S-methyl-1-piperidinecarbothioate sulfone | 402561-21-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: S-methyl-1-piperidinecarbothioate sulfone
• 英文别名: Methylsulfonyl(piperidin-1-yl)methanone
• CAS: 402561-21-1
• 化学式: C₇H₁₃NO₃S
• 分子量: 191.251
• InChiKey: KUIWFWFDIWWSAG-UHFFFAOYSA-N

物化性质

• 沸点：
  307.5±25.0 °C(Predicted)
• 密度：
  1.276±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  62.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  S-methyl-1-piperidinecarbothioate sulfone 、 L-cysteine 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 24.0h， 生成 S-(piperidine-1-ylcarbonyl)cysteine
  参考文献：
  名称：

  Identification of a S-Hexahydro-1H-azepine-1-carbonyl Adduct Produced by Molinate on Rat Hemoglobin β₂ and β₃ Chains in Vivo

  摘要：

  Molinate is a thiocarbamate herbicide used in the rice industry for over 25 years, and regulatory reports have shown that administration of molinate results in reproductive toxicity in male rats. Previous in vitro studies indicate that molinate undergoes oxidative metabolism, forming reactive electrophilic intermediates capable of undergoing nucleophilic addition by protein nucleophiles. On the basis of in vitro studies, carbamylation of an active site serine residue in Hydrolase A has been proposed to be the mechanism responsible for the observed testicular toxicity. The experiments presented here utilize hemoglobin to characterize covalent protein modifications produced in vivo by molinate. Rats were dosed intraperitoneally with molinate as a function of exposure duration, Examination of globin from molinate-treated rats by HPLC demonstrated a new peak in the isolated samples and, when collected and analyzed using MALDI-TOF MS, revealed a 126 Da increase in mass relative to the native beta(3) chain. Digestion of the globin using Glu-C and analysis by MALDI-TOF MS revealed two modified peptide fragments at m/z 2743 and 4985 consistent with a 126 Da increase to peptide fragments [122-146] and [102-146] in the unmodified beta(2) and beta3 chains of globin. Using selected reaction monitoring LC/MS/MS, S-hexahydro-1H-azepine-1-carbonyl cysteine HHAC-Cys) was identified in the globin hydrolysates isolated from the molinate-treated rats, but not in the control samples, and the quantity of adduct exhibited a cumulative dose response. These experiments demonstrate the ability of molinate to covalently modify proteins in vivo in a dose dependent manner. For hemoglobin this modification was a carbamylation at Cys-125 similar to the modification produced by disulfiram and NIV-diethyldithiocarbamate. The ability of molinate to covalently modify cysteine residues provides a potential mechanism to account for enzyme inhibition following molinate exposure and suggests that enzymes with cysteine residues in their active site may be inhibited by molinate.

  DOI：

  10.1021/tx015564a
• 作为产物：
  描述：

  哌啶 、 alkaline earth salt of/the/ methylsulfuric acid 在 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 S-methyl-1-piperidinecarbothioate sulfone
  参考文献：
  名称：

  Identification of a S-Hexahydro-1H-azepine-1-carbonyl Adduct Produced by Molinate on Rat Hemoglobin β₂ and β₃ Chains in Vivo

  摘要：

  Molinate is a thiocarbamate herbicide used in the rice industry for over 25 years, and regulatory reports have shown that administration of molinate results in reproductive toxicity in male rats. Previous in vitro studies indicate that molinate undergoes oxidative metabolism, forming reactive electrophilic intermediates capable of undergoing nucleophilic addition by protein nucleophiles. On the basis of in vitro studies, carbamylation of an active site serine residue in Hydrolase A has been proposed to be the mechanism responsible for the observed testicular toxicity. The experiments presented here utilize hemoglobin to characterize covalent protein modifications produced in vivo by molinate. Rats were dosed intraperitoneally with molinate as a function of exposure duration, Examination of globin from molinate-treated rats by HPLC demonstrated a new peak in the isolated samples and, when collected and analyzed using MALDI-TOF MS, revealed a 126 Da increase in mass relative to the native beta(3) chain. Digestion of the globin using Glu-C and analysis by MALDI-TOF MS revealed two modified peptide fragments at m/z 2743 and 4985 consistent with a 126 Da increase to peptide fragments [122-146] and [102-146] in the unmodified beta(2) and beta3 chains of globin. Using selected reaction monitoring LC/MS/MS, S-hexahydro-1H-azepine-1-carbonyl cysteine HHAC-Cys) was identified in the globin hydrolysates isolated from the molinate-treated rats, but not in the control samples, and the quantity of adduct exhibited a cumulative dose response. These experiments demonstrate the ability of molinate to covalently modify proteins in vivo in a dose dependent manner. For hemoglobin this modification was a carbamylation at Cys-125 similar to the modification produced by disulfiram and NIV-diethyldithiocarbamate. The ability of molinate to covalently modify cysteine residues provides a potential mechanism to account for enzyme inhibition following molinate exposure and suggests that enzymes with cysteine residues in their active site may be inhibited by molinate.

  DOI：

  10.1021/tx015564a

文献信息

• [EN] AMINOPYRIMIDINE DERIVATIVES AS JNK INHIBITORS<br/>[FR] DERIVES D'AMINOPYRIMIDINE EN TANT QU'INHIBITEURS DE LA JNK
  申请人：CELLTECH R&D LTD

  公开号：WO2006038001A1

  公开（公告）日：2006-04-13

  A compound of formula (I) or a pharmaceutically acceptable salt, solvate or N-­oxide thereof: wherein A represents a pyrrole, pyrazole, imidazole or triazole ring; B represents a benzene, pyridine or pyrimidine ring; M represents the residue of an azetidine, pyrrolidine or piperidine ring; E represents a covalent bond or an optionally substituted straight or branched alkylene chain containing from 1 to 4 carbon atoms; Z represents hydrogen, -CORa, -C02Rb, -CONKc Rd, -CONRcORb, -COCO2Rb, - COCONRcRd, -COCH2NRcRd, -COCH2NRcCONKcRd, COCH2NRcCO2Rb, -NRcCORa, - NRcCO2Rb, -NRcCONRcRd, -S02Re, -SO2NRcRd or -SO2NRcC02Rb; or Z represents an optionally substituted phenyl, heteroaryl or C3-7 heterocycloalkyl group; R1 and R2 independently represent hydrogen, halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1-6 alkylsulphonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, aminocarbonyl or C2-6 alkoxycarbonyl; R3 represents hydrogen, C1-6 alkyl, -CH2CONRcRd or -SO2Re; R4 represents hydrogen, C1-6 alkoxy, oxo, -CO2Rb or -CONKcRd. The compounds of the present invention are potent inhibitors of JNK.

  式（I）的化合物或其药学上可接受的盐、溶剂或N-氧化物：其中A代表吡咯、吡唑、咪唑或三唑环；B代表苯、吡啶或嘧啶环；M代表氮杂环丙烷、吡咯丙烷或哌啶环的残基；E代表共价键或含有1至4个碳原子的可选取代的直链或支链烷基链；Z代表氢、-CORa、-C02Rb、-CONKcRd、-CONRcORb、-COCO2Rb、-COCONRcRd、-COCH2NRcRd、-COCH2NRcCONKcRd、COCH2NRcCO2Rb、-NRcCORa、-NRcCO2Rb、-NRcCONRcRd、-S02Re、-SO2NRcRd或-SO2NRcC02Rb；或Z代表可选取代的苯基、杂环芳基或C3-7杂环烷基基团；R1和R2独立地代表氢、卤素、氰基、硝基、C1-6烷基、三氟甲基、羟基、C1-6烷氧基、二氟甲氧基、三氟甲氧基、C1-6烷基磺酰基、氨基、C1-6烷基氨基、二(C1-6)烷基氨基、氨基甲酰基或C2-6烷氧羰基；R3代表氢、C1-6烷基、-CH2CONRcRd或-SO2Re；R4代表氢、C1-6烷氧基、氧代、-CO2Rb或-CONKcRd。本发明的化合物是JNK的有效抑制剂。