4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide | 71125-38-7

• 物质功能分类: 原料药 - 解热镇痛药 - 非甾抗炎药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide
• 英文别名: meloxicam；4-hydroxy-N-(5-methyl-1,3-thiazol-2-yl)-1,1-dioxo-2H-1λ6,2-benzothiazine-3-carboxamide
• CAS: 71125-38-7
• 化学式: C₁₃H₁₁N₃O₄S₂
• 分子量: 337.38
• InChiKey: INYLJXGSWGWXFU-UHFFFAOYSA-N

物化性质

• 熔点：
  255 °C
• 密度：
  1.613±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  7

安全信息

• 危险等级：
  6.1
• 危险品标志：
  Xn
• 安全说明：
  S26
• 危险类别码：
  R22
• WGK Germany：
  2,3
• 海关编码：
  2934999090
• 危险品运输编号：
  UN 2811 6.1/PG 3
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P501,P270,P264,P301+P310+P330,P405
• 危险性描述：
  H301

制备方法与用途

美洛昔康是一种非甾体抗炎药(NSAID)，主要用于治疗类风湿性关节炎、风湿性关节炎、骨关节炎和软组织损伤疼痛等。

药理作用

1. 选择性COX-2抑制：美洛昔康是环氧合酶(COX) - 2的选择性抑制剂。COX是一种催化前列腺素合成的酶，而前列腺素具有抗炎、止痛及发热的作用。
2. 减少炎症反应和疼痛感：通过抑制COX-2活性，减少了炎症介质（如前列腺素）的产生，从而减轻了炎症反应和疼痛。

药动学

1. 吸收与分布：口服后在胃肠道中迅速被吸收，并广泛分布于全身组织。
2. 代谢：主要通过肝脏进行代谢，少量经肾脏排泄。
3. 消除半衰期：大约4-6小时左右。

用途

主要用于缓解成人和15岁及以上青少年的骨关节炎、类风湿性关节炎引起的疼痛以及炎症。此外，也适用于治疗急性疼痛、手术后疼痛等。

不良反应

常见的副作用包括消化不良、腹痛、恶心、腹泻、头晕、头痛及皮疹等。较为罕见但严重的不良事件有肝功能异常、肾损伤（包括急性肾衰竭）、胃肠道溃疡或穿孔、血细胞减少症、过敏性休克等。

注意事项

1. 禁忌人群：对非甾体抗炎药过敏者、消化性溃疡病史患者、严重肝脏疾病患者以及妊娠及哺乳期妇女禁用。
2. 慎用人群：患有高血压或心脏病的老年人群需谨慎使用。
3. 监测指标：长期用药时应定期检查肝肾功能。

药物相互作用

• 与口服抗凝剂合用可能增加出血风险；
• 与锂盐、甲氨蝶呤等合用时需注意调整剂量或密切观察药物浓度变化；
• 可减弱降糖药和抗高血压药物的效果，影响其临床效果。

化学性质

• 熔点：约254℃（分解）
• 酸碱度：在水中的pKa值约为4.08，在不同比例的水-乙醇混合溶剂中有所变化
• 急性毒性测试显示对小鼠和大鼠口服致死剂量分别为470毫克/公斤

生产方法

美洛昔康可通过如下合成路线制备：从二氯甲烷结晶获得纯品，收率为74%。

应急措施与储存条件

• 存储于低温、通风且干燥的地方；
• 远离食品原料和其他非危险化学品存放；
• 由专门机构保管以确保安全。

反应信息

• 作为反应物：
  描述：

  碘乙烷 、 4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 在 silica gel 、 chloroform ethanol 作用下， 以 甲醇 、 sodium hydroxide 为溶剂， 反应 24.0h， 以yielding 0.35 mgm (48% of theory) of 2-ethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide的产率得到2-ethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide
  参考文献：
  名称：

  4-Hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides and salts

  摘要：

  该公式化合物的化学式为##STR1##其中R.sub.1是氢、甲基或乙基；R.sub.2是甲基、乙基或正丙基；Y是氢、甲基、甲氧基、氟或氯；以及与无机或有机碱形成的无毒、药理学上可接受的盐。这些化合物及其盐在抗炎方面有用。

  公开号：

  US04233299A1
• 作为产物：
  描述：

  2,3-二氢-3-氧代-1,2-苯并异噻唑-2-乙酸甲酯1,1-二氧化物 在 甲醇 、 sodium methylate 作用下， 以 甲苯 、 xylene 为溶剂， 反应 52.0h， 生成 4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide
  参考文献：
  名称：

  Effect of Structural Modification of Enol−Carboxamide-Type Nonsteroidal Antiinflammatory Drugs on COX-2/COX-1 Selectivity

  摘要：

  Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothiazines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.

  DOI：

  10.1021/jm9607010

文献信息

• Topical gels compositions
  申请人：Spann-Wade Monique

  公开号：US20070053984A1

  公开（公告）日：2007-03-08

  Topical alcoholic gel compositions are disclosed that are useful for delivering therapeutic levels of an NSAID to target in and below the skin. The compositions comprise a topically active drug, an alcoholic solvent, a polymeric thickener, and optionally a keratolytic agent. In one embodiment, excellent viscosity for dermal application is attained without the need of a step for neutralizing the pH of the composition. Alcoholic and alcohol-free topical compositions comprising an NSAID prodrug are also disclosed. The compositions are particularly useful for the treatment of pseudofolliculitis barbae.
• Topical Compositions
  申请人：Spann-Wade Monique

  公开号：US20080317684A1

  公开（公告）日：2008-12-25

  Topical compositions are disclosed that are useful for delivering a therapeutic level of an NSAID to a target within a subject having a local inflammatory disorder. A composition of the present invention comprises a Drug and a solvent system, wherein the solvent system comprises at least two solvent alcohols and wherein the solvent system is present in an amount sufficient to solubilize the Drug, the solvent system is a low alkanol system, and the composition is a single phase composition. Exemplary solvent systems are those for which one of the at least two solvent alcohols is polyethylene glycol, glycerin, butylene glycol, dipropylene glycol, propylene glycol, ethanol, isopropanol, or a derivative thereof. Optionally the local inflammatory disorder is pseudofolliculitis barbae, dermatitis, psoriasis, wounds, or sunburn.
• Topical Gel Compositions
  申请人：Spann-Wade Monique

  公开号：US20100158993A1

  公开（公告）日：2010-06-24

  Topical alcoholic gel compositions are disclosed that are useful for delivering therapeutic levels of an NSAID to target in and below the skin. The compositions comprise a topically active drug, an alcoholic solvent, a polymeric thickener, and optionally a keratolytic agent. In one embodiment, excellent viscosity for dermal application is attained without the need of a step for neutralizing the pH of the composition. Alcoholic and alcohol-free topical compositions comprising an NSAID prodrug are also disclosed. The compositions are particularly useful for the treatment of pseudofolliculitis barbae.
• Topical Composition
  申请人：Spann-Wade Monique

  公开号：US20110217248A1

  公开（公告）日：2011-09-08

  Topical compositions are disclosed that are useful for delivering a therapeutic level of an NSAID to a target within a subject having a local inflammatory disorder. A composition of the present invention comprises a Drug and a solvent system, wherein the solvent system comprises at least two solvent alcohols and wherein the solvent system is present in an amount sufficient to solubilize the Drug, the solvent system is a low alkanol system, and the composition is a single phase composition. Examplary solvent systems are those for which one of the at least two solvent alcohols is polyethylene glycol, glycerin, butylene glycol, diproylene glycol, propylene glycol, ethanol, isopropanol, or a derivative therof. Optionally the local inflammatory disorder is pseudofolliculitis barbae, dermatitis, psoriasis, wounds, or sunburn.
• TOPICAL COMPOSITIONS
  申请人：GREEN Monique Renata

  公开号：US20130243707A1

  公开（公告）日：2013-09-19

  Topical compositions are disclosed that are useful for delivering a therapeutic level of an NSAID to a target within a subject having a local inflammatory disorder. A composition of the present invention comprises a Drug and a solvent system, wherein the solvent system comprises at least two solvent alcohols and wherein the solvent system is present in an amount sufficient to solubilize the Drug, the solvent system is a low alkanol system, and the composition is a single phase composition. Exemplary solvent systems are those for which one of the at least two solvent alcohols is polyethylene glycol, glycerin, butylene glycol, diproylene glycol, propylene glycol, ethanol, isopropanol, or a derivative thereof. Optionally the local inflammatory disorder is pseudofolliculitis barbae, dermatitis, psoriasis, wounds, or sunburn.