N-[2-[4-(bromomethyl)phenyl]propan-2-yl]-3-(2,2-difluoroethoxy)benzenesulfonamide | 1309653-72-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[2-[4-(bromomethyl)phenyl]propan-2-yl]-3-(2,2-difluoroethoxy)benzenesulfonamide
• CAS: 1309653-72-2
• 化学式: C₁₈H₂₀BrF₂NO₃S
• 分子量: 448.329
• InChiKey: LBKXWYQEZQMESB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  63.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[2-[4-(bromomethyl)phenyl]propan-2-yl]-3-(2,2-difluoroethoxy)benzenesulfonamide 、 2,4-二(三甲硅氧基)嘧啶 在 碘 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 3.0h， 以32.7 mg的产率得到3-(2,2-difluoroethoxy)-N-(2-(4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phenyl)propan-2-yl)-benzenesulfonamide
  参考文献：
  名称：

  Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

  摘要：

  Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.

  DOI：

  10.1021/jm300416h
• 作为产物：
  描述：

  1-(4-甲基苯基)-1-甲基乙胺 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 potassium carbonate 、 三乙胺 、 甲胺 作用下， 以 甲醇 、 四氯化碳 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.83h， 生成 N-[2-[4-(bromomethyl)phenyl]propan-2-yl]-3-(2,2-difluoroethoxy)benzenesulfonamide
  参考文献：
  名称：

  Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

  摘要：

  Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.

  DOI：

  10.1021/jm300416h

文献信息

• [EN] 5-FLUOROURACIL COMPOUND HAVING dUTPase-INHIBITING ACTIVITY OR SALT THEREOF<br/>[FR] 5-FLUOROURACILE PRÉSENTANT UNE ACTIVITÉ INHIBITRICE DE LA dUTPase OU L'UN DE SES SELS
  申请人：TAIHO PHARMACEUTICAL CO LTD

  公开号：WO2011065545A1

  公开（公告）日：2011-06-03

  　優れたdUTPase 阻害活性を有し、抗腫瘍薬の効果増強剤等として有用な、一般式（Ｉ）で表される５－フルオロウラシル化合物又はその塩を提供する。 （一般式（Ｉ）中、ｎは１～３の数を示し、Ｘは、結合、酸素原子、硫黄原子、炭素数２～６のアルケニレン基、置換基を有していてもよい２価の芳香族炭化水素基、又は置換基を有していてもよい２価の飽和若しくは不飽和複素環基を示し、Ｙは、結合、又は炭素数１～８の直鎖状若しくは分枝状のアルキレン基を示し、Ｚは、－ＳＯ2ＮＲ1Ｒ2、－ＮＲ3ＳＯ2－Ｒ4、又は下記右式（Ⅱ）（Ｒ5 置換ピロリジニルカルボニル）を示し、Ｒ1 及びＲ2 は、水素原子等を示し、Ｒ3 は、水素原子等を示し、Ｒ4 は、置換基を有していてもよい芳香族炭化水素基等を示し、Ｒ5 は、置換基を有していてもよいメチル基を示す。）
• Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy
  作者：Seiji Miyahara、Hitoshi Miyakoshi、Tatsushi Yokogawa、Khoon Tee Chong、Junko Taguchi、Toshiharu Muto、Kanji Endoh、Wakako Yano、Takeshi Wakasa、Hiroyuki Ueno、Yayoi Takao、Akio, Fujioka、Akihiro Hashimoto、Kenjirou Itou、Keisuke Yamamura、Makoto Nomura、Hideko Nagasawa、Satoshi Shuto、Masayoshi Fukuoka

  DOI：10.1021/jm300416h

  日期：2012.6.14

  Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.