N-{4-[3-(4-tert-Butyl-benzyl)-thioureidomethyl]-phenyl}-methanesulfonamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-{4-[3-(4-tert-Butyl-benzyl)-thioureidomethyl]-phenyl}-methanesulfonamide
• 英文别名: MK 0056；MK-056；1-(4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl) thiourea；1-(4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea；3-[(4-Tert-butylphenyl)methyl]-1-[(4-methanesulfonamidophenyl)methyl]thiourea；1-[(4-tert-butylphenyl)methyl]-3-[[4-(methanesulfonamido)phenyl]methyl]thiourea
• 化学式: C₂₀H₂₇N₃O₂S₂
• 分子量: 405.585
• InChiKey: LOMAEJPLJSUBML-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-硝基苄胺 在 palladium on activated charcoal 吡啶 、 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 N-{4-[3-(4-tert-Butyl-benzyl)-thioureidomethyl]-phenyl}-methanesulfonamide
  参考文献：
  名称：

  N-4-Substituted-benzyl-N′-tert-butylbenzyl thioureas as vanilloid receptor ligands: investigation on the role of methanesulfonamido group in antagonistic activity

  摘要：

  A series of N-4-substituted-benzyl-N'-tert-butylbenzyl thioureas were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor in rat DRG neurons. Their structure-activity relationship reveals that not only the two oxygens and amide hydrogen of sulfonamido group, but also the optimal size of methyl in methanesulfonamido group play an integral role for the antagonistic activity on vanilloid receptor. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.11.019

文献信息

• High Affinity Antagonists of the Vanilloid Receptor
  作者：Yun Wang、Tamas Szabo、Jacqueline D. Welter、Attila Toth、Richard Tran、Jiyoun Lee、Sang Uk Kang、Young-Ger Suh、Peter M. Blumberg、Jeewoo Lee

  DOI：10.1124/mol.62.4.947

  日期：2002.10.1

  The vanilloid receptor VR1 has attracted great interest as a sensory transducer for capsaicin, protons, and heat, and as a therapeutic target. Here we characterize two novel VR1 antagonists, KJM429 [ N -(4- tert -butylbenzyl)- N ′-[4-(methylsulfonylamino)benzyl]thiourea] and JYL1421 [ N -(4- tert -butylbenzyl)- N ′-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea], with enhanced activity compared with capsazepine on rat VR1 expressed in Chinese hamster ovary (CHO) cells. JYL1421, the more potent of the two novel antagonists, inhibited [3H]resiniferatoxin binding to rVR1 with an affinity of 53.5 ± 6.5 nM and antagonized capsaicin-induced calcium uptake with an EC50 of 9.2 ± 1.6 nM, reflecting 25- and 60-fold greater potencies than capsazepine. Both JYL1421 and KJM429 antagonized RTX as well as capsaicin and their mechanism was competitive. The responses to JYL1421 and KJM429 differed for calcium uptake by rVR1 induced by heat or pH. JYL1421 antagonized the response to both pH 6.0 and 5.5, whereas KJM429 antagonized at pH 6.0 but was an agonist at lower pH (<5.5). For heat, JYL1421 fully antagonized and KJM429 partially antagonized. Capsazepine showed only weak antagonism for both pH and heat. Responses of rVR1 to different activators could thus be differentially affected by different ligands. In cultured dorsal root ganglion neurons, JYL1421 and KJM429 likewise behaved as antagonists for capsaicin, confirming that the antagonism is not limited to heterologous expression systems. Finally, JYL1421 and KJM429 had little or no effect on ATP-induced calcium uptake in CHO cells lacking rVR1, unlike capsazepine. We conclude that JYL1421 is a competitive antagonist of rVR1, blocking response to all three of the agonists (capsaicin, heat, and protons) with enhanced potency relative to capsazepine.

  香草素受体VR1因其作为辣椒素、质子和热的传感转换器以及作为治疗靶点而引起了极大的兴趣。在这里，我们描述了两种新的VR1拮抗剂，KJM429[N-(4-叔丁基苄基)-N′-[4-(甲磺酰氨基)苄基]硫脲]和JYL1421[N-(4-叔丁基苄基)-N′-[3-氟-4-(甲磺酰氨基)苄基]硫脲]，它们在大鼠VR1在中国仓鼠卵巢(CHO)细胞中表达时，活性比capsazepine更强。在这两种新型拮抗剂中，JYL1421的活性更强，它抑制[3H]树脂毒素与rVR1的结合，亲和力为53.5±6.5 nM，并拮抗辣椒素诱导的钙吸收，EC50为9.2±1.6 nM，反映出比capsazepine强25倍和60倍的效力。JYL1421和KJM429均能拮抗RTX和辣椒素，其机制为竞争性。JYL1421和KJM429在钙吸收上的反应不同，前者对热或pH诱导的rVR1反应产生拮抗或激动作用。JYL1421拮抗pH 6.0和5.5的反应，而KJM429在pH 6.0时拮抗，但在更低的pH(<5.5)时为激动剂。对于热刺激，JYL1421完全拮抗，而KJM429部分拮抗。Capsazepine对pH和热的拮抗作用很弱。因此，rVR1对不同激动剂的反应可以被不同的配体不同程度地影响。在培养的背根神经节神经元中，JYL1421和KJM429同样表现为辣椒素的拮抗剂，证实了这种拮抗作用不仅限于异源表达系统。最后，与capsazepine不同，JYL1421和KJM429对缺乏rVR1的CHO细胞中的ATP诱导的钙吸收几乎没有影响。我们得出结论，JYL1421是rVR1的竞争性拮抗剂，相对于capsazepine，它阻止了对所有三种激动剂(辣椒素、热和质子)的反应，并增强了效力。
• Novel thiourea derivatives and the pharmaceutical compositions containing the same
  申请人：——

  公开号：US20030153596A1

  公开（公告）日：2003-08-14

  The present invention relates to novel thiourca derivatives as a modulator for vanilloid receptor (VR) and the phar- maceutical compositions containing the same. As diseases associated with the activity of vanilloid receptor, pain acute pain, chronic pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, fervescence, stomach-duodenal ulcer, inflam- matory bowel disease and inflammatory diseases can be enumerated. The present invention provides a pharmaceutical composition for prevention or treatment of these diseases.

  本发明涉及一种新型硫脲衍生物，作为辣椒素受体（VR）的调节剂，以及含有该衍生物的药物组合物。作为与辣椒素受体活性相关的疾病，可以列举急性疼痛、慢性疼痛、神经痛、术后疼痛、偏头痛、关节痛、神经病变、神经损伤、糖尿病性神经病变、神经退行性疾病、神经性皮肤疾病、中风、膀胱过敏、肠易激综合征、哮喘或慢性阻塞性肺病等呼吸道疾病、皮肤、眼睛或黏膜刺激、发热、胃十二指肠溃疡、炎症性肠病和炎症性疾病。本发明提供了一种用于预防或治疗这些疾病的药物组合物。
• [EN] NOVEL THIOUREA DERIVATIVES AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME<br/>[FR] NOUVEAUX DERIVES DE THIOUREA ET COMPOSITIONS PHARMACEUTIQUES RENFERMANT CEUX-CI
  申请人：PACIFIC CORP

  公开号：WO2002016318A1

  公开（公告）日：2002-02-28

  The present invention relates to novel thiourea derivatives as a modulator for vanilloid receptor (VR) and the pharmaceutical compositions containing the same. As diseases associated with the activity of vanilloid receptor, pain acute pain, chronic pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel disease and inflammatory diseases can be enumerated. The present invention provides a pharmaceutical composition for prevention or treatment of these diseases.

  本发明涉及一种新型硫脲衍生物，作为vanilloid受体（VR）的调节剂以及含有该化合物的制药组合物。作为与vanilloid受体活性相关的疾病，可以列举急性疼痛、慢性疼痛、神经病性疼痛、术后疼痛、偏头痛、关节痛、神经病变、神经损伤、糖尿病神经病变、神经退行性疾病、神经性皮肤疾病、中风、膀胱过敏、肠易激综合症、哮喘或慢性阻塞性肺疾病、皮肤、眼或粘膜刺激、发热、胃十二指肠溃疡、炎症性肠病和炎症性疾病等。本发明提供了用于预防或治疗这些疾病的制药组合物。
• TRPV-1 RECEPTOR ANTAGONIST COMPOUND DERIVED FROM 1,3,4-THIADIAZOLE ALKYLAMIDES AND CHALCONES
  申请人：UNIVERSIDAD DE CONCEPCION

  公开号：US20160039778A1

  公开（公告）日：2016-02-11

  This technology encompasses compounds derived from 1,3,4-thiadiazole alkylamides and chalcone, which inhibit the activation of the TRPV-1 receptor using capsaicin and temperature. Also disclosed is the use of these compounds in the treatment of diseases with TRPV-1 overexpression, such as chronic pain.

  这项技术包括从1,3,4-噻二唑烷基酰胺和查尔酮中提取的化合物，这些化合物通过使用辣椒素和温度抑制TRPV-1受体的激活。此外，还披露了这些化合物在治疗TRPV-1过度表达的疾病，如慢性疼痛方面的用途。
• Novel non-vanilloid VR1 antagonist of high analgesic effects and its structural requirement for VR1 antagonistic effects
  作者：Young-Ger Suh、Yong-Sil Lee、Kyung-Hoon Min、Ok-Hui Park、Ho-Sun Seung、Hee-Doo Kim、Hyoung-Geun Park、Ji-Yeon Choi、Jeewoo Lee、Sang-Wook Kang、Uh-taek Oh、Jae-yeon Koo、Yung-Hyup Joo、Sun-Young Kim、Jin Kwan Kim、Young-Ho Park

  DOI：10.1016/j.bmcl.2003.09.024

  日期：2003.12

  A novel non-vanilloid VR1 antagonist consisting of a new vanilloid equivalent exhibits excellent analgesic effects as well as highly potent antagonistic activities in both capsaicin single channel and calcium uptake assays. In addition, the structural requirement for the vanilloid equivalent of the potent VR1 antagonist has also been elucidated. (C) 2003 Elsevier Ltd. All rights reserved.