脱氧助间型霉素 | 53910-25-1

• 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 - 有机杂环化合物 - 咪唑二氮卓类
• 中文名称: 脱氧助间型霉素
• 中文别名: 喷司他丁；(R)-3-((2R,4S,5R)-4-羟基-5-(羟甲基)四氢呋喃-2-基)-3,6,7,8-四氢咪唑[4,5-d][1,3]二氮杂卓-8-醇；2'-脱氧助间型霉素；蛹虫草提取物(喷司他丁)
• 英文名称: 2'-deoxycoformycin
• 英文别名: (R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol；(R)-3-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3,6,7,8-tetrahydroimidazo-[4,5-d]-[1,3]diazepin-8-ol；2′-deoxycoformycin；2'-deoxy-D-coformycin；2-deoxycoformycin；deoxycoformycin；Pentostatin；(8R)-3-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7,8-dihydro-4H-imidazo[4,5-d][1,3]diazepin-8-ol
• CAS: 53910-25-1
• 化学式: C₁₁H₁₆N₄O₄
• 分子量: 268.272
• InChiKey: FPVKHBSQESCIEP-JQCXWYLXSA-N

物化性质

• 熔点：
  154-157?C
• 比旋光度：
  D25 +76.4° (c = 1 in water); D23 +73.0° (c = 1, pH 7 buffer)
• 沸点：
  411.43°C (rough estimate)
• 密度：
  1.2576 (rough estimate)
• 溶解度：
  在水中的溶解度为10mg/mL，澄清
• 物理描述：
  Solid
• 颜色/状态：
  White crystals from methanol/water
• 稳定性/保质期：
  Commercially available pentostatin powder for injection should be stored at 2-8 °C. ... When stored at 2-8 °C, the manufacturer states that currently available pentostatin powder for injection is stable for 18 mo after the date of manufacture when stored as directed. ... Pentostatin is compatible with 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's. When reconstituted with 0.9% sodium chloride injection to a final concentration of 2 mg/ml, pentostatin solutions are physically and chemically stable for at least 72 hr at room temperature (22-25 °C). When diluted to a final concentration of 20 ug/ml, the drug is chemically compatible at room temperature with 0.9% sodium chloride or lactated Ringer's injection for at least 48 hr and with 5% dextrose injection for at least 24 hr. Up to an 8-10% loss in potency has been reported to occur within 48 hr in such solutions diluted in 5% dextrose, However, because such reconstituted and/or diluted pentostatin solutions contain no preservatives, the manufacturer recommends that they be used within 8 hr when stored at room temperature in ambient light, and that unused portions be discarded.
• 旋光度：
  Specific optical rotation: + 76.4 deg at 25 °C/D (concentration by volume = 1 g 100 ml water); specific optical rotation: + 73.0 deg at 23 °C/D (concentration by volume = 1 g in 100 ml water pH 7 buffer)
• 解离常数：
  pKa = 5.2 in water

计算性质

• 辛醇/水分配系数(LogP)：
  -2.1
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  6

ADMET

代谢

主要在肝脏，但只有少量被代谢。

Primarily hepatic, but only small amounts are metabolized.

来源:DrugBank

代谢

主要在肝脏，但只有少量被代谢。 消除途径：在人体中，单次剂量为4 mg/m2的喷托司汀，静脉滴注5分钟后，大约90%的剂量以未改变的喷托司汀和/或代谢物的形式通过尿液排出，通过腺苷脱氨酶抑制活性来衡量。 半衰期：5.7小时（范围在2.6到16小时之间）

Primarily hepatic, but only small amounts are metabolized. Route of Elimination: In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. Half Life: 5.7 hours (with a range between 2.6 and 16 hrs)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

Pentostatin 是一种强效的腺苷脱氨酶（ADA）的过渡态抑制剂，ADA 在淋巴系统的细胞中活性最高。T 细胞的 ADA 活性高于 B 细胞，T 细胞恶性肿瘤的活性高于 B 细胞恶性肿瘤。由于阻止了腺苷或去氧腺苷的分解代谢，导致的细胞毒性被认为是由于细胞内 dATP 水平升高，这可以通过抑制核糖核苷酸还原酶来阻断 DNA 合成。细胞内活化导致其作为错误的嘌呤碱基被并入 DNA 中。另一种细胞毒性效果与其并入 RNA 有关。细胞毒性对细胞周期阶段具有特异性（S 阶段）。

Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在临床试验中，高达25%接受喷托松汀治疗的患者的血清酶水平升高，但这些异常通常是轻微和短暂的，很少需要调整剂量。喷托松汀引起的临床上明显的肝损伤是罕见的，但已有描述成人及儿童因喷托松汀引起的严重肝损伤，迅速导致多器官衰竭和死亡的情况。发病时间从几天到六个月不等。在这些病例中，休克、缺血、机会性感染和败血症的可能作用并不总是明确的。已经描述了肝细胞和胆汁淤积的酶升高模式。免疫过敏特征和自身抗体并不典型。

In clinical trials, serum enzymes elevations occurred in up to 25% of patients receiving pentostatin, but the abnormalities were generally mild and transient and rarely required dose modification. Clinically apparent liver injury from pentostatin is rare, but striking instances of severe liver injury leading rapidly to multiorgan failure and death have been described both in adults and children. The time to onset varied from a few days to six months. The possible role of shock, ischemia, opportunistic infections and sepsis in these cases has not always been well defined. Both hepatocellular and cholestatic patterns of enzyme elevations have been described. Immunoallergic features and autoantibodies were not typical.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：喷司他丁

Compound:pentostatin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

未通过口服吸收，可穿过血脑屏障。

Not absorbed orally, crosses blood brain barrier.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在人体中，单次剂量为4 mg/m2的喷托司汀在5分钟内输注后，大约90%的剂量以未改变的喷托司汀和/或代谢物的形式通过尿液排出，通过腺苷脱氨酶抑制活性来衡量。

In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity.

来源:DrugBank

吸收、分配和排泄

• 清除

68毫升/分钟/平方米

68 mL/min/m2

来源:DrugBank

吸收、分配和排泄

经静脉注射0.25 mg/kg剂量的戊酸酯，每日一次，连续4或5天，对少数晚期、难治性癌症患者进行监测，其血药浓度大约在3.2-9.7 ng/ml之间。血药浓度似乎随剂量的增加而线性增加；在一项针对白血病患者的研究中，给药0.25或1 mg/kg戊酸酯30分钟静脉输注后1小时测定的血药浓度平均值分别约为0.4或1.26 ug/ml。

Plasma concentrations of pentostatin following direct iv injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/ml. Plasma concentrations appear to increase linearly with dose; in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30 min iv infusion averaged approximately 0.4 or 1.26 ug/ml, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚未有文献记录平均或绝对血浆腺苷或脱氧腺苷浓度与喷托司汀治疗反应或毒性反应之间存在明显相关性；然而，有限的数据表明，对药物的反应可能与淋巴母细胞中脱氧腺苷三磷酸与腺苷三磷酸的比率有关。此外，据报道，血浆中脱氧腺苷的增加与红细胞和淋巴母细胞中脱氧腺苷三磷酸的积累平行，并且毒性反应似乎与红细胞中脱氧腺苷三磷酸与腺苷三磷酸的比率有关。

No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin; however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts. In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts, and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R22
• WGK Germany：
  3
• 危险品运输编号：
  UN 2811 6.1 / PGIII
• 海关编码：
  2934999090
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P264,P270,P301+P310,P321,P330,P405,P501
• 危险性描述：
  H301,H350,H360

制备方法与用途

生物活性

Pentostatin 是有效的腺苷脱氨酶抑制剂，在治疗多种恶性淋巴增生，尤其是毛细胞白血病中非常有效。它还能与某些抗肿瘤药物发挥协同作用，并具有免疫抑制活性。

化学性质

从甲醇-水混合溶液结晶得到白色晶体，熔点为204～209.5℃或220～225℃（>150℃时会变黑）。在pH 7的水中，最大紫外吸收波长为282nm（ε值约为8000）；在pH 11的水中，最大吸收波长为283nm（ε值约为7970）；在pH 2的水中，初始吸收波长为273nm（开始时ε值约为7570，在6.5小时后变为3143）。[α]D^23+ 值分别为+76.4°（水溶液中C=1）和+73.0°（pH 7的缓冲液中C=1）。水中pKa值为5.2。

用途

Pentostatin 是腺苷脱氨酶(ADA)抑制剂，主要用于α-干扰素治疗无效的毛细胞白血病。

生产方法

大规模生产可通过喷妥司汀产生菌 Streptomyces cetrivioticus 的浸入或深层培养来制备：

1. 发酵

   • 选择合适的培养基植入无菌水溶性营养液，在20～45℃（最佳为33～40℃）条件下进行充气和搅拌培育，直至培养液中出现喷妥司汀。
   • 发酵时间受设备类型、大小、搅拌速度及充气速率等因素影响。大规模工业发酵通常需3～7天可得最大收率；短时间发酵则收率较低。

2. 分离与提纯

   • 分离：采用压滤或离心分离，滤饼用水彻底洗涤后合并洗液和滤液，并调pH值至约9.2。减压浓缩并冷却析出沉淀，用硅藻土作助滤剂过滤除去。
   • 滤液用水稀释并调pH值至约8.3，然后吸附于活性炭或Darco G-60柱子上进行纯化。分批或连续操作均可。
   • 丙酮水溶液用于洗脱，浓缩后通过活性炭柱进一步纯化，得到喷妥司汀的固体产物。

以上方法确保了Pentostatin 的高效生产和高纯度。

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
  ——	3-(2-deoxy-β-D-erythro-pentofuranosyl)-6,7-dihydroimidazo<4,5-d><1,3>diazepin-8(3H)-one	69196-03-8	C11H14N4O4	266.257

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	pentostatin	82264-17-3	C11H16N4O4	268.272
  ——	[3-(2-Deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8 tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol]-5'-phosphoric Acid-(3-dodecylmercapto-2-decyloxy)-propyl Ester	——	C36H67N4O8PS	746.99
  腺苷	adenosine	58-61-7	C10H13N5O4	267.244

反应信息

• 作为反应物：
  描述：

  phosphoric acid mono(3-dodecylmercapto-2-decyloxy)-1-propyl ester 、 脱氧助间型霉素 在 吡啶 、 甲烷磺酸 作用下， 以27%的产率得到[3-(2-Deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8 tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol]-5'-phosphoric Acid-(3-dodecylmercapto-2-decyloxy)-propyl Ester
  参考文献：
  名称：

  LIPID CLEAVAGE ENZYME

  摘要：

  一种尚未在现代技术中描述的膜酶可以从血液白细胞或单核/巨噬细胞的细胞膜分离物中提取。还公开了使用该酶底物制备含有这些底物作为药物活性成分的药物的用途。这些药物可用于将药理活性物质定向到目标细胞并用该物质富集目标细胞。还公开了含有该酶的体外研究系统，用于检测该酶的其他底物。

  公开号：

  US20020106363A1
• 作为产物：
  描述：

  苯酚 生成 脱氧助间型霉素
  参考文献：
  名称：

  Chlorination process, alkylation of products of said process and some

  摘要：

  具有酸性质子和能够共轭碱离子的电子密度离域的分子结构（目标化合物）通过将这些化合物与高氯烷和水溶性碱以及存在相转移催化剂（四烷基铵羟基）接触而被氯化。产生氯化产物，优选产生宝石二氯化合物。这些宝石二氯化合物可用于芳香化合物的烷基化。例如，萘被氯化形成9,9-二氯萘，然后与酚或苯胺等化合物反应，形成9,9-双（羟基苯基）萘、9,9-双（氨基苯基）萘或9-氨基苯基-9-氯萘等化合物。

  公开号：

  US05387725A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [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。
• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。