茶碱 | 58-55-9

• 物质功能分类: 原料药 - 呼吸系统用药 - 平喘药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 茶碱
• 中文别名: 二氧二甲基嘌呤；1,3-二甲基黄嘌呤；无水茶碱；2,6-二氧-1,3-二甲基嘌呤；1,3-二甲基-3,7-二氢-1H-嘌呤-2,6-二酮
• 英文名称: theophylline
• 英文别名: 1,3-dimethylxanthine；1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione；1,3-dimethyl-7H-purine-2,6-dione
• CAS: 58-55-9
• 化学式: C₇H₈N₄O₂
• mdl: MFCD00079619
• 分子量: 180.166
• InChiKey: ZFXYFBGIUFBOJW-UHFFFAOYSA-N

物化性质

• 熔点：
  271-273 °C
• 沸点：
  312.97°C (rough estimate)
• 密度：
  1.3640 (rough estimate)
• 闪点：
  11 °C
• 溶解度：
  可溶于0.1MHCl
• LogP：
  -0.020
• 物理描述：
  Theophylline is an odorless white crystalline powder. Odorless. Bitter taste. (NTP, 1992)
• 颜色/状态：
  White, crystalline alkaloid
• 气味：
  Odorless
• 味道：
  Bitter
• 蒸汽压力：
  5.12X10-9 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 1.79X10-14 atm-cu m/mol at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• Caco2细胞的药物渗透性：
  -4.35
• 解离常数：
  8.81
• 碰撞截面：
  137.6 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]
• 保留指数：
  1900 ;1917 ;1917 ;1917 ;1904 ;1909 ;1923 ;1962 ;1947 ;1990 ;1948.2 ;1935 ;1962.7 ;1900 ;1921 ;1917 ;1917

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.285
• 拓扑面积：
  69.3
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

肝脏。生物转化通过去甲基化生成1-甲基黄嘌呤和3-甲基黄嘌呤，以及羟基化生成1,3-二甲基尿嘧啶酸。1-甲基黄嘌呤进一步被黄嘌呤氧化酶羟基化，生成1-甲基尿嘧啶酸。大约6%的可可碱剂量会N-甲基化成咖啡因。咖啡因和3-甲基黄嘌呤是唯一具有药理活性的可可碱代谢物。

Hepatic. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity.

来源:DrugBank

代谢

茶碱生物转化的N-去甲基化和羟基化途径都是受限于代谢能力的。由于茶碱代谢速率的个体间差异较大，一些患者在血清茶碱浓度低于10微克/毫升时，消除过程可能就开始出现非线性。由于这种非线性导致血清茶碱浓度随着剂量的变化出现不成比例的变化，因此建议在调整剂量时应该小幅度递增或递减，以便达到预期的血清茶碱浓度变化。在患者中准确预测茶碱代谢的剂量依赖性是不可能的，但是初始清除率非常高（即，在高于平均剂量时血清茶碱浓度较低）的患者最有可能在剂量变化时经历血清茶碱浓度的大幅变化。

Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations <10 ug/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations. Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes.

来源:Hazardous Substances Data Bank (HSDB)

代谢

咖啡因和3-甲基黄嘌呤是唯一具有药理活性的茶碱代谢物。3-甲基黄嘌呤的药理活性大约是茶碱的十分之一，正常肾功能成年人的血清浓度小于1微克/毫升。在终末期肾病患者中，3-甲基黄嘌呤可能会积累到接近未代谢茶碱浓度的水平。无论肾功能如何，成年人的咖啡因浓度通常是检测不到的。在新生儿中，咖啡因可能会积累到接近未代谢茶碱浓度的水平，从而产生药理效果。

Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 ug/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.

来源:Hazardous Substances Data Bank (HSDB)

代谢

茶碱由肝脏代谢为1,3-二甲基尿酸、1-甲基尿酸和3-甲基黄嘌呤。... 不同个体对茶碱的代谢速率不同；但是，药物的个人代谢通常是可重复的。茶碱及其代谢物主要通过肾脏排出。然而，茶碱的肾清除率仅占茶碱总体血浆清除率的8-12%。少量未经改变的茶碱随粪便排出。

Theophylline is metabolized by the liver to 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine. ... Individuals metabolize theophylline at different rates; however, individual metabolism of the drug is generally reproducible. Theophylline and its metabolites are excreted mainly by the kidneys. Renal clearance of the drug, however, contributes only 8-12% of the overall plasma clearance of theophylline. Small amounts of theophylline are excreted in feces unchanged.

来源:Hazardous Substances Data Bank (HSDB)

代谢

未改变的茶碱（占尿液放射活性的35%）和1,3-二甲基尿酸（34%）是尿液中排出的主要化合物，其次是1-甲基尿酸（18%）、3-甲基黄嘌呤（3%）和未识别的极性代谢物（4.8%）。在大鼠妊娠第18天，茶碱代谢受损，表现为茶碱排泄增加（73%）；这可以通过1,3-二甲基尿酸形成减少（-68%）和1-甲基尿酸形成减少（-30%）来解释。在怀孕的狒狒中也获得了基本相似的结果。每种动物物种都以其尿液回收的代谢物谱的差异为特征；此外，即使在不同的小鼠品系中，也观察到了茶碱代谢途径的定量差异。

Unchanged theophylline (35% of urinary radioactivity) and 1,3-dimethyluric acid (34%) are the main compounds excreted in urine, followed by 1-methyluric acid (18%), 3-methylxanthine (3%) and unidentified polar metabolites (4.8%). Theophylline metabolism was impaired in rats at day 18 of gestation, as shown by increased excretion of theophylline (73%); this was explained by a decreased formation of 1,3-dimethyluric acid (-68%) and 1-methyluric acid (-30%). Essentially similar results were obtained with pregnant baboons. Each animal species is characterized by differences in the profile of the metabolites recovered in urine; in addition, quantitative differences in theophylline metabolic pathways were seen even in different strains of mice.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：茶碱是一种白色、结晶状的生物碱。它被用作支气管扩张剂。茶碱是一种老药，由于其在对慢性呼吸道疾病如哮喘和慢性阻塞性肺病的有益抗炎效果，正在经历一种复兴。人类暴露和毒性：茶碱的治疗指数较低。当血清浓度超过20微克/毫升时，茶碱毒性最有可能发生，并且随着血清浓度的升高，毒性逐渐加重。在没有低氧血症、发热或使用拟交感神经药物的情况下，心动过速可能是茶碱毒性的迹象。厌食、恶心和偶尔呕吐、腹泻、失眠、烦躁不安和头痛常见。其他毒性症状可能包括激动性狂躁行为、频繁呕吐、极度口渴、轻微发热、耳鸣、心悸和心律失常、谵妄、肌肉抽搐、严重脱水、蛋白尿、呕吐出“咖啡渣”物质、高热和大量出汗。即使没有其他毒性前兆症状，也可能发生癫痫发作，且常常导致死亡。成人死亡通常发生在静脉注射大剂量氨茶碱的患者中，这些患者有肾脏、肝脏或心血管并发症。在其他患者中，注射的快速性而非使用的剂量似乎是诱发急性低血压、癫痫、昏迷、心脏停搏、心室纤颤和死亡的重要因素。因此，静脉注射茶碱应缓慢进行。在儿童中，死亡通常是由于过量服用和对茶碱对中枢神经系统的刺激高度敏感。急性单次过量通常是由于自杀尝试或儿童意外摄入，但也可能是由于意外或医源性的误用（治疗过量）。常见表现包括呕吐（有时伴有呕血）、震颤、焦虑和心动过速。代谢效应包括明显的低钾血症、低磷血症、高血糖和代谢性酸中毒。当血清水平超过90-100毫克/升时，低血压、心室心律失常和癫痫常见；癫痫持续状态常常对抗癫痫药物耐药。癫痫发作和其他严重毒性的表现可能在摄入后12-16小时或更长时间后延迟出现，部分原因是药物从缓释制剂中的延迟吸收。茶碱还抑制人成纤维细胞样EUE细胞的DNA合成，剂量-反应曲线的形状和茶碱诱导的DNA链断裂的缺失表明，茶碱不是直接损害DNA，而是作为代谢抑制剂。一项使用同步HeLa S3细胞的研究表明，DNA复制阻断是由于组蛋白1磷酸化的抑制，这阻止了G1和S期之间染色质结构的正常释放。 动物研究：在兔子的测试中，未稀释的茶碱导致的平均分数为角膜混浊0.6，结膜红肿1.8，肿胀0.6。在第8天，3只动物中有1只出现1级混浊和2级结膜炎。表现出轻微角膜混浊的动物还患有角膜炎。这些效果可能是由于结晶测试物质的机械刺激。单次口服剂量400毫克/千克体重的茶碱对大鼠和小鼠具有急性毒性。以两个200毫克/千克体重的剂量每天给药对大鼠具有急性毒性，但对小鼠则不然。在狗中，茶碱的最小口服毒性浓度（37-60微克/毫升血浆）似乎高于人类（>20微克/毫升）。据报道，茶碱对心脏、支气管和肾脏的毒性大于咖啡因或可可碱。将25天大的雌性小鼠分组，皮下注射0.1毫克/克体重的尿素，紧接着每隔6小时腹腔注射一次茶碱（0.05微摩尔/克体重），共注射七次，直到尿素处理后36小时，给予总剂量63微克/克体重的茶碱。小鼠在尿素处理后五个月被处死。小鼠肺部肿瘤的数量或每个肺部的肿瘤数量没有显著差异。在一项生殖研究中，小鼠在配对前一周和共同生活13周期间，通过饮食摄入0.075%、0.15%或0.30%的茶碱（平均每日剂量，125、265或530毫克/千克体重）。在所有处理组中，每窝活产幼仔的数量与剂量相关减少；在高剂量组中，每对繁殖动物的窝数显著减少，活产幼仔的体重显著下降。在高剂量和中剂量组中，观察到活产幼仔的百分比显著下降。成人在这些剂量下仅观察到轻微毒性。在19周暴露于0.3%茶碱后的交叉配对试验中，每性别的动物都受到影响，尽管雌性比雄性受到的影响更严重。将茶碱喂给未成熟（五至六周大）的大鼠，饮食中含量为0.5%（大约每天300毫克/千克体重），持续75周，导致50%的动物出现严重睾丸萎缩，少精症和无精症。茶碱已在 Ames沙门氏菌试验、体内和体外细胞遗传学、微核和中国仓鼠卵巢试验系统中进行研究，并未显示出遗传毒性。

IDENTIFICATION AND USE: Theophylline is a white, crystalline alkaloid. It is used as bronchodilator agent. Theophylline is an old drug experiencing a renaissance owing to its beneficial antiinflammatory effects in chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. HUMAN EXPOSURE AND TOXICITY: Theophylline has a low therapeutic index. Theophylline toxicity is most likely to occur when serum concentrations exceed 20 ug/mL and becomes progressively more severe at higher serum concentrations. Tachycardia, in the absence of hypoxia, fever, or administration of sympathomimetic drugs, may be an indication of theophylline toxicity. Anorexia, nausea and occasional vomiting, diarrhea, insomnia, irritability, restlessness, and headache commonly occur. Other symptoms of toxicity may include agitated maniacal behavior, frequent vomiting, extreme thirst, slight fever, tinnitus, palpitation, and arrhythmias, delirium, muscle twitching, severe dehydration, albuminuria, emesis of a "coffee ground" material, hyperthermia, and profuse diaphoresis. Seizures may occur even without other preceding symptoms of toxicity and often result in death. Fatalities in adults have generally occurred during or following IV administration of large doses of aminophylline in patients with renal, hepatic, or cardiovascular complications. In other patients, the rapidity of the injection, rather than the dose used, appears to be the more important factor precipitating acute hypotension, seizures, coma, cardiac standstill, ventricular fibrillation, and death. IV theophylline should therefore be given slowly. In children, fatalities usually are a result of overdosage and marked sensitivity to the CNS stimulation of theophylline. Acute single overdose is usually a result of a suicide attempt or accidental childhood ingestion but may also be caused by accidental or iatrogenic misuse (therapeutic overdose). Usual manifestations include vomiting (sometimes with hematemesis), tremor, anxiety, and tachycardia. Metabolic effects include pronounced hypokalemia, hypophosphatemia, hyperglycemia, and metabolic acidoses. With serum levels above 90-100 mg/L, hypotension, ventricular arrhythmias, and seizures are common; status epilepticus is frequently resistant to anticonvulsant drugs. Seizures and other manifestations of severe toxicity may be delayed 12-16 hr or more after ingestion, in part owing to delayed absorption of drug from sustained-release preparations. Theophylline also inhibited DNA synthesis in human fibroblastoid EUE cells, and the shape of the dose-response curves and the absence of theophylline-induced DNA strand breaks indicated that theophylline does not directly damage the DNA but acts as a metabolic inhibitor. The results of a study with synchronized HeLa S3 cells exposed to theophylline indicate that the block in DNA replication results from inhibition of histone 1 phosphorylation, which prevents the normal release of chromatin structure between G1 and S phases. ANIMAL STUDIES: In tests performed in rabbits, undiluted theophylline induced mean scores of 0.6 for cornea opacity, 1.8 for conjunctival redness, and 0.6 for swelling. On day 8, one of 3 animals showed opacity grade 1 and conjunctivitis grade 2. The animal showing slight corneal opacity had also keratitis. The effects could possibly be due to mechanical irritation by the crystalline test substance. A single oral dose of 400 mg/kg bw theophylline was acutely toxic to rats and mice. Administration of the same daily dose as two separate doses of 200 mg/kg bw was acutely toxic to rats but not to mice. In dogs, the minimal oral toxic concentration of theophylline appears to be higher (37-60 ug/mL plasma) than in man ( > 20 g/mL). Theophylline has been reported to be more toxic than caffeine or theobromine to the heart, bronchi and kidneys. Groups of female mice 25 days of age, received a single subcutaneous injection of 0.1 mg/g bw urethane followed immediately by seven intraperitoneal injections (0.05 umol/g bw) of theophylline at 6-hr intervals up to 36 hr after urethane treatment, to give a total dose of 63 ug/g bw theophylline. Mice were killed five months after urethane treatment. No significant difference was noted in the numbers of mice with lung tumors or in the numbers of tumors/lung. In a reproductive study, mice were administered 0.075, 0.15 or 0.30% theophylline in the diet (average daily doses, 125, 265 or 530 mg/kg bw) for one week before mating and during 13 weeks of cohabitation. Among all treated groups, there was a dose-related decrease in the number of live pups per litter; in the high-dose groups, there was a significant decrease in the number of litters per breeding pair and a significant decrease in live pup weight. In the high- and mid-dose groups, a significant decrease in the percentage of pups born alive was observed. Only mild toxicity was observed in adults at these doses. In a cross-over mating trial at the end of a 19-week exposure to 0.3% theophylline, animals of each sex were found to be affected, although females were more severely affected than males. Feeding theophylline to immature (five to six weeks old) rats at 0.5% in the diet (approximately 300 mg/kg bw per day) for 75 weeks produced severe testicular atrophy in 50% of animals, oligo-spermatogenesis and aspermatogenesis. Theophylline has been studied in Ames Salmonella test, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

茶碱能放松支气管气道和肺血管的平滑肌，并减少气道对组胺、乙酰胆碱、腺苷和过敏原的敏感性。茶碱竞争性地抑制平滑肌细胞中负责分解环磷酸腺苷（cAMP）的III型和IV型磷酸二酯酶（PDE），可能导致支气管扩张。茶碱还与腺苷A2B受体结合，阻止腺苷介导的支气管收缩。在炎症状态下，茶碱激活组蛋白去乙酰化酶，以防止需要组蛋白乙酰化才能开始转录的炎症基因的转录。

Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

前瞻性研究表明，长期口服茶碱治疗的患者中，不到1%的患者出现ALT升高，这使得这种升高比偶然发生的可能性更小。没有确切的实例将临床上明显的肝损伤与茶碱使用联系起来。肝损伤可能是由于高剂量茶碱引起的一般性毒性的一部分，可能是由于药物引起的低血压或缺氧（如癫痫发作或心律不齐）导致的肝脏并发症。实际上，已经证明茶碱可以减轻几种实验性急性肝损伤的形式，而且慢性咖啡因（另一种黄嘌呤）摄入与慢性肝病、肝硬化和肝癌的较低发生率有关。

Prospective studies have shown that ALT elevations occur in less than 1% of patients receiving long term oral therapy with theophylline, making it unlikely that such elevations are more common than might occur by chance. No instances of clinically apparent liver injury have been convincingly linked to theophylline use. Liver injury may occur as a part of generalized toxicity from high doses of theophylline probably as a result of hepatic complications of hypotension or anoxia from seizures or cardiac arrhythmias caused by the drug. Theophylline actually has been shown to attenuate several forms of experimental acute liver injury, and chronic caffeine (another xanthine) intake has been associated with decreased rates of chronic liver disease, cirrhosis and liver cancer.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：茶碱

Compound:theophylline

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

茶碱在口服溶液或速释固体口服剂型后，能迅速且完全吸收。

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.

来源:DrugBank

吸收、分配和排泄

• 消除途径

茶碱不会经历任何明显的系统前消除，它自由地分布到无脂肪组织中，并且在肝脏中广泛代谢。新生儿中未改变的茶碱的肾排泄量大约占剂量的50%，而三个月以上的儿童和成人中这一比例大约为10%。

Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.3到0.7升/千克

0.3 to 0.7 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

0.29 毫升/千克/分钟 [早产儿，出生后年龄 3-15 天] 0.64 毫升/千克/分钟 [早产儿，出生后年龄 25-57 天] 1.7 毫升/千克/分钟 [1-4 岁儿童] 1.6 毫升/千克/分钟 [4-12 岁儿童] 0.9 毫升/千克/分钟 [13-15 岁儿童] 1.4 毫升/千克/分钟 [16-17 岁儿童] 0.65 毫升/千克/分钟 [成人（16-60 岁），其他方面健康的非吸烟哮喘患者] 0.41 毫升/千克/分钟 [老年人（>60 岁），不吸烟且心脏、肝脏和肾功能正常者] 0.33 毫升/千克/分钟 [急性肺水肿] 0.54 毫升/千克/分钟 [60 岁以上慢性阻塞性肺疾病（COPD）患者，病情稳定，已戒烟超过1年] 0.48 毫升/千克/分钟 [慢性阻塞性肺疾病（COPD）伴有肺心病] 1.25 毫升/千克/分钟 [囊性纤维化（14-28 岁）] 0.31 毫升/千克/分钟 [肝硬化肝脏疾病] 0.35 毫升/千克/分钟 [急性肝炎] 0.65 毫升/千克/分钟 [胆汁淤积] 0.47 毫升/千克/分钟 [多器官衰竭的败血症] 0.38 毫升/千克/分钟 [甲状腺功能减退] 0.8 毫升/千克/分钟 [甲状腺功能亢进]

0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days] 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days] 1.7 mL/kg/min [Children 1-4 years] 1.6 mL/kg/min [Children 4-12 years] 0.9 mL/kg/min [Children 13-15 years] 1.4 mL/kg/min [Children 16-17 years] 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease cirrhosis] 0.35 mL/kg/min [acute hepatitis] 0.65 mL/kg/min [cholestasis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid]

来源:DrugBank

吸收、分配和排泄

当通过肌内注射给药时，茶碱通常吸收缓慢且不完全。肛门栓剂（在美国已不再商业供应）无论其栓剂基质是亲水性的还是亲脂性的，吸收都缓慢且不规则。

When administered IM, theophylline is usually absorbed slowly and incompletely. Rectal suppositories (no longer commercially available in the US) are slowly and erratically absorbed, regardless of whether the suppository base is hydrophilic or lipophilic.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• TSCA：
  Yes
• 危险等级：
  6.1(b)
• 危险品标志：
  Xn
• 安全说明：
  S16,S36/37,S45,S7
• 危险类别码：
  R22
• WGK Germany：
  1
• 海关编码：
  2939590000
• 危险品运输编号：
  UN 2811 6.1/PG 3
• 危险类别：
  6.1(b)
• RTECS号：
  XH3850000
• 包装等级：
  III
• 危险性防范说明：
  P301+P310
• 危险性描述：
  H301
• 储存条件：
  本品应密封存放在阴凉、干燥且避光的地方保存。

SDS

Name:	Theophylline Anhydrous U.S.P./N.F. Material Safety Data Sheet
Synonym:	1,3-Dimethylxanthine; 3,7-Dihydro-1,3-Dimethyl-1H-Purine-2,6-Dione; 1,3-Dimethyl-2,6-Dioxo-1,2,3,6-Tetrahydropurin
CAS:	58-55-9

Section 1 - Chemical Product MSDS Name:Theophylline Anhydrous U.S.P./N.F. Material Safety Data Sheet
Synonym:1,3-Dimethylxanthine; 3,7-Dihydro-1,3-Dimethyl-1H-Purine-2,6-Dione; 1,3-Dimethyl-2,6-Dioxo-1,2,3,6-Tetrahydropurin

---

Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
58-55-9	Theophylline, Anhydrous	>99	200-385-7

Hazard Symbols: XN
Risk Phrases: 22

---

Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Harmful if swallowed.The toxicological properties of this material have not been fully investigated.
Potential Health Effects
Eye:
May cause eye irritation. The toxicological properties of this material have not been fully investigated.
Skin:
May cause skin irritation. The toxicological properties of this material have not been fully investigated.
Ingestion:
Harmful if swallowed. May cause irritation of the digestive tract.
May cause headache, nausea, fatigue, and dizziness.
Inhalation:
May cause respiratory tract irritation. The toxicological properties of this substance have not been fully investigated.
Chronic:
No information found.

---

Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Wash clothing before reuse.
Ingestion:
Never give anything by mouth to an unconscious person. Get medical aid. Do NOT induce vomiting. If conscious and alert, rinse mouth and drink 2-4 cupfuls of milk or water.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid.
Notes to Physician:

---

Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear. During a fire, irritating and highly toxic gases may be generated by thermal decomposition or combustion.
Extinguishing Media:
Use agent most appropriate to extinguish fire. Use water spray, dry chemical, carbon dioxide, or appropriate foam.

---

Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Clean up spills immediately, observing precautions in the Protective Equipment section. Sweep up, then place into a suitable container for disposal. Avoid generating dusty conditions. Provide ventilation.

---

Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use with adequate ventilation. Avoid contact with eyes, skin, and clothing. Keep container tightly closed. Avoid ingestion and inhalation.
Storage:
Keep container closed when not in use. Store in a tightly closed container. Store in a cool, dry, well-ventilated area away from incompatible substances.

---

Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 58-55-9: Russia: 0.5 mg/m3 TWA Personal Protective Equipment Eyes: Wear appropriate protective eyeglasses or chemical safety goggles as described by OSHA's eye and face protection regulations in 29 CFR 1910.133 or European Standard EN166.
Skin:
Wear appropriate protective gloves to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to prevent skin exposure.
Respirators:
Follow the OSHA respirator regulations found in 29 CFR 1910.134 or European Standard EN 149. Use a NIOSH/MSHA or European Standard EN 149 approved respirator if exposure limits are exceeded or if irritation or other symptoms are experienced.

---

Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Powder
Color: white
Odor: None reported.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 270.00 - 274.00 deg C
Autoignition Temperature: Not available.
Flash Point: Not available.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water: slightly soluble
Specific Gravity/Density:
Molecular Formula: C7H8N4O2
Molecular Weight: 180.17

---

Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
Incompatible materials, dust generation, excess heat, strong oxidants.
Incompatibilities with Other Materials:
Oxidizing agents.
Hazardous Decomposition Products:
Nitrogen oxides, carbon monoxide, irritating and toxic fumes and gases, carbon dioxide, nitrogen.
Hazardous Polymerization: Has not been reported.

---

Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 58-55-9: XH3850000 LD50/LC50:
CAS# 58-55-9: Oral, mouse: LD50 = 235 mg/kg; Oral, rabbit: LD50 = 350 mg/kg; Oral, rat: LD50 = 225 mg/kg.
Carcinogenicity:
Theophylline, Anhydrous - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

---

Section 12 - ECOLOGICAL INFORMATION

---

Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

---

Section 14 - TRANSPORT INFORMATION

IATA
Not regulated as a hazardous material.
IMO
Not regulated as a hazardous material.
RID/ADR
Not regulated as a hazardous material.

---

Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: XN
Risk Phrases:
R 22 Harmful if swallowed.
Safety Phrases:
S 22 Do not breathe dust.
S 24/25 Avoid contact with skin and eyes.
S 28A After contact with skin, wash immediately with
plenty of water.
S 37 Wear suitable gloves.
S 45 In case of accident or if you feel unwell, seek
medical advice immediately (show the label where
possible).
WGK (Water Danger/Protection)
CAS# 58-55-9: 2
Canada
CAS# 58-55-9 is listed on Canada's DSL List.
CAS# 58-55-9 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 58-55-9 is listed on the TSCA inventory.

---

SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

嘌呤类生物碱 茶碱 (Theophylline)

茶碱是从茶叶和咖啡中提取的一种生物碱，属于嘌呤类。在植物界广泛分布，特别是山茶科和茜草科的高等植物中更为常见。茶碱是山茶科植物茶（Camellia sinensis）的有效成分之一，并可通过合成方法获得。

• 物理性质：茶碱的一水合物为单斜片状结晶，白色结晶性粉末，1g可溶于120mL水、80mL乙醇和110mL氯仿。它还溶于热水、氢氧化钠、氨、稀盐酸或硝酸中，并微溶于乙醚。
• 化学性质：紫外吸收特征波长为270nm，熔点为270-274℃。常温下，茶碱可溶于水（1:120）、乙醇（1:18）、氯仿（1:86）和氢氧化钠、氨水、稀盐酸及硝酸中，并微溶于乙醚。
• 毒性：茶碱具有中等毒性，LD50值为300mg/kg（大鼠经口给药）。

功效与作用

• 茶碱常用于治疗心绞痛药物。外用可使平滑肌松弛，并能提高黑色素细胞活性。
• 作为增效剂的葡萄糖酸铜盐可用于发水和乌发，防止灰发生成。与奇数碳原子的长链脂肪酸或醇配合使用效果更好。
• 茶碱还具有抗炎作用，结合海藻的含水甘油萃取物可治疗蜂窝组织炎症。

化学性质

茶碱是一种无臭、苦味的白色结晶或结晶性粉末。它在常温下能溶于水（1:120）、乙醇（1:18）和氯仿（1:86），也能溶于氢氧化钠、氨水、稀盐酸及硝酸，并微溶于乙醚。

用途

• 生化研究
• 咖啡因等药物合成中间体
• 甲基嘌呤类药物，具有强心、利尿、扩张冠状动脉、松弛支气管平滑肌和兴奋中枢神经系统等多种作用。
• 主要用于治疗支气管哮喘、肺气肿、支气管炎及心脏性呼吸困难。
• 还可用于治疗支气管性和心脏性哮喘，预防心源性水肿。
• 作为磷酸二酯酶抑制剂，并用作医药中间体。

生产方法

1. 第一种方法：通过将1,3-二甲基-4-氨基-5-甲酰胺基脲嘧啶与氢氧化钠溶液在90-95℃反应，制得茶碱粗品，经热水重结晶、活性炭脱色得到成品。
2. 第二种方法：以氰乙酸乙酯和二甲基尿素为原料，经缩合、亚硝化、还原、甲酰化及环合反应获得粗品，并通过重结晶而最终制成茶碱。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  咖啡因	3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione	58-08-2	C8H10N4O2	194.193
  8-氯茶碱	8-chlorotheophylline	85-18-7	C7H7ClN4O2	214.611
  3-甲基黄嘌呤	3-methyl-xanthine	1076-22-8	C6H6N4O2	166.139
  8-溴茶碱	8-bromotheophylline	10381-75-6	C7H7BrN4O2	259.062
  ——	7-(hydroxymethyl)theophylline	31542-43-5	C8H10N4O3	210.192
  7-氨基-1,3-二甲基-3,7-二氢-1H-嘌呤-2,6-二酮	7-aminotheophylline	81281-58-5	C7H9N5O2	195.181
  1-甲基黄嘌呤	1-methylxanthine	6136-37-4	C6H6N4O2	166.139
  9-氨基茶碱	9-Aminotheophylline	113613-78-8	C7H9N5O2	195.181
  ——	8-(3-aminopropyl)theophylline	76748-76-0	C10H15N5O2	237.261
  ——	7-diethylaminomethyl-1,3-dimethyl-3,7-dihydro-purine-2,6-dione	71527-02-1	C12H19N5O2	265.315
• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  1,3-二甲基尿酸	1,3-dimethyluric acid	944-73-0	C7H8N4O3	196.166
  1,3,9-三甲基黄嘌呤	isocaffeine	519-32-4	C8H10N4O2	194.193
  咖啡因	3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione	58-08-2	C8H10N4O2	194.193
  ——	1,3-dimethyl-7-(111C)methylpurine-2,6-dione	——	C8H10N4O2	193.19
  8-氯茶碱	8-chlorotheophylline	85-18-7	C7H7ClN4O2	214.611
  3-甲基黄嘌呤	3-methyl-xanthine	1076-22-8	C6H6N4O2	166.139
  1,3,7-三甲基尿酸	1,3,7-Trimethyluric acid	5415-44-1	C8H10N4O3	210.192
  ——	8-aminotheophylline	19410-53-8	C7H9N5O2	195.181
  3,7-二氢-1,3-二甲基-8-碘-1H-嘌呤-2,6-二酮	8-iodotheophylline	24255-56-9	C7H7IN4O2	306.063
  7-乙基茶碱	7-ethyl-1,3-dimethyl-3,7-dihydro-purine-2,6-dione	23043-88-1	C9H12N4O2	208.22

反应信息

• 作为反应物：
  描述：

  茶碱 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 12.0h， 生成 羟丙茶碱
  参考文献：
  名称：

  N 7-Tosyltheophylline (TsTh): A Highly Efficient Reagent for the One-Pot Synthesis of N 7-Alkyltheophyllines from Alcohols

  摘要：

  A convenient and highly efficient one-pot N-alkylation of theophylline from alcohols via N-7-tosyltheophylline (TsTh) is described. In this protocol, the treatment of primary and/or secondary alcohols with a mixture of TsTh and 1,8-diazabicyclo[5.4.0]undec-7-ene in refluxing acetonitrile affords the corresponding N-7-alkyltheophylline in good to excellent yields; the reaction was optimized for solvent and base. This methodology is highly efficient for various structurally diverse primary and secondary alcohols. A plausible mechanism for the one-pot N-alkylation of theophylline with alcohols via TsTh has been suggested.

  DOI：

  10.1055/s-0033-1341026
• 作为产物：
  描述：

  1,3-dimethyl-5-bromo-6-methylaminopyrimidine-2,4-dione 在 sodium azide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以47%的产率得到茶碱
  参考文献：
  名称：

  A High Chemical Reactivity of 5-Azidouracils and Its Synthetic Application: Novel Synthesis of 8-Substituted 1,3-Dimethylxanthine Derivatives

  摘要：

  A novel method for the preparation of 8-substituted 1,3-dimethylxanthine derivatives (7 or 8) is described: treatment of 6-alkylamino-5-bromo-1,3-dimethyluracils (6a-e), easily prepared by bromination of the corresponding 6-alkylamino-1, 3-dimethyluracils (5), with sodium azide in DMF at ambient temperature allowed the direct formation of the 8-substituted 1,3-dimethylxanthines (7) proceeding via a transient formation of the corresponding 5-azido-1 ,3-dimethyluracils. The 5-bromo-1,3-dimethyluracils (6f, g) possessing an ct-branched alkylamino group at the 6-position similarly react with sodium azide to afford 8,8-disubstituted 1,3-dimethyl-8H-xanthines (8,8-disubstituted 1,3-dimethyl-3,g-dihydropurine-2,6-diones)(8).

  DOI：

  10.3987/com-97-s68
• 作为试剂：
  描述：

  水合茚三酮 、 benzo[a]phenazin-5-ol 、 丙二腈 在 茶碱 作用下， 反应 0.12h， 以0.422 g的产率得到3-amino-1',3'-dioxo-1',3'-dihydrospiro[benzo[a]pyrano[2,3-c]-phenazine-1,2'-indene]-2-carbonitrile
  参考文献：
  名称：

  茶碱作为一种新型绿色催化剂，可在无溶剂条件下一锅合成螺[苯并[a]吡喃并[2,3-c]吩嗪]和苯并[a]吡喃并[2,3-c]吩嗪衍生物

  摘要：

  通过2-羟基萘-1,4-之间多米诺骨牌多组分缩合反应合成新型螺[苯并[a]吡喃并[2,3-c]吩嗪]衍生物的绿色简便方法催化量的1,3-二甲基-7H-嘌呤-2,6-二酮（茶碱）的存在下，二酮，苯1,2-二胺，茚三酮和丙二腈作为一种方便，生态友好且可重复使用的固体碱催化剂在热，微波辐射和无溶剂条件下。该方法也已成功用于苯并[a]吡喃并[2,3-c]吩嗪的合成。

  DOI：

  10.1016/j.cclet.2016.09.016

文献信息

• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• [EN] 3-[(HYDRAZONO)METHYL]-N-(TETRAZOL-5-YL)-BENZAMIDE AND 3-[(HYDRAZONO)METHYL]-N-(1,3,4-OXADIAZOL-2-YL)-BENZAMIDE DERIVATIVES AS HERBICIDES<br/>[FR] DÉRIVÉS DE 3-[(HYDRAZONO))MÉTHYL]-N-(TÉTRAZOL-5-YL)-BENZAMIDE ET DE 3-[(HYDRAZONO)MÉTHYL]-N-(1,3,4-OXADIAZOL-2-YL)-BENZAMIDE UTILISÉS EN TANT QU'HERBICIDES
  申请人：SYNGENTA CROP PROTECTION AG

  公开号：WO2021013969A1

  公开（公告）日：2021-01-28

  The present invention related to compounds of Formula (I): or an agronomically acceptable salt thereof, wherein Q, R2, R3, R4, R5 and R6 are as described herein. The invention further relates to compositions comprising said compounds, to methods of controlling weeds using said compositions, and to the use of compounds of Formula (I) as a herbicide.

  本发明涉及以下式（I）的化合物或其农业上可接受的盐，其中Q、R2、R3、R4、R5和R6如本文所述。该发明还涉及包含所述化合物的组合物，使用这些组合物控制杂草的方法，以及将式（I）的化合物用作除草剂的用途。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• HERBICIDAL AND FUNGICIDAL 5-OXY-SUBSTITUTED 3-PHENYLISOXAZOLINE-5-CARBOXAMIDES AND 5-OXY-SUBSTITUTED 3-PHENYLISOXAZOLINE-5-THIOAMIDES
  申请人：BAYER CROPSCIENCE AG

  公开号：US20150245616A1

  公开（公告）日：2015-09-03

  Herbicidally and fungicidally active 5-oxy-substituted 3-phenylisoxazoline-5-carboxamides and 5-oxy-substituted 3-phenylisoxazoline-5-thioamides of the formula (I) are described. In this formula (I), X, X 2 to X 6 , R 1 to R 4 are radicals such as hydrogen, halogen and organic radicals such as substituted alkyl. A is a bond or a divalent unit. Y is a chalcogen.

  具有除草和杀菌活性的5-氧代取代的3-苯基异噁唑啉-5-羧酰胺和5-氧代取代的3-苯基异噁唑啉-5-硫酰胺的化合物如下式（I）所述。 在这个式子（I）中，X，X2至X6，R1至R4是氢、卤素和有机基团，如取代烷基等。A是一个键或二价基团。Y是硫族元素。
• [EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。

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