 -alkyl, C 3-12 -cycloalkyl, —[CH 2 CH 2 O] 1-10 —(C 1-6 -alkyl), C 1-12 -alkenyl, aryl, heterocyclyl, heteroaryl; R 3 : C 1-12 -alkyl, C 3-12 -cycloalkyl, —[CH 2 CH 2 O] 1-10 —(C 1-6 -alkyl), C 1-12 -alkenyl, aryl, heterocyclyl, heteroaryl; or R 2 and R 3 : N-containing heterocyclic/heteroaromatic ring; R 4 and R 4 *: H, C 1-12 -alkyl, C 1-12 -alkenyl; and pharmaceutically acceptable salts and prodrugs thereof, and their use in the treatment of diseases/conditions caused by an elevated level of NAMPRT (inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and CPOD, osteoarthritis, osteoporosis and fibrotic diseases; dermatosis; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, cachexia, inflammation associated with infection and viral infections, adult respiratory distress syndrome, ataxia telengiectasia).

  本申请公开了公式A的新型苯二甲酸衍生物：从—C（═O）—，—S（═O）2—，—C（═S）—和—P（═O）（R5）—；B：-，—O—，—NR6—和—C（═O）—NR6—；D：-，—O—，—CR7R8—和—NR9；m=0-12；n=0-12；m+n=1-20；p=0-2；R1：杂环芳基，芳基；R2：H，C1-12-烷基，C3-12-环烷基，—[CH2CH2O]1-10—（C1-6-烷基），C1-12-烯基，芳基，杂环烷基，杂环芳基；R3：C1-12-烷基，C3-12-环烷基，—[CH2CH2O]1-10—（C1-6-烷基），C1-12-烯基，芳基，杂环烷基，杂环芳基；或R2和R3：含氮杂环/杂芳基环；R4和R4*：H，C1-12-烷基，C1-12-烯基；以及其药学上可接受的盐和前药，以及它们在治疗由NAMPRT水平升高引起的疾病/状况中的用途（炎症和组织修复障碍，特别是类风湿性关节炎，炎症性肠病，哮喘和CPOD，骨关节炎，骨质疏松症和纤维性疾病；皮肤病；自身免疫性疾病，包括系统性红斑狼疮，多发性硬化症，银屑病性关节炎，强直性脊柱炎，组织和器官排斥，阿尔茨海默病，中风，动脉粥样硬化，再狭窄，糖尿病，肾小球肾炎，癌症，消瘦症，与感染和病毒感染相关的炎症，成人呼吸窘迫综合征，遗传性毛细血管扩张性共济失调）。
• US9006426B2
  申请人：——

  公开号：US9006426B2

  公开（公告）日：2015-04-14
• Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship
  作者：Mette K. Christensen、Kamille D. Erichsen、Uffe H. Olesen、Jette Tjørnelund、Peter Fristrup、Annemette Thougaard、Søren Jensby Nielsen、Maxwell Sehested、Peter B. Jensen、Einars Loza、Ivars Kalvinsh、Antje Garten、Wieland Kiess、Fredrik Björkling

  DOI：10.1021/jm4009949

  日期：2013.11.27

  Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.