2-(2-氨基-6-甲氧基嘌呤-9-基)-5-(羟基甲基)四氢呋喃-3,4-二醇 | 7803-88-5

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗代谢类抗肿瘤药
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 中文名称: 2-(2-氨基-6-甲氧基嘌呤-9-基)-5-(羟基甲基)四氢呋喃-3,4-二醇
• 英文名称: O⁶-methyl-guanosine
• 英文别名: 2-Amino-6-methoxypurinribonucleosid；(2R,3S,4S,5R)-2-(2-amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol；2-(2-amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 7803-88-5；34793-34-5；121032-29-9
• 化学式: C₁₁H₁₅N₅O₅
• 分子量: 297.271
• InChiKey: IXOXBSCIXZEQEQ-UHFFFAOYSA-N

物化性质

• 熔点：
  209-217°
• 比旋光度：
  D20 +55.9° (c = 0.27 in DMF)
• 沸点：
  721.0±70.0 °C(Predicted)
• 密度：
  1.98±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO（轻微）、甲醇（轻微、加热）、水（轻微、超声处理）

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  149
• 氢给体数：
  4
• 氢受体数：
  9

安全信息

• 储存条件：
  存储温度应控制在0-10°C之间，并请避免加热。

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Nelarabine
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Nelarabine
CAS number: 121032-29-9

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C11H15N5O5
Molecular weight: 297.3

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

物理性质

奈拉滨是一种白色或类白色的结晶性粉末，微溶于水，在25℃、pH值4~10的水中溶解度约为8-9mg/ml。

葛兰素史克研发成功

奈拉滨由葛兰素史克（GlaxoSmithKline）公司首次研发成功。2005年10月28日，经美国食品与药品管理局批准，成为治疗至少对两种化疗方案无反应或治疗后复发的急性T-细胞淋巴母细胞性白血病(T-ALL)和T-细胞淋巴母细胞性淋巴瘤(T-LBL)的新药，并于2006年在美国正式上市。该产品在中国未申请专利和行政保护，因此不存在知识产权问题。

奈拉滨是一种脱氧鸟苷类似物9-β-D-阿糖呋喃糖鸟嘌呤(ara-G)的前体药物，在腺苷脱氨酶(ADA)的作用下，脱去甲基转变为ara-G。随后在脱氧鸟苷激酶和脱氧胞苷激酶作用下，经单磷酸化生成具有活性的 ara-G 三磷酸盐（ara-GTP）。在白血病母细胞中逐渐积累并与DNA相结合，抑制DNA合成，促进白血病细胞死亡。此外，其抗癌机制可能还与其细胞毒性和全身毒性有关。

药理及药代动力学

奈拉滨为脱氧鸟苷类似物9-β-D-阿糖鸟嘌呤(ara-G)的前体药物，在体内经腺苷脱胺酶催化生成 ara-G，再依次通过脱氧鸟苷激酶和脱氧胞嘧啶核苷激酶单磷酸化生成活性的5’-三磷酸 ara-GTP。白血病母细胞中积聚，由于缺乏磷酸核糖聚合酶（PNP），dGTP 在 T 细胞中选择性积累并抑制 DNA 合成，从而毒杀 T 细胞白血病细胞。

奈拉滨和 ara-G 体内迅速消除，在给予1500mg/m²剂量的奈拉滨后，两者半衰期分别为30分钟和3小时。ara-G 通常在奈拉滨给药完毕时达到峰浓度，并且其峰浓度数值大于奈拉滨的峰浓度，表明奈拉滨可在体内迅速、完全地转化为 ara-G。奈拉滨和 ara-G 部分经肾脏消除，28名成年患者给予奈拉滨后24小时测得的平均肾排泄率分别为6.6±4.7% 和 27±15%。

临床试验

规模的临床试验表明，奈拉滨治疗 T-细胞幼淋巴细胞白血病（T-PLL）和外周 T-细胞淋巴瘤结果令人鼓舞。其潜在适应症还包括靶组织中有高水平核苷酸激酶的非 T 细胞疾病。实际上，在 I 和 II 期临床试验中，接受过鞘内化疗或颅脊放疗的患者使用奈拉滨后出现神经毒性的风险增加。

用法用量

奈拉滨主要用于曾接受至少两种化疗方案治疗但仍无应答、或者病情复发的急性 T 细胞型淋巴母细胞白血病及 T 细胞型淋巴母细胞性淋巴瘤患者。成人推荐剂量为1500mg/m²，静脉输注2小时，每21天为一疗程，在第1、3、5天给药，无需稀释；儿童推荐剂量为650mg/m²，静脉输注1小时，每21天为一疗程，并连续输注5天，无需稀释。成人和儿童的推荐治疗期未明确，临床试验中，除非患者病情加重，不能耐受毒性、即将进行骨髓移植或不再进行治疗。

注意事项

奈拉滨所致神经毒性属于剂量限制性毒性反应，在用药期间应注意观察是否出现意识模糊、嗜睡、惊厥、共济失调、感觉异常和感觉减退等症状。接受过鞘内化疗或颅脊放疗的患者使用奈拉滨后，发生神经毒性的风险增加。

奈拉滨可能导致白细胞减少症、血小板减少症、贫血及中性粒细胞减少症（包括发热性中性粒细胞减少症），因此应常规进行全血细胞计数（包括血小板计数）。肿瘤溶解综合征患者并发高尿酸血症时，可通过静脉水合治疗缓解。存在高尿酸血症风险的患者可考虑服用别嘌醇。

免疫缺陷患者使用奈拉滨期间应避免注射活疫苗。

文献信息

• 5'-POSITION DIBENZYL MONOPHOSPHATE DERIVATIVE OF NUCLEOSIDE-BASED ANTICANCER AGENT OR ANTIVIRUS AGENT
  申请人：Ohara Pharmaceutical Co., Ltd.

  公开号：US20200123190A1

  公开（公告）日：2020-04-23

  To provide, in place of injected agents (nucleoside-based anticancer agents or antivirus agents) clinically used as therapeutic drugs for cancer or virus infections, a medicine that has high stability with respect to various hydrolytic metabolic enzymes, is absorbed into the body even by oral administration, and exhibits a cytocidal effect by being incorporated into a DNA and RNA biosynthetic route and inhibiting the modification and extension of DNA and RNA or inhibiting reverse transcriptases or inhibiting protein synthesis. The aforementioned problem is solved by a novel compound represented by formula (I). (In the formula, D is the 5′-position moiety of a nucleoside-based anticancer agent or an antivirus agent, and R 1 and R 2 are each a benzyl group that may have the same substituent or different substituents.)

  提供一种替代核苷酸类抗癌药物或抗病毒药物注射剂的药物，该药物具有对各种水解代谢酶高稳定性，即使口服也能被身体吸收，并通过被纳入到DNA和RNA生物合成途径中并抑制DNA和RNA的修饰和延伸或抑制逆转录酶或抑制蛋白质合成而表现出细胞毒性的特点。上述问题通过一种新化合物（I）来解决。（在公式中，D是核苷酸类抗癌药物或抗病毒药物的5'-位置基团，R1和R2分别是苯甲基，可以具有相同的取代基或不同的取代基。）
• Compositions Containing Antiviral Compounds and Methods of Using the Same
  申请人：Cantrell Gary L.

  公开号：US20090258843A1

  公开（公告）日：2009-10-15

  The present invention is directed to compositions and methods for the treatment of various diseases, pathological disorders, and medical conditions such as viral infections and cancer. The compositions include (A) an antiviral compound or a pharmaceutically acceptable salt thereof; and (B) an agent selected from the group consisting of a substituted or unsubstituted imidazole or a pharmaceutically acceptable salt thereof; a non-steroidal anti-inflammatory agent or a pharmaceutically acceptable salt thereof; an amino acid or a pharmaceutically acceptable salt thereof; a carboxylic acid or a pharmaceutically acceptable salt thereof; a sulfonic acid or a pharmaceutically acceptable salt thereof; and a combination thereof.

  本发明涉及用于治疗各种疾病、病理障碍和医疗条件，如病毒感染和癌症的组合物和方法。所述组合物包括（A）抗病毒化合物或其药学上可接受的盐；和（B）从以下组中选择的药剂：取代或未取代的咪唑或其药学上可接受的盐；非甾体抗炎药或其药学上可接受的盐；氨基酸或其药学上可接受的盐；羧酸或其药学上可接受的盐；磺酸或其药学上可接受的盐；或其组合物。
• DOUBLE-LIVER-TARGETING PHOSPHORAMIDATE AND PHOSPHONOAMIDATE PRODRUGS
  申请人：NANJING MOLECULAR RESEARCH, INC.

  公开号：US20130210757A1

  公开（公告）日：2013-08-15

  This application discloses phosphoramidate and phosphonoamidate prodrugs of alcohol-based therapeutic agents, such as nucleosides, nucleotides, acyclonucleosides, C-nucleosides, and C-nucleotides, and use of these prodrugs for treatment of diseases or disorders, including infectious diseases and cancers. This application also discloses a general method for enhancing bioavailability and/or liver-targeting property of alcohol drugs through converting the alcohol drugs to phosphoramidate or phosphonoamidate prodrugs, and methods of preparation of these prodrugs.

  本申请公开了醇类治疗剂的磷酰胺酸和磷酸胺酯前药，例如核苷、核苷酸、非环核苷、C-核苷和C-核苷酸，以及使用这些前药治疗疾病或疾病的方法，包括传染病和癌症。本申请还公开了一种通用方法，通过将醇类药物转化为磷酰胺酸或磷酸胺酯前药，增强醇类药物的生物利用度和/或肝靶向性，以及这些前药的制备方法。
• O-(SUBSTITUTED BENZYL) PHOSPHORAMIDATE COMPOUNDS AND THERAPEUTIC USE
  申请人：Wang Zheng

  公开号：US20140038916A1

  公开（公告）日：2014-02-06

  This application discloses novel phosphoramidate and phosphonoamidate prodrugs of nucleosides, nucleotides, C-nucleosides, C-nucleotides, phosphonates, and other alcohol-containing drugs; use of these prodrugs for treatment of infectious diseases and cancers, in particular, liver infections and cancers; and methods of preparing these novel phosphoramidate and phosphonoamidate prodrugs.
• IBANDRONATE CONJUGATES OF NUCLEOSIDE ANTIMETABOLITES
  申请人：MBC Pharma, Inc.

  公开号：US20200163978A1

  公开（公告）日：2020-05-28

  Provided herein are conjugates of nucleoside antimetabolites and their analogs with ibandronate, pharmaceutical compositions including one or more of said conjugates, methods of synthesizing the same as well as methods of treating diseases and or conditions using the same.