(1-甲基-1H-咪唑-4-基)-乙酸 | 2625-49-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: (1-甲基-1H-咪唑-4-基)-乙酸
• 中文别名: 2-(1-甲基-1H-咪唑-4-基)乙酸
• 英文名称: methylimidazoleacetic acid
• 英文别名: 1-methyl-4-imidazoleacetic acid；2-(1-methyl-1H-imidazol-4-yl)acetic acid；2-(1-methylimidazol-4-yl)acetic acid
• CAS: 2625-49-2
• 化学式: C₆H₈N₂O₂
• 分子量: 140.142
• InChiKey: ZHCKPJGJQOPTLB-UHFFFAOYSA-N

物化性质

• 熔点：
  187-189 °C
• 沸点：
  384.4±17.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)
• 物理描述：
  Solid
• 颜色/状态：
  Crystalline solid
• 溶解度：
  In water, 1.91X10+5 mg/L at 25 °C (est)
• 蒸汽压力：
  6.54X10-5 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  10
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

在哺乳动物大脑中，组胺被认为仅通过组胺甲基转移酶（HMT）进行代谢，形成远端甲基组胺（t-MH），然后形成远端甲基咪唑乙酸（t-MIAA）。我们之前已经表明，咪唑乙酸（IAA），一种GABA激动剂，以及组胺在外周的代谢物，在大脑中存在，其浓度在HMT被抑制后增加。此外，当向大鼠脑室内注入[3H]组胺时，一部分会转化为IAA，这一过程在HMT被抑制后增加。这些结果表明大脑具有氧化组胺的能力，但没有显示这一途径在生理条件下是否发挥作用。为了解决这个问题，大鼠被连续输注了超过4周的alpha-氟甲基组胺（alpha-FMHis），这是组胺合成酶L-组氨酸脱羧酶的不可逆抑制剂。与对照组（未处理和生理盐水处理的大鼠）相比，处理组大鼠所有区域的大脑组胺、t-MH和t-MIAA水平显著降低。作为对照组的百分比，所有区域的t-MIAA耗尽>t-MH>组胺，且组胺的区域性耗尽与其在大鼠大脑区域的周转率相一致。相比之下，IAA的水平没有变化，与组胺代谢无关的t-MIAA异构体前甲基咪唑乙酸的水平也没有变化。结果表明，在大鼠的大脑中，与外周不同，大多数IAA可能通常不是来自组胺。因为大脑中的组胺在某些条件下可以转化为IAA，直接氧化组胺可能是一种有条件的现象。我们的结果也支持大脑中存在一个非常缓慢的周转组胺池，以及使用慢性alpha-FMHis输注作为研究大脑组胺能系统的模型。

In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), forming tele-methylhistamine (t-MH), then tele-methylimidazoleacetic acid (t-MIAA). We previously showed that imidazoleacetic acid (IAA), a GABA agonist, and histamine's metabolite in the periphery, is present in brain where its concentration increased after inhibition of HMT. Also, when [3H]histamine was given intracerebro-ventricularly to rats, a portion was converted to IAA, a process increased by inhibition of HMT. These results indicated that brain has the capacity to oxidize histamine but did not show whether this pathway is operative under physiological conditions. To address this question, rats were infused for > 4 weeks with alpha-fluoromethylhistidine (alpha-FMHis), an irreversible inhibitor of histamine's synthetic enzyme, L-histidine decarboxylase. Compared with controls (untreated and saline-treated rats), brain levels of histamine, t-MH, and t-MIAA in all regions were markedly reduced in treated rats. As a percentage of controls, depletion of t-MIAA > t-MH > histamine in all regions, and regional depletions of histamine co-responded to its turnover rates in regions of rat brain. In contrast, levels of IAA were unchanged as were levels of pros-methylimidazoleacetic acid, an isomer of t-MIAA unrelated to histamine metabolism. Results suggest that in brains of rats, unlike in the periphery, most IAA may not normally derive from histamine. Because histamine in brain can be converted to IAA under certain conditions, direct oxidation of histamine may be a conditional phenomenon. Our results also support the existence of a very slow turnover pool of brain histamine and use of chronic alpha-FMHis infusion as a model to probe the histaminergic system in brain.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：甲基咪唑乙酸是组胺的尿液代谢物和组胺代谢的最终产物。人体研究：无数据可用。动物研究：无数据可用。

IDENTIFICATION AND USE: Methylimidazoleacetic acid is a urinary metabolite of histamine and end-product of histamine metabolism. HUMAN STUDIES: There are no data available. ANIMAL STUDIES: There are no data available.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球阀口罩装置或口袋口罩，按培训操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者向前倾或放在左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒药A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽插管以控制气道。使用带气囊的面罩进行正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注5%葡萄糖水（D5W），保持通路开放，最低流量/ SRP: "To keep open", minimal flow rate /. 如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用安定（地西泮）或劳拉西泮（阿蒂万）治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒素A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

AIM：研究组胺脱羧酶（HDC）在正常和肿瘤性胃神经内分泌细胞中的表达，以及其与主要组胺代谢物之间的关系。方法：对6例接受胃腺癌手术的患者正常组织（包括基底部粘膜3例和体部粘膜3例）以及64例原发性胃神经内分泌肿瘤（GNETs）患者的活检和/或胃手术标本进行研究，同时还包括其中22例患者的转移灶。研究采用常规免疫组化方法和双免疫荧光法，使用商业抗体对囊泡单胺转运蛋白2（VMAT-2）、HDC和生长激素释放肽进行检测。在64名患者中的27名患者中，使用高效液相色谱法测定主要组胺代谢物甲基咪唑乙酸（U-MeImAA）的尿排泄量。结果：在正常组织的胃粘膜中，共定位研究表明神经内分泌细胞仅对VMAT-2或仅对HDC有免疫反应性。第三种细胞群体同时表达这两种抗原。HDC和生长激素释放肽没有共表达。在与慢性萎缩性胃炎A型相关的神经内分泌细胞增生灶中，以及肿瘤中，得到了相似的结果。在使用常规免疫组化方法检查的肿瘤中，这三种前述标记的相对发生率不同。所有这些GNETs都显示出VMAT-2和HDC的免疫反应性，它们的转移灶显示出与原发肿瘤相似的免疫组化模式和频率。在4名患者中检测到U-MeImAA排泄量增加，但只有2名患者表现出相关的内分泌症状。结论：人类的肠嗜铬样细胞似乎部分共表达VMAT-2和HDC。VMAT-2和HDC的共表达可能是在GNETs患者中增加组胺生产所需的。

AIM: To study histidine decarboxylase (HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite. METHODS: Control tissues from fundus (n = 3) and corpus (n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours (GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2 (VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid (U-MeImAA) was determined using high-performance liquid chromatography in 27 of the 64 patients. RESULTS: In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cell population co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumors. The relative incidence of the three aforementioned markers varied in the tumors that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumors. In four patients, increased U-MeImAA excretion was detected, but only two of the patients exhibited related endocrine symptoms. CONCLUSION: Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

与其他胺类递质代谢物类似，大脑中的组胺代谢物，即tele-methylhistamine (t-MH) 和 tele-methylimidazoleacetic acid (t-MIAA)，在脑脊液（CSF）的头端和尾端之间可能存在浓度梯度。为了检验这个假设，从八只猴子（Macaca mulatta）中成对收集了枕骨和腰椎CSF样本，并通过气相色谱-质谱法测量了t-MH和t-MIAA的水平。还测量了pros-Methylimidazoleacetic acid (p-MIAA)，它是t-MIAA的内生同分异构体，但不是组胺代谢物。在每只猴子中，枕骨水平（以皮摩尔每毫升计，平均值+/-标准误）的t-MH（9.9 +/- 1.4）和t-MIAA（40.8 +/- 7.6）超过了腰椎CSF中的水平（t-MH，1.8 +/- 0.3；t-MIAA，6.8 +/- 0.9；p-MIAA，9.7 +/- 1.2），而p-MIAA（9.7 +/- 1.2）的水平则没有。t-MH（6.6 +/- 1.1）和t-MIAA（6.5 +/- 1.3）的平均枕骨-腰椎浓度梯度的幅度是相同的。这些梯度超过了大多数其他递质代谢物的梯度。p-MIAA的水平没有梯度。枕骨中的t-MH和t-MIAA水平相关，而腰椎中的水平则不相关。枕骨（4.0 +/- 0.4）和腰椎（4.4 +/- 0.9）CSF中代谢物浓度比（t-MIAA/t-MH）的平均值之间没有显著差异。这些梯度的陡度表明，腰椎CSF中的t-MH和t-MIAA水平可能是有用的探针，用于检测大脑中的组胺代谢。

Similar to metabolites of other aminergic transmitters, histamine metabolites of brain, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), could have a concentration gradient between rostral and caudal sites of CSF. To test this hypothesis, cisternal and lumbar CSF samples were collected in pairs from eight monkeys (Macaca mulatta), and levels of t-MH and t-MIAA were measured by gas chromatography-mass spectrometry. pros-Methylimidazoleacetic acid (p-MIAA), an endogenous isomer of t-MIAA that is not a histamine metabolite, was also measured. Cisternal levels (in picomoles per milliliter, mean +/- SEM) of t-MH (9.9 +/- 1.4) and t-MIAA (40.8 +/- 7.6), but not of p-MIAA (9.7 +/- 1.2), exceeded those in lumbar CSF (t-MH, 1.8 +/- 0.3; t-MIAA, 6.8 +/- 0.9; p-MIAA, 8.6 +/- 0.6) in every monkey. The magnitudes of the mean cisternal-lumbar concentration gradients for t-MH (6.6 +/- 1.1) and t-MIAA (6.5 +/- 1.3) were indistinguishable. These gradients exceed those of metabolites of most other transmitters. There was no gradient for the levels of p-MIAA. The cisternal, but not lumbar, levels of t-MH and t-MIAA were correlated. There was no significant difference between the means of the metabolite concentration ratios (t-MIAA/t-MH) in cisternal (4.0 +/- 0.4) and lumbar (4.4 +/- 0.9) CSF. The steepness of these gradients suggests that levels of t-MH and t-MIAA in lumbar CSF might be useful probes of histaminergic metabolism in brain.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

tele-甲基咪唑乙酸(t-MIAA)，一种主要的大脑组胺代谢物，通过一种同时测量前体胺tele-甲基组胺(t-MH)的气相色谱-质谱法在九个大鼠脑区进行了测量。小脑、延髓-桥脑、中脑、尾状核、下丘脑、额叶皮层、海马和丘脑的t-MIAA浓度变化了15倍，下丘脑显示最高水平(2.21 nmol/g)，小脑最低(0.15 nmol/g)。除中脑外，所有区域的t-MIAA和t-MH浓度显著相关，中脑的t-MIAA相对较多。丙磺舒并未改变全脑t-MIAA水平。用单胺氧化酶抑制剂帕吉林治疗后，所有区域的t-MIAA水平降低。

tele-Methylimidazoleacetic acid (t-MIAA), a major brain histamine metabolite, was measured in nine rat brain regions by a gas chromatography-mass spectrometric method that also measures the precursor amine, tele-methylhistamine (t-MH). The t-MIAA concentration of cerebellum, medulla-pons, midbrain, caudate nucleus, hypothalamus, frontal cortex, hippocampus, and thalamus varied 15-fold, hypothalamus showing the highest level (2.21 nmol/g) and cerebellum the lowest (0.15 nmol/g). The concentrations of t-MIAA and t-MH were significantly correlated in all regions except midbrain, which had relatively more t-MIAA. Probenecid did not alter whole-brain t-MIAA levels. Treatment with pargyline, an inhibitor of monoamine oxidase, lowered the t-MIAA levels in all regions.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933290090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8°C，干燥

反应信息

• 作为反应物：
  描述：

  (1-甲基-1H-咪唑-4-基)-乙酸 、 2-Amino-5-cyanobenzophenon 在 三氯氧磷 作用下， 生成 2-Chloro-3-(1-methylimidazol-4-yl)-4-phenylquinoline-6-carbonitrile
  参考文献：
  名称：

  Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors

  摘要：

  A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4yl)-2-quinolone-6-carbonitrile 21b, has an IC50 of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.01.088
• 作为产物：
  描述：

  alkaline earth salt of/the/ methylsulfuric acid 在 sodium hydroxide 作用下， 生成 (1-甲基-1H-咪唑-4-基)-乙酸
  参考文献：
  名称：

  Pyman, Journal of the Chemical Society, 1911, vol. 99, p. 2181

  摘要：

  DOI：

文献信息

• Alpha2C adrenoreceptor agonists
  申请人：McCormick D. Kevin

  公开号：US20070093477A1

  公开（公告）日：2007-04-26

  In its many embodiments, the present invention relates to a novel class of phenylmorpholine and phenylthiomorpholine compounds useful as α2C adrenergic receptor agonists, pharmaceutical compositions containing the compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the α2C adrenergic receptor agonists using such compounds or pharmaceutical compositions.

  在其多种实施形式中，本发明涉及一类新型的苯基吗啡啶和苯基硫代吗啡啶化合物，这些化合物可用作α2C肾上腺素受体激动剂，包含这些化合物的药物组合物，以及使用这些化合物或药物组合物治疗、预防、抑制或改善与α2C肾上腺素受体激动剂相关的一种或多种疾病的方法。
• [EN] INHIBITORS OF APOL1 AND USE OF THE SAME<br/>[FR] INHIBITEURS D'APOL1 ET LEUR UTILISATION
  申请人：VERTEX PHARMA

  公开号：WO2021252859A1

  公开（公告）日：2021-12-16

  The disclosure provides at least one compound, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of formula (I), deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, compositions comprising the same, and methods of making and using the same, including use in treating APOL1 mediated kidney disease.

  本公开提供了至少一种化合物、重氢化衍生物或药用可接受的盐，选自公式(I)化合物、其重氢化衍生物以及任何前述物质的药用可接受的盐，包含同一的组成物，以及制造和使用同一的方法，包括用于治疗APOL1介导的肾脏疾病。
• SYNERGISTIC MODULATION OF FLT3 KINASE USING A FLT3 INHIBITOR AND A FARNESYL TRANSFERASE INHIBITOR
  申请人：Baumann Andrew Christian

  公开号：US20060281788A1

  公开（公告）日：2006-12-14

  The invention is directed to a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a farnesyl transferase inhibitor and a FLT3 kinase inhibitor selected from compounds of Formula I′: Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3.

  本发明涉及一种抑制FLT3酪氨酸激酶活性或表达或减少细胞或受试者中FLT3激酶活性或表达的方法，包括管理法尼基转移酶抑制剂和从公式I'的化合物中选择的FLT3激酶抑制剂。 本发明包括用于治疗处于发展细胞增殖障碍或与FLT3相关障碍风险（或易感性）的受试者的预防和治疗方法。
• METHOD OF INHIBITING C-KIT KINASE
  申请人：Illig R. Carl

  公开号：US20080051402A1

  公开（公告）日：2008-02-28

  A method of reducing or inhibiting kinase activity of C-KIT in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to C-KIT using a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. The present invention is further directed to methods for treating conditions such as cancers and other cell proliferative disorders.

  本发明提供了一种减少或抑制细胞或主体中C-KIT激酶活性的方法，以及使用本发明的化合物预防或治疗主体中的细胞增殖障碍和/或与C-KIT相关疾病的应用：或其溶剂化物、水合物、互变异构体或药用可接受盐。本发明进一步涉及治疗癌症和其他细胞增殖障碍等条件的方法。
• Inhibitors of protein isoprenyl transferases
  申请人：University of Pittsburgh

  公开号：US20020193596A1

  公开（公告）日：2002-12-19

  Compounds having the formula 1 or a pharmaceutically acceptable salt thereof wherein R 1 is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L 2 —, and (i) heterocyclic-L 2 —; R 2 is selected from (a) 2 (b) —C(O)NH—CH(R 14 )—C(O)OR 15 , (c) 3 (d) —C(O)NH—CH(R 14 )—C(O)NHSO 2 R 16 (e) —C(O)NH—CH(R 14 )-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R 14 )—C(O)NR 17 R 18 ; R 3 is heterocyclic, aryl, substituted or unsubstituted cycloalkyl; R 4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L 1 is absent or is selected from (a) —L 4 —N(R 5 )—L 5 —, (b) —L 4 —O—L 5 —, (c) —L 4 —S(O) n —L 5 — (d) —L 4 -L 6 —C(W)—N(R 5 )—L 5 —, (e) —L 4 -L 6 —S(O) m —N(R 5 )—L 5 —, (f) —L 4 —N(R 5 )—C(W)—L 7 -L 5 —, (g) —L 4 —N(R 5 )—S(O) p —L 7 —L 5 —, (h) optionally substituted alkylene, (i) optionally substituted alkenylene, and (j) optionally substituted alkynylene are inhibitors of protein isoprenyl transferases. Also disclosed are protein isoprenyl transferase inhibiting compositions and a method of inhibiting protein isoprenyl transferases.

  具有以下公式的化合物或其药学上可接受的盐，其中R1为(a)氢，(b)较低的烷基，(c)烯基，(d)烷氧基，(e)硫代烷氧基，(f)卤素，(g)卤代烷基，(h)芳基-L2—，以及(i)杂环-L2—；R2从(a)中选择，(b) -C(O)NH-CH(R14)-C(O)OR15，(c)中选择，(d) -C(O)NH-CH(R14)-C(O)NHSO2R16，(e) -C(O)NH-CH(R14)-四唑基，(f) -C(O)NH-杂环，以及(g) -C(O)NH-CH(R14)-C(O)NR17R18；R3为杂环，芳基，取代或未取代的环烷基；R4为氢，较低烷基，卤代烷基，卤素，芳基，芳基烷基，杂环基，或(杂环)烷基；L1为空缺或从(a) -L4-N(R5)-L5-，(b) -L4-O-L5-，(c) -L4-S(O)n-L5-，(d) -L4-L6-C(W)-N(R5)-L5-，(e) -L4-L6-S(O)m-N(R5)-L5-，(f) -L4-N(R5)-C(W)-L7-L5-，(g) -L4-N(R5)-S(O)p-L7-L5-，(h)可选择取代的烷基，(i)可选择取代的烯基，以及(j)可选择取代的炔基是蛋白异戊二烯转移酶的抑制剂。还公开了蛋白异戊二烯转移酶抑制组合物和抑制蛋白异戊二烯转移酶的方法。