4-[2-[4-(2-甲氧基乙基)哌嗪-1-基]-1,3-噻唑-4-基]苯甲酸 | 860343-99-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 4-[2-[4-(2-甲氧基乙基)哌嗪-1-基]-1,3-噻唑-4-基]苯甲酸
• 英文名称: 4-{2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-yl}-benzoic acid
• 英文别名: Benzoic acid, 4-[2-[4-(2-methoxyethyl)-1-piperazinyl]-4-thiazolyl]-；4-[2-[4-(2-methoxyethyl)piperazin-1-yl]-1,3-thiazol-4-yl]benzoic acid
• CAS: 860343-99-3
• 化学式: C₁₇H₂₁N₃O₃S
• 分子量: 347.438
• InChiKey: AECPLWYYFCBDJC-UHFFFAOYSA-N

物化性质

• 沸点：
  532.0±60.0 °C(Predicted)
• 密度：
  1.269±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  94.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-[2-[4-(2-甲氧基乙基)哌嗪-1-基]-1,3-噻唑-4-基]苯甲酸 、 1-amino-N-(cyanomethyl)cyclohexanecarboxamide methanesulfonate 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-[2-[4-(2-methoxyethyl)piperazin-1-yl]-1,3-thiazol-4-yl]benzamide
  参考文献：
  名称：

  Design and Synthesis of Tri-Ring P₃ Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K

  摘要：

  We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P-2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/ L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.

  DOI：

  10.1021/jm058198r
• 作为产物：
  描述：

  4-乙酰基苯甲酸 在 溴 、 溶剂黄146 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 4-[2-[4-(2-甲氧基乙基)哌嗪-1-基]-1,3-噻唑-4-基]苯甲酸
  参考文献：
  名称：

  Design and Synthesis of Tri-Ring P₃ Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K

  摘要：

  We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P-2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/ L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.

  DOI：

  10.1021/jm058198r

文献信息

• [EN] CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE CYSTEINE PROTEASE
  申请人：MEDIVIR AB

  公开号：WO2005066180A1

  公开（公告）日：2005-07-21

  A compound of the formula (II) wherein one of R1 and R2 is halo and the other is H or halo; R3 is C1-C4 straight or branched chain, optionally fluorinated, alkyl; R4 is H; or R3 together with R4 and the adjoining backbone carbon defines: a spiro-C5-C7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C4 alkyl or C1-C4 haloalkyl; or optionally bridged with a methylene group; or a C4-C6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(=O)2 ; where Ra is H, C1-C4 alkyl or CH3C(=O); R5 is independently selected from H or methyl; E is -C(=O)-, -S(=O)m-, -NR5S(=O)m-, -NR5C(=O)-, -OC(=O)-, R6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle; m is independently 0,1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.

  一个公式为(II)的化合物，其中R1和R2中的一个是卤素，另一个是H或卤素；R3是C1-C4直链或支链，可选择氟代的烷基；R4是H；或者R3与R4和相邻的骨架碳一起定义：一个螺环C5-C7环烷基，可选地用1至3个卤素、羟基、C1-C4烷基或C1-C4卤代烷基中的取代基取代；或者可选地用亚甲基桥接；或者是一个具有O、NRa、S、S(=O)2等异原子的C4-C6饱和杂环；其中Ra是H、C1-C4烷基或CH3C(=O)；R5独立地选择自H或甲基；E是-C(=O)-、-S(=O)m-、-NR5S(=O)m-、-NR5C(=O)-、-OC(=O)-；R6是稳定的、可选择取代的、单环或双环的、碳环或杂环；m独立地为0、1或2；是猫hepsin K的抑制剂，并且在骨质疏松症的治疗或预防中有用。
• Furo[3,2-B] pyrrol -3-one derivatives and their use as cysteinyl porteinase inhibitors
  申请人：Quibell Martin

  公开号：US20100010009A1

  公开（公告）日：2010-01-14

  The present invention relates to compounds of formula (1), and pharmaceutically acceptable salts thereof, A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof (I), wherein: one of R 1 and R 2 is H, and the other is selected from F and Cl, or R 1 and R 2 are both F; R 3 is selected from cyclopentyl and cyclohexyl; R 4 is an optionally substituted 5- or 6-membered monocyclic or an 8- to 10-membered bicyclic aryl or heteroaryl ring which includes up to four heteroatoms. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget's disease, Chagas's disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

  本发明涉及式（1）的化合物及其药学上可接受的盐，式（I）的化合物或药学上可接受的盐、水合物、配合物或前药，其中：R1和R2中的一个为H，另一个为F和Cl中的一种，或R1和R2均为F；R3选自环戊基和环己基；R4为可选取代的5-或6-成员单环或8-到10-成员的双环芳基或杂环芳基环，其中包含最多四个杂原子。本发明还涉及包括式（I）的化合物的制药组合物，并且在治疗骨质疏松症、帕盖特病、查加斯病、疟疾、牙龈疾病、高钙血症、代谢性骨病、涉及基质或软骨降解的疾病以及骨癌疾病如骨转移和相关疼痛中使用这种化合物的用途。
• Cysteine Protease inhibitors
  申请人：Nilsson Magnus

  公开号：US20080234260A1

  公开（公告）日：2008-09-25

  A compound of the formula II wherein one of R 1 and R 2 is halo and the other is H or halo; R 3 is C 1 -C 4 straight or branched chain, optionally fluorinated, alkyl; R 4 is H; or R 3 together with R 4 and the adjoining backbone carbon defines: a spiro-C 5 -C 7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; or optionally bridged with a methylene group; or a C 4 -C 6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(═O) 2 ; where Ra is H, C 1 -C 4 alkyl or CH 3 C(═O); R 5 is independently selected from H or methyl; E is —C(═O)—, —S(═O) m —, —NR 5 S(═O) m —, —NR 5 C(═O)—, —OC(═O)—, R 6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or heterocycle; m is independently 0,1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.

  化合物II的公式为其中R1和R2中的一个是卤素，另一个是氢或卤素;R3是C1-C4直链或支链，可选择氟代的烷基;R4是氢;或R3与R4和相邻的骨架碳一起定义:一个螺旋C5-C7环烷基，可选地被1至3个取代基所取代，所述取代基选自卤素、羟基、C1-C4烷基或C1-C4卤代烷基;或者可选地通过亚甲基基桥接;或者是一个C4-C6饱和杂环，其中杂原子选自O、NRa、S、S(═O)2;其中Ra是H、C1-C4烷基或CH3C(═O);R5是独立选择的H或甲基;E是—C(═O)—、—S(═O)m—、—NR5S(═O)m—、—NR5C(═O)—、—OC(═O)—;R6是稳定的、可选地取代的、单环或双环、碳环或杂环;m独立地为0、1或2;是猫hepsin K的抑制剂，用于治疗或预防骨质疏松症。
• COMPOUNDS
  申请人：QUIBELL MARTIN

  公开号：US20110077254A1

  公开（公告）日：2011-03-31

  A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, wherein one of R 1 and R 2 is H, and the other is selected from C 1-8 -alkyl, C 3-6 -cycloalkyl and C 1-8 -alkyl-C 5-10 -aryl; R 3 is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl; R 9 is selected from the following: wherein: R 4 is selected from C 1-8 -alkyl and C 3-8 -cycloalkyl; G is selected from: CH, CMe and N; E is selected from: O, S, SO 2 , NH, NMe and N-oxide ( N→O); J and R are independently selected from: CH, N and N-oxide ( N→O); and R 41 is selected from amino, methylamino, dimethylamino, isopropylamino, isopropyl(methyl)amino, cyclopropylamino, cyclopropyl(methyl)amino, cyclopentylamino, morpholino, piperidin-1-yl, piperidin-1-ylmethyl, morpholinomethyl, 4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl, 1-morpholino ethyl, 1-(dimethylamino)ethyl, 1-(methylamino)ethyl, 4-fluoro-1-methylpyrrolidin-2-yl, 4,4-difluoropiperidin-1-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, pyridin-3-ylamino, pyridin-2-ylamino, 1-methylpyrrolidin-3-yl, methyl, isopropyl. The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of various diseases.

  化合物的式(I)，或其药学上可接受的盐、水合物、复合物或前药，其中R1和R2中的一个是H，另一个选自C1-8-烷基、C3-6-环烷基和C1-8-烷基-C5-10-芳基；R3选自叔丁基甲基、异丙基甲基、仲丁基、叔丁基、环戊基、环己基和1-甲基环戊基；R9选自以下内容：其中：R4选自C1-8-烷基和C3-8-环烷基；G选自：CH、CMe和N；E选自：O、S、SO2、NH、NMe和N-氧化物（N→O）；J和R独立选自：CH、N和N-氧化物（N→O）；R41选自氨基、甲基氨基、二甲基氨基、异丙基氨基、异丙基（甲基）氨基、环丙基氨基、环丙基（甲基）氨基、环戊基氨基、吗啉基、哌啶-1-基、哌啶-1-基甲基、吗啉基甲基、4-甲基哌嗪-1-基、4-(2-甲氧基乙基)哌嗪-1-基、1-吗啉基乙基、1-(二甲基氨基)乙基、1-(甲基氨基)乙基、4-氟-1-甲基吡咯烷-2-基、4,4-二氟哌啶-1-基、哌啶-4-基、1-甲基哌啶-4-基、吡啶-3-基氨基、吡啶-2-基氨基、1-甲基吡咯烷-3-基、甲基、异丙基。本发明还涉及包含式(I)化合物的制药组合物，以及在治疗各种疾病中使用这些化合物的方法。
• Cysteine Protease Inhibitors
  申请人：NILSSON Magnus

  公开号：US20110112089A1

  公开（公告）日：2011-05-12

  A compound of the formula II wherein one of R 1 and R 2 is halo and the other is H or halo; R 3 is C 1 -C 4 straight or branched chain, optionally fluorinated, alkyl; R 4 is H; or R 3 together with R 4 and the adjoining backbone carbon defines: a spiro-C 5 -C 7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; or optionally bridged with a methylene group; or a C 4 -C 6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(═O) 2 ; where Ra is H, C 1 -C 4 alkyl or CH 3 C(═O); R 5 is independently selected from H or methyl; E is —C(═O)—, —S(═O) m —, —NR 5 S(═O) m —, —NR 5 C(═O)—, —OC(═O)—, R 6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle; m is independently 0, 1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.

  该化合物的公式为II，其中R1和R2中的一个是卤素，另一个是氢或卤素；R3是直链或支链的C1-C4烷基，可以是氟代的；R4是氢；或者R3与R4和相邻的骨架碳共同定义了一个螺旋状的C5-C7环烷基，可以选择性地用1至3个取代基中的卤素、羟基、C1-C4烷基或C1-C4卤代烷基进行取代；或者选择性地用亚甲基桥接；或者是一个具有O、NRa、S、S(═O)2等杂原子的C4-C6饱和杂环，其中Ra是H、C1-C4烷基或CH3C(═O)；R5是独立选择的H或甲基；E是—C(═O)—、—S(═O)m—、—NR5S(═O)m—、—NR5C(═O)—、—OC(═O)—；R6是一个稳定的、可以选择性地取代的单环或双环的碳环或杂环；m是独立选择的0、1或2。这些化合物是猫hepsin K的抑制剂，并且在治疗或预防骨质疏松症方面有用。