diethyl 2,2'-((2R,6S)-1-methylpiperazine-2,6-diyl)diacetate acetate | 1149624-33-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: diethyl 2,2'-((2R,6S)-1-methylpiperazine-2,6-diyl)diacetate acetate
• 英文别名: cis-(6-ethoxycarbonylmethyl-1-methylpiperazin-2-yl)acetic acid ethyl ester acetate；acetic acid;ethyl 2-[(2R,6S)-6-(2-ethoxy-2-oxoethyl)-1-methylpiperazin-2-yl]acetate
• CAS: 1149624-33-8
• 化学式: C₂H₄O₂*C₁₃H₂₄N₂O₄
• 分子量: 332.397
• InChiKey: FNOXQUTUTLFFHB-NJJJQDLFSA-N

物化性质

• 熔点：
  88-90°

计算性质

• 辛醇/水分配系数(LogP)：
  0.26
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  8

安全信息

• 危险等级：
  IRRITANT

反应信息

• 作为反应物：
  描述：

  diethyl 2,2'-((2R,6S)-1-methylpiperazine-2,6-diyl)diacetate acetate 在 potassium tert-butylate 作用下， 以 甲苯 为溶剂， 反应 16.0h， 生成
  参考文献：
  名称：

  高效，非肽型，可生物利用的肾素抑制剂的设计和制备†

  摘要：

  从已知的哌啶肾素抑制剂开始，合理设计和制备了一系列新的3,9-二氮杂双环[3.3.1]壬烯衍生物。优化二氮杂双环烯模板的位置3、6和7导致有效的肾素抑制剂。在6和7位上连接的取代基对于这些化合物对肾素的结合亲和力是必不可少的。引入在3位上连接的取代基不会改变结合亲和力，但可以调节ADME性质。我们的努力导致发现抑制肾素的化合物（+）- 26g，在缓冲液中的IC 50为0.20 nM，在血浆中的IC 50为19 nM。讨论了该化合物和其他类似化合物的药代动力学特性。化合物（+）- 26克 在大鼠中被很好地吸收，在体内10 mg / kg时有效。

  DOI：

  10.1021/jm900022f
• 作为产物：
  描述：

  diethyl 2,2'-(4-benzyl-1-methylpiperazine-2,6-diyl)diacetate 、 溶剂黄146 在 10% palladium on activated carbon 、 氢气 作用下， 以 乙醇 、 甲基叔丁基醚 为溶剂， 1.0~40.0 ℃ 、123.0 MPa 条件下， 反应 72.0h， 以47%的产率得到diethyl 2,2'-((2R,6S)-1-methylpiperazine-2,6-diyl)diacetate acetate
  参考文献：
  名称：

  高效，非肽型，可生物利用的肾素抑制剂的设计和制备†

  摘要：

  从已知的哌啶肾素抑制剂开始，合理设计和制备了一系列新的3,9-二氮杂双环[3.3.1]壬烯衍生物。优化二氮杂双环烯模板的位置3、6和7导致有效的肾素抑制剂。在6和7位上连接的取代基对于这些化合物对肾素的结合亲和力是必不可少的。引入在3位上连接的取代基不会改变结合亲和力，但可以调节ADME性质。我们的努力导致发现抑制肾素的化合物（+）- 26g，在缓冲液中的IC 50为0.20 nM，在血浆中的IC 50为19 nM。讨论了该化合物和其他类似化合物的药代动力学特性。化合物（+）- 26克 在大鼠中被很好地吸收，在体内10 mg / kg时有效。

  DOI：

  10.1021/jm900022f

文献信息

• [EN] NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF<br/>[FR] NOUVEAUX ACTIVATEURS DE LA GUANYLATE CYCLASE SOLUBLES À DOUBLE MODE D'ACTION, INHIBITEURS DE PHOSPHODIESTÉRASE ET LEURS UTILISATIONS
  申请人：TOPADUR PHARMA AG

  公开号：WO2018215433A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.

  本发明涉及公式I的化合物或其药用可接受的盐、溶剂或水合物，以及它们在治疗或预防通过抑制人类或非人类哺乳动物中的PDE5而缓解的疾病的方法中的应用。
• Dual mode of action soluble guanylate cyclase activators and phosphodiesterase inhibitors and uses thereof
  申请人：TOPADUR PHARMA AG

  公开号：US11155558B2

  公开（公告）日：2021-10-26

  The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein at least one of R1, R2, R3, R4, or R5 independently of each other comprises at least one ONO2 or ONO moiety; R1 is C1-C3alkyl optionally substituted with F, C3-C6cycloalkyl, C1-C3alkoxy, ONO, ONO2; R2 is H, C1-C3alkyl optionally substituted with OH, ONO, ONO2; C(O)OH, C(O)OC1-C3alkyl, CHO, CN, C(O)N(R6)OR7, CR8═N—OR9, CR8═N—NR10R11, CR8═NR12, CR8═N—ONO2, C1-C3alkoxy; C1-C3alkylene-Y, wherein Y is ONO, ONO2, C(O)OH, C(O)OC1-C3alkyl, CHO, CN, OH, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl, CR8═N—OR9, CR8═N—NR10R11, CR8═NR12 or CR8═N—ONO2; R3 is C1-C4alkyl optionally substituted with F, OH, ONO, ONO2, C1-C3alkoxy, C3-C6cycloalkyl; C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkynyl; R4 is C1-C6alkyl optionally substituted with C3-C6cycloalkyl, C1-C6alkoxy, F, ONO, ONO2; C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl; R5 is H, SO2NR13R14, NHSO2NR13R14; R6 is H or C1-C3alkyl; R7 is H, C1-C3alkyl, C1-C3alkoxy, C1-C3alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C1-C3alkyl, F; R8 is H, CH3 or C2H5; R9 is H, C1-C3alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOC1-C3alkyl, C1-C3alkoxy, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl; R10 and R11 are each independently H, C1-C3alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOC1-C3, C1-C3alkoxy, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C1-C3 alkyl; R12 is C1-C3 alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOC1-C3alkyl, C1-C3alkoxy, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl; R13 and R14 are each independently H or C1-C6alkyl optionally substituted with F, OH, ONO, ONO2, COOH, C1-C3alkoxy, C3-C6cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R15; R15 is C1-C6alkyl optionally substituted with halogen, OH, ONO, ONO2, C1-C3alkoxy, C1-C3haloalkoxy, COOR16, NR17R18, C═NR19, or with a tetrazole moiety which is optionally substituted with C1-C3alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen; R16 is H, or C1-C4alkyl optionally substituted with F, OH, ONO, ONO2, NR17R18, or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C1-C4 alkyl; R17 and R18 are each independently H or C1-C4alkyl optionally substituted with ONO, ONO2; R19 is C1-C4alkyl optionally substituted with F, ONO, ONO2; C3-C6cycloalkyl; and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.

  本发明涉及式 I 的化合物 或其药学上可接受的盐、溶液或水合物，其中 R1、R2、R3、R4 或 R5 中至少有一个相互独立地包含至少一个 ONO2 或 ONO 分子； R1 是任选被 F、C3-C6 环烷基、C1-C3 烷氧基、ONO、ONO2 取代的 C1-C3 烷基； R2 是 H、任选被 OH、ONO、ONO2 取代的 C1-C3 烷基；C(O)OH、C(O)OC1-C3 烷基、CHO、CN、C(O)N(R6)OR7、CR8═N-OR9、CR8═N-NR10R11、CR8═NR12、CR8═N-ONO2、C1-C3 烷氧基；C1-C3 烷基-Y，其中 Y 是 ONO、ONO2、C(O)OH、C(O)OC1-C3 烷基、CHO、CN、OH、OC(O)H、OC(O)-C1-C3 烷基、C(O)N(R6)OR7、OC1-C3 烷基-C(O)OH、OC1-C3烷基-C(O)OC1-C3烷基、OC1-C3烷基-C(O)N(R6)OR7、S(O0-2)C1-C3烷基、CR8═N-OR9、CR8═N-NR10R11、CR8═NR12 或 CR8═N-ONO2； R3 是任选被 F、OH、ONO、ONO2、C1-C3 烷氧基、C3-C6 环烷基、C3-C6 环烷基、C2-C6 烯基、C2-C6炔基取代的 C1-C4 烷基； R4 是被 C3-C6环烷基、C1-C6烷氧基、F、ONO、ONO2、C2-C6烯基、C2-C6炔基、C3-C6环烷基任选取代的 C1-C6 烷基； R5 是 H、SO2NR13R14、NHSO2NR13R14； R6 是 H 或 C1-C3 烷基 R7 是 H、C1-C3烷基、C1-C3烷氧基、被苯基、苄基或杂环取代的 C1-C3烷基，其中所述苯基、苄基或所述杂环独立地任选被 C1-C3烷基、F 取代； R8 是 H、CH3 或 C2H5； R9 是 H、任选被 OH、ONO、ONO2、CN、COOH、COOC1-C3 烷基、C1-C3 烷氧基、OC(O)H、OC(O)-C1-C3 烷基、C(O)N(R6)OR7、OC1-C3 亚烷基-C(O)OH、OC1-C3 亚烷基-C(O)OC1-C3 烷基、OC1-C3 亚烷基-C(O)N(R6)OR7、S(O0-2)C1-C3 烷基取代的 C1-C3 烷基； R10和R11各自独立地为H、被OH、ONO、ONO2、CN、COOH、COOC1-C3、C1-C3烷氧基、OC(O)H、OC(O)-C1-C3烷基、C(O)N(R6)OR7、OC1-C3亚烷基-C(O)OH、OC1-C3亚烷基-C(O)OC1-C3烷基、OC1-C3亚烷基-C(O)N(R6)OR7、S(O0-2)C1-C3烷基任选取代的C1-C3烷基；或与所连接的氮原子一起形成杂环，其中优选所述杂环选自氮丙啶、氮杂环丁烷、吡咯烷、哌啶、吗啉、哌嗪和均哌嗪，其中所述杂环任选被 C1-C3 烷基取代； R12 是任选被 OH、ONO、ONO2、CN、COOH、COOC1-C3 烷基、C1-C3 烷氧基、OC(O)H、OC(O)-C1-C3 烷基、C(O)N(R6)OR7、OC1-C3 亚烷基-C(O)OH、OC1-C3 亚烷基-C(O)OC1-C3 烷基、OC1-C3 亚烷基-C(O)N(R6)OR7、S(O0-2)C1-C3 烷基取代的 C1-C3 烷基； R13 和 R14 各自独立地为 H 或被 F、OH、ONO、ONO2、COOH、C1-C3 烷氧基、C3-C6 环烷基任选取代的 C1-C6 烷基；或与所连接的氮原子一起形成杂环，其中优选所述杂环选自氮丙啶、氮杂环丁烷、吡咯烷、哌啶、吗啉、哌嗪、均哌嗪、2,5-二氮杂双环[2,2,1]庚烷和 3,7-二氮杂双环[3,3,0]辛烷，其中所述杂环任选被 R15 取代； R15 是被卤素、OH、ONO、ONO2、C1-C3 烷氧基、C1-C3 卤烷氧基、COOR16、NR17R18、C═NR19 或被 C1-C3 烷基任选取代的四唑分子任选取代的 C1-C6 烷基；或被 F 任选取代的杂芳基环，其中所述杂芳基环的至少一个杂原子是氮； R16 是 H，或被 F、OH、ONO、ONO2、NR17R18 或杂芳基环任选取代的 C1-C4 烷基，其中所述杂芳基环的至少一个杂原子是氮，优选所述杂芳基环选自吡咯烷、哌啶、哌嗪、吗啉、吡咯和咪唑，其中氮原子直接与 C1-C4 烷基结合； R19是任选被F、ONO、ONO2取代的C1-C4烷基；C3-C6环烷基； 以及它们在治疗或预防通过抑制人或非人哺乳动物中的 PDE5 而减轻的疾病的方法中的用途。
• NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF
  申请人：TOPADUR PHARMA AG

  公开号：US20200181149A1

  公开（公告）日：2020-06-11

  The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein at least one of R 1 , R 2 , R 3 , R 4 , or R 5 independently of each other comprises at least one ONO 2 or ONO moiety; R 1 is C 1 -C 3 alkyl optionally substituted with F, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, ONO, ONO 2 ; R 2 is H, C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 ; C(O)OH, C(O)OC 1 -C 3 alkyl, CHO, CN, C(O)N(R 6 )OR 7 , CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , CR 8 ═NR 12 , CR 8 ═N—ONO 2 , C 1 -C 3 alkoxy; C 1 -C 3 alkylene-Y, wherein Y is ONO, ONO 2 , C(O)OH, C(O)OC 1 -C 3 alkyl, CHO, CN, OH, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl, CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , CR 8 ═NR 12 or CR 8 ═N—ONO 2 ; R 3 is C 1 -C 4 alkyl optionally substituted with F, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; R 4 is C 1 -C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, F, ONO, ONO 2 ; C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl; R 5 is H, SO 2 NR 13 R 14 , NHSO 2 NR 13 R 14 ; R 6 is H or C 1 -C 3 alkyl; R 7 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C 1 -C 3 alkyl, F; R 8 is H, CH 3 or C 2 H 5 ; R 9 is H, C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 alkyl, C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl; R 10 and R 11 are each independently H, C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 , C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C 1 -C 3 alkyl; R 12 is C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 alkyl, C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl; R 13 and R 14 are each independently H or C 1 -C 6 alkyl optionally substituted with F, OH, ONO, ONO 2 , COOH, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R 15 ; R 15 is C 1 -C 6 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 16 , NR 17 R 18 , C═NR 19 , or with a tetrazole moiety which is optionally substituted with C 1 -C 3 alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen; R 16 is H, or C 1 -C 4 alkyl optionally substituted with F, OH, ONO, ONO 2 , NR 17 R 18 , or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C 1 -C 4 alkyl; R 17 and R 18 are each independently H or C 1 -C 4 alkyl optionally substituted with ONO, ONO 2 ; R 19 is C 1 -C 4 alkyl optionally substituted with F, ONO, ONO 2 ; C 3 -C 6 cycloalkyl; and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.
• DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF
  申请人：TOPADUR PHARMA AG

  公开号：US20220073529A1

  公开（公告）日：2022-03-10

  The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.
• Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors
  作者：Olivier Bezençon、Daniel Bur、Thomas Weller、Sylvia Richard-Bildstein、Luboš Remeň、Thierry Sifferlen、Olivier Corminboeuf、Corinna Grisostomi、Christoph Boss、Lars Prade、Stéphane Delahaye、Alexander Treiber、Panja Strickner、Christoph Binkert、Patrick Hess、Beat Steiner、Walter Fischli

  DOI：10.1021/jm900022f

  日期：2009.6.25

  Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent

  从已知的哌啶肾素抑制剂开始，合理设计和制备了一系列新的3,9-二氮杂双环[3.3.1]壬烯衍生物。优化二氮杂双环烯模板的位置3、6和7导致有效的肾素抑制剂。在6和7位上连接的取代基对于这些化合物对肾素的结合亲和力是必不可少的。引入在3位上连接的取代基不会改变结合亲和力，但可以调节ADME性质。我们的努力导致发现抑制肾素的化合物（+）- 26g，在缓冲液中的IC 50为0.20 nM，在血浆中的IC 50为19 nM。讨论了该化合物和其他类似化合物的药代动力学特性。化合物（+）- 26克 在大鼠中被很好地吸收，在体内10 mg / kg时有效。