1,1-dibromo-3-(S)-tetrahydropyranyloxy-4-(3-methoxymethylphenyl)-1-butene | 253350-36-6

• 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: 1,1-dibromo-3-(S)-tetrahydropyranyloxy-4-(3-methoxymethylphenyl)-1-butene
• 英文别名: (3S)-1,1-dibromo-4-(3-methoxymethylphenyl)-3-(2-tetrahydropyranyloxy)-1-butene；(3S)-1,1-Dibromo-4-(3-methoxymethylphenyl)-3-(2-tetrahydropyranyloxy)-1-buten；2-[(2S)-4,4-dibromo-1-[3-(methoxymethyl)phenyl]but-3-en-2-yl]oxyoxane
• CAS: 253350-36-6
• 化学式: C₁₇H₂₂Br₂O₃
• 分子量: 434.168
• InChiKey: XFTJLZSTXHOBKL-MYJWUSKBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  27.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,1-dibromo-3-(S)-tetrahydropyranyloxy-4-(3-methoxymethylphenyl)-1-butene 在 吡啶 、 咪唑 、 4-二甲氨基吡啶 、 Schwartz's reagent 、 正丁基锂 、 偶氮二异丁腈 、 二叔丁基过氧化物 、 (HF)n*Py 、 叔丁基锂 、 三正丁基氢锡 、 对甲苯磺酸 、 甲基磺酰氯 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 、 正戊烷 为溶剂， 反应 8.25h， 生成 甲基4-({2-[(1R,2R,3S)-3-羟基-2-{(1E)-3-羟基-4-[3-(甲氧基甲基)苯基]-1-丁烯-1-基}-5-氧代环戊基]乙基}硫基)丁酸酯
  参考文献：
  名称：

  Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE1 and 9-β-halo derivatives with improved stability

  摘要：

  To identify a new selective EP4-agonist with improved chemical stability, further chemical modification of those reported previously was continued. We focused our attention on chemical modification of the alpha chain of 3,7-dithiaPGE(1), and selected 5-thiaPGE(1), as a new chemical lead, Introduction of an optimized omega to chain to the 5-thiaPG skeleton afforded in-methoxymethyl derivative 33a, which showed the most potent EP4-receptor agonist activity and good subtype-selectivity both in vitro and in vivo. 9beta-HaloPGF derivatives were also synthesized and biologically evaluated in an attempt to block self-degradation of the beta-hydroxyketone moiety. Among these series, 39a and 39b showed potent agonist activity and good subtype-selectivity. Structure-activity relationships (SARs) are also discussed. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00031-7
• 作为产物：
  描述：

  1-acetoxy-3-(3-methoxymethylphenyl)-2-(S)-tetrahydropyranyloxypropane 在 sodium hydroxide 、 草酰氯 、 二甲基亚砜 、 三乙胺 、 三苯基膦 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 0.75h， 生成 1,1-dibromo-3-(S)-tetrahydropyranyloxy-4-(3-methoxymethylphenyl)-1-butene
  参考文献：
  名称：

  Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE1 and 9-β-halo derivatives with improved stability

  摘要：

  To identify a new selective EP4-agonist with improved chemical stability, further chemical modification of those reported previously was continued. We focused our attention on chemical modification of the alpha chain of 3,7-dithiaPGE(1), and selected 5-thiaPGE(1), as a new chemical lead, Introduction of an optimized omega to chain to the 5-thiaPG skeleton afforded in-methoxymethyl derivative 33a, which showed the most potent EP4-receptor agonist activity and good subtype-selectivity both in vitro and in vivo. 9beta-HaloPGF derivatives were also synthesized and biologically evaluated in an attempt to block self-degradation of the beta-hydroxyketone moiety. Among these series, 39a and 39b showed potent agonist activity and good subtype-selectivity. Structure-activity relationships (SARs) are also discussed. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00031-7

文献信息

• 5-thia-&ohgr;-substituted phenyl-prostaglandin E derivatives, process for producing the same and drugs containing the same as the active ingredient
  申请人：Ono Pharmaceutical Co., Ltd.

  公开号：US06462081B1

  公开（公告）日：2002-10-08

  The present invention relates to 5-thia-&ohgr;-substituted phenylprostaglandin E derivatives of the formula (I) (wherein, all the symbols are as defined in the specification), process for producing them and pharmaceutical compositions comprising them as active ingredient. The compounds of the formula (I) can bind to PGE2 receptors (especially, subtype EP4) strongly, so they are expected to be useful for prevention and/or treatment of immunological diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic lupus erythematosus etc., and rejection after organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, lung failure, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardiac ischemia, systemic inflammatory response syndrome, ambustion pain, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, and shock etc. Further, it is thought that EP4 subtype receptor relates to sleeping disorder and blood platelet aggregation, so the compounds of the present invention are expected to be useful for the prevention and/or treatment of such diseases.

  本发明涉及公式(I)的5-硫代-ω-取代苯基前列腺素E衍生物（其中，所有符号如规范中所定义），生产它们的方法以及包含它们作为活性成分的药物组合物。公式(I)的化合物可以强烈结合到PGE2受体（尤其是EP4亚型），因此预计它们对预防和/或治疗免疫性疾病（自身免疫疾病，如肌萎缩性侧索硬化（ALS），多发性硬化症，Sjögren综合症，慢性风湿性关节炎和系统性红斑狼疮等，器官移植后的排斥等），哮喘，异常骨形成，神经细胞死亡，肺功能衰竭，肝损伤，急性肝炎，肾炎，肾功能不全，高血压，心肌缺血，全身性炎症反应综合征，烧伤疼痛，败血症，血吞噬综合征，巨噬细胞活化综合征，Still氏病，川崎病，烧伤，全身性肉芽肿，溃疡性结肠炎，克罗恩病，透析时的高细胞因子血症，多器官功能衰竭和休克等方面有用。此外，据认为EP4亚型受体与睡眠障碍和血小板聚集有关，因此本发明的化合物预计对预防和/或治疗此类疾病有用。
• 3,7-dithiaprostanoic acid derivative
  申请人：Ono Pharmaceutical Co., Ltd.

  公开号：US06043275A1

  公开（公告）日：2000-03-28

  A 3,7-dithiaprostanoic acid derivative of the formula (I) ##STR1## (wherein, R.sup.1 is OH, C1.about.6 alkyloxy, NR.sup.6 R.sup.7 (R.sup.6, R.sup.7 are H, C1.about.6 alkyl.); R.sup.2 is H, OH; R.sup.3 is single bond, C1.about.6 alkylene; R.sup.4 is (i) C1.about.8 alkyl substituted by C1.about.6 alkyloxy, halogen etc., (ii) phenyloxy, C3.about.7 cycloalkyloxy, (iii) furyl, furyloxy, thienyl, thienyloxy, naphthyl, naphthyloxy, phthalanyl, phthalanyloxy, (iv) phenyl, phenyloxy, C3.about.7 cycloalkyl, C3.about.7 cycloalkyloxy substituted by C1.about.6 alkyl etc., (v) furyl, furyloxy, thienyl, thienyloxy, naphthyl, naphthyloxy, phthalanyl, phthalanyloxy substituted by C1.about.6 alkyl etc.; R.sup.5 is H, C1.about.6 alkyl.) can bind PGE.sub.2 receptor (particularly, EP4 subtype receptor) strongly. So, they are useful for the prevention and/or treatment of immunological diseases (autoimmune diseases, rejection after organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, liver damage, nephritis, hypertension, myocardiac ischemia and sleeping disorder etc.

  一种具有以下结构的3,7-二硫代丙氧酸衍生物（I）##STR1##（其中，R.sup.1为OH，C1至C6烷氧基，NR.sup.6 R.sup.7（R.sup.6、R.sup.7为H，C1至C6烷基）；R.sup.2为H，OH；R.sup.3为单键，C1至C6烷基；R.sup.4为（i）C1至C8烷基，被C1至C6烷氧基、卤素等取代，（ii）苯氧基，C3至C7环烷氧基，（iii）呋喃基，呋喃氧基，噻吩基，噻吩氧基，萘基，萘氧基，邻苯二甲酰基，邻苯二甲酰氧基，（iv）苯基，苯氧基，C3至C7环烷基，被C1至C6烷基等取代，（v）呋喃基，呋喃氧基，噻吩基，噻吩氧基，萘基，萘氧基，邻苯二甲酰基，邻苯二甲酰氧基，被C1至C6烷基等取代；R.sup.5为H，C1至C6烷基），可以强烈结合PGE.sub.2受体（特别是EP4亚型受体）。因此，它们对于预防和/或治疗免疫性疾病（自身免疫疾病，器官移植后的排斥等），哮喘，异常骨骼形成，神经细胞死亡，肝脏损伤，肾炎，高血压，心肌缺血和睡眠障碍等方面是有用的。
• A 3.7-dithiaprostanoic acid derivative
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP0985663A1

  公开（公告）日：2000-03-15

  A 3,7-dithiaprostanoic acid derivative of the formula (I) (wherein, R1 is OH, C1∼6 alkyloxy, NR6R7 (R6, R7 are H, C1∼6 alkyl.); R2 is H, OH; R3 is single bond, C1∼6 alkylene; R4 is (i) C1∼8 alkyl substituted by C1∼6 alkyloxy, halogen etc., (ii) phenyloxy, C3∼7 cycloalkyloxy, (iii) furyl, furyloxy, thienyl, thienyloxy, naphthyl, naphthyloxy, phthalanyl, phthalanyloxy, (iv) phenyl, phenyloxy, C3∼7 cycloalkyl, C3∼7 cycloalkyloxy substituted by C1∼6 alkyl etc., (v) furyl, furyloxy, thienyl, thienyloxy, naphthyl, naphthyloxy, phthalanyl, phthalanyloxy substituted by C1∼6 alkyl etc.; R5 is H, C1∼6 alkyl.) can bind PGE2 receptor (particularly, EP4 subtype receptor) strongly. So, they are useful for the prevention and/or treatment of immunological diseases (autoimmune diseases, rejection after organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, liver damage, nephritis, hypertension, myocardiac ischemia and sleeping disorder etc.

  一种 3,7-二硫代前列腺酸衍生物，其式为(I) (其中，R1 是 OH、C1∼6 烷氧基、NR6R7（R6、R7 是 H、C1∼6 烷基）；R2 是 H、OH；R3 是单键、C1∼6 亚烷基；R4 是 (i) 被 C1∼6 烷氧基、卤素等取代的 C1∼8 烷基、(iii) 呋喃基、呋喃氧基、噻吩基、噻吩氧基、萘基、萘氧基、酞酰基、酞氧基， (iv) 被 C1∼6 烷基等取代的苯基、苯基氧基、C3∼7 环烷基、C3∼7 环烷氧基(v) 呋喃基、呋喃氧基、噻吩基、噻吩氧基、萘基、萘氧基、被 C1∼6 烷基取代的酞酰基、酞氧基等；R5 为 H、C1∼6 烷基）能与 PGE2 受体（尤其是 EP4 亚型受体）强烈结合。因此，它们可用于预防和/或治疗免疫性疾病（自身免疫性疾病、器官移植后的排斥反应等）、哮喘、骨骼形成异常、神经细胞死亡、肝损伤、肾炎、高血压、心肌缺血和睡眠障碍等。
• 5-THIA-OMEGA-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THE SAME AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP1097922A1

  公开（公告）日：2001-05-09

  5-Thia-ω-substituted phenyl-prostaglandin E derivatives represented by general formula (I) wherein each symbol is as defined in the specification. Because of being capable of bonding strongly to PEG2receptors (in particular, the subtype EP4), the compounds represented by general formula (I) are expected as useful in preventing and/or treating immunologic diseases, asthma, bone dysplasia, nerve cell death, lung failure, hepatopathy, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, ambustion pain, sepsis, hemophagous syndrome, macrophage activation syndrome, Still disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock, etc. Moreover, these compounds participate in sleep disorders and platelet aggregation and, therefore, are expected as useful in preventing/treating these diseases.

  通式（I）代表的 5-噻-ω-取代苯基-前列腺素 E 衍生物，其中各符号如说明书中所定义。肾功能不全、高血压、心肌缺血、全身炎症综合征、灸痛、败血症、嗜血综合征、巨噬细胞活化综合征、斯蒂尔病、川崎病、烧伤、全身肉芽肿病、溃疡性结肠炎、克罗恩病、透析时的高细胞血症、多器官衰竭、休克等。此外，这些化合物还参与睡眠障碍和血小板聚集，因此有望用于预防/治疗这些疾病。
• $g(v)-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP1114816A1

  公开（公告）日：2001-07-11

  An ω-substituted phenyl-prostaglandin derivative of formula (I), a process for the preparation thereof, a medicament comprising it as active ingredient (all symbols have the same meaning as described in the specification). The compounds of the formula (I) bind strongly on PGE2 receptor (especially subtype EP4) and therefore are useful for the prophylaxis and/or treatment of immune diseases (autoimmune diseases (amyotrophic lateral sclerosis (ALS) etc.), post-transplantation graft rejection, etc.), asthma, abnormal bone formation, neurocyte death, pulmopathy, hepatopathy, etc. They are also related to sleeping disorders and platelet coagulations, and therefore they are also applicable to these diseases.

  一种式(I)的ω-取代苯基-前列腺素衍生物，其制备方法，一种以其为活性成分的药物（所有符号的含义与说明书中描述的相同）。 式（I）化合物与 PGE2 受体（尤其是亚型 EP4）结合力强，因此可用于预防和/或治疗免疫性疾病（自身免疫性疾病（肌萎缩性脊髓侧索硬化症（ALS）等）、移植后移植物排斥等）、哮喘、骨形成异常、神经细胞死亡、肺病、肝病等。它们还与睡眠障碍和血小板凝结有关，因此也适用于这些疾病。