Ethyl Imidoacetate-d3 Hydrochloride | 74929-87-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 甲亚胺酸及其衍生物
• 英文名称: Ethyl Imidoacetate-d3 Hydrochloride
• 英文别名: 1-Ethoxyethanimine-D3 Hydrochloride；ethyl 2,2,2-trideuterioethanimidate;hydrochloride
• CAS: 74929-87-6
• 化学式: C₄H₉NO*ClH
• 分子量: 126.559
• InChiKey: WGMHMVLZFAJNOT-MUTAZJQDSA-N

物化性质

• 熔点：
  114-116 °C (decomp)
• 溶解度：
  二氯甲烷；

计算性质

• 辛醇/水分配系数(LogP)：
  1.44
• 重原子数：
  7.0
• 可旋转键数：
  2.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  33.08
• 氢给体数：
  1.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  Ethyl Imidoacetate-d3 Hydrochloride 在 氨 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以89.3%的产率得到acetamidine-d3 hydrochloride
  参考文献：
  名称：

  [EN] SYNTHESIS OF 3-METHYL-1,2,4-THIADIAZOLE-5-CARBOHYDRAZIDE OR OF THE METHYL-d3 DEUTERATED FORM THEREOF
  [FR] SYNTHÈSE DE 3-MÉTHYL-1,2,4-THIADIAZOLE-5-CARBOHYDRAZIDE OU DE SA FORME DEUTÉRÉE MÉTHYL-D3

  摘要：

  本发明涉及一种合成化合物(I)的方法，其中R1代表甲基或甲基-d3，因此对应于3-甲基-1,2,4-噻二唑-5-羧肼或其氘代甲基-d3形式。这些化合物在制备药物化合物，特别是费佐利那替和氘代费佐利那替的合成中作为关键中间体非常有用。

  公开号：

  WO2020128003A1
• 作为产物：
  描述：

  乙醇 、 氘代乙腈 在 盐酸 作用下， 反应 22.5h， 以104.3 g的产率得到Ethyl Imidoacetate-d3 Hydrochloride
  参考文献：
  名称：

  [EN] SYNTHESIS OF 3-METHYL-1,2,4-THIADIAZOLE-5-CARBOHYDRAZIDE OR OF THE METHYL-d3 DEUTERATED FORM THEREOF
  [FR] SYNTHÈSE DE 3-MÉTHYL-1,2,4-THIADIAZOLE-5-CARBOHYDRAZIDE OU DE SA FORME DEUTÉRÉE MÉTHYL-D3

  摘要：

  本发明涉及一种合成化合物(I)的方法，其中R1代表甲基或甲基-d3，因此对应于3-甲基-1,2,4-噻二唑-5-羧肼或其氘代甲基-d3形式。这些化合物在制备药物化合物，特别是费佐利那替和氘代费佐利那替的合成中作为关键中间体非常有用。

  公开号：

  WO2020128003A1

文献信息

• [EN] COMPETITIVE AND NONCOMPETITIVE INHIBITORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M5<br/>[FR] INHIBITEURS COMPÉTITIFS ET NON COMPÉTITIFS DU RÉCEPTEUR DE L'ACÉTYLCHOLINE MUSCARINIQUE M5
  申请人：UNIV VANDERBILT

  公开号：WO2021237038A8

  公开（公告）日：2022-06-02
• Mechanistic Studies of the Inactivation of Inducible Nitric Oxide Synthase by <i>N</i>⁵-(1-Iminoethyl)-<scp>l</scp>-ornithine (<scp>l</scp>-NIO)
  作者：Walter Fast、Dejan Nikolic、Richard B. Van Breemen、Richard B. Silverman

  DOI：10.1021/ja982318l

  日期：1999.2.1

  Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide. N-5-(1-Iminoethyl)-L-ornithine (L-NIO, 5) is a natural product known to inactivate NOS, but the mechanism of inactivation is unknown. Upon incubation of iNOS with L-NIO a type I binding difference spectrum is observed, indicating that binding at the substrate binding site occurs. L-NIO is shown to be a time-dependent, concentration-dependent, and NADPH-dependent irreversible inhibitor of iNOS with K-I and k(inact) values of 13.7 +/- 1.6 mu M and 0.073 +/- 0.003 min(-1), respectively. During inactivation the heme chromophore is partially lost (Figure 1); HPLC shows that the loss corresponds to about 50% of the heme. Inclusion of catalase during incubation does not prevent heme loss. N-5-(1-Imino-2-[C-14]ethyl)-L-ornithine (11) inactivates iNOS, but upon dialysis or gel filtration, no radioactivity remains bound to the protein or to a cofactor. The only radioactive product detected after enzyme inactivation is Nw-hydroxy-L-NIO (12); no C-omega-hydroxy-L-NIO (13) or N-delta-acetyl-L-ornithine (14) is observed (Figure 2). The amount of 12 produced during the inactivation process is 7.7 +/- 0.2 equiv per inactivation event. Incubations of 12 with iNOS show time-, concentration-, and NADPH-dependent inactivation that is not reversible upon dilution into the assay solution. Incubations that include an excess of L-arginine or with substitution of NADP(+) for NADPH result in no significant loss of enzyme activity. The K-I and k(inact) values for 12 an 830 +/- 160 mu M and 0.0073 +/- 0.0007 min(-1), respectively. The magnitude of these kinetic constants (compared with those of 5) suggest that 12 is not an intermediate of L-NIO inactivation of iNOS. Compound 12 also is a substrate for iNOS, exhibiting saturation kinetics with K-m and k(cat) values of 800 +/- 85 mu M and 2.22 min(-1), respectively; the product is shown to be N-delta-acetyl-L-ornithine (14) (Figure 3). The k(cat) and k(inact) values for 12 can be compared directly to give a partition ratio (k(cat)/k(inact)) for inactivation of 304; i.e., there are 304 turnovers to give NO per inactivation event. This high partition ratio further supports the notion that 12 is not involved in L-NIO inactivation of iNOS. C-omega-Hydroxy-L-NIO (13) is not an inactivator of iNOS. These results suggest that L-NIO inactivation occurs after an oxidation step (NADPH is required for inactivation) but prior to a hydroxylation step (12 and 13 are not involved). Inactivation of iNOS by N-5-(1-imino-2-[H-2(3)]-ethyl)-L-ornithine (15) exhibits a kinetic isotope effect on (H)k(inact)/(D)k(inact) of 1.35 +/- 0.08 and on H(k(inact)/K-I)/(D)(k(inact)/K-I) of 1.51 +/- 0.3, suggesting that the methyl C-H bond is cleaved in a partially rate-determining step prior to hydroxylation, and that leads to inactivation.A new NADPH-dependent 400 nm peak in the HPLC of L-NIO-inactivated iNOS is produced (Figure 4). LC-electrospray mass spectrometry (Figure 5) demonstrates the mit of the new metabolite to be 583, which is shown to correspond to biliverdin (23) (Figures 6 and 7). Two possible mechanisms for the formation of biliverdin during inactivation are proposed (Schemes 10 and 11). When 14 is incubated with iNOS, time-, concentration-, and NADPH-dependent loss of enzyme activity is observed (K-I and k(inact) values are 490 mM and 0.24 min(-1), respectively); iNOS inactivation by 14 can be prevented by inclusion of L-arginine, but not D-arginine, in the inactivation mixtures, suggesting that the inactivator acts at the arginine binding site. However, 14 is not produced from L-NIO (Figure 2) and, therefore, is not involved in L-NIO inactivation.
• Hayes, Roger N.; Paltridge, R. Lee; Bowie, John H., Journal of the Chemical Society. Perkin transactions II, 1985, p. 567 - 572
  作者：Hayes, Roger N.、Paltridge, R. Lee、Bowie, John H.

  DOI：——

  日期：——
• Miyano, Masateru; Smith, Jeffrey N., Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 659 - 661
  作者：Miyano, Masateru、Smith, Jeffrey N.

  DOI：——

  日期：——
• Mechanism of Inactivation of Inducible Nitric Oxide Synthase by Amidines. Irreversible Enzyme Inactivation without Inactivator Modification
  作者：Yaoqiu Zhu、Dejan Nikolic、Richard B. Van Breemen、Richard B. Silverman

  DOI：10.1021/ja0445645

  日期：2005.1.1

  Nitric oxide synthases (NOS) are hemoproteins that catalyze the reaction Of L-arginine to L-Citrulline and nitric oxide. N-(3-(Aminomethyl)benzyl)acetamidine (1400W) was reported to be a slow, tight-binding, and highly selective inhibitor of iNOS in vitro and in vivo. Previous mechanistic studies reported that 1400W was recovered quantitatively after iNOS fully lost its activity and modification to iNOS was not detected. Here, it is shown that 1400W is a time-, concentration-, and NADPH-dependent irreversible inactivator of iNOS. HPLC-electrospray mass spectrometric analysis of the incubation mixture of iNOS with 1400W shows both loss of heme cofactor and formation of bilivedin, as was previously observed for iNOS inactivation by another amidine-containing compound, N-5(1-iminoethyl)-L-ornithine (L-NIO). The amount of biliverdin produced corresponds to the amount of heme lost by 1400W inactivation of iNOS. A convenient MS/MS-HPLC methodology was developed to identify the trace amount of biliverdin produced by inactivation of iNOS with either 1400W or L-NIO to be biliverdin \Xalpha out of the four possible regioisomers. Two mechanisms were previously proposed for iNOS inactivation by L-NIO: (1) uncoupling of the heme peroxide intermediate, leading to destruction of the heme to biliverdin; (2) abstraction of a hydrogen atom from the amidine methyl group followed by attachment to the heme cofactor, which causes the enzyme to catalyze the heme oxygenase reaction. The second mechanistic proposal was ruled out by inactivation of iNOS with d(3)-1400W, which produced no d(2)-1400W. Detection of carbon monoxide as one of the heme-degradation products further excludes the covalent heme adduct mechanism. On the basis of these results, a third mechanism is proposed in which the amidine inactivators of iNOS bind as does substrate L-arginine, but because of the amidine methyl group, the heme peroxy intermediate cannot be protonated, thereby preventing its conversion to the heme oxo intermediate. This leads to a change in the enzyme mechanism to one that resembles that of heme oxygenase, an enzyme known to convert heme to biliverdin \Xalpha.. This appears to be the first example of a compound that causes irreversible inactivation of an enzyme without itself becoming modified in any way.