长春新碱 | 57-22-7

• 物质功能分类: 原料药 - 抗肿瘤药 - 天然来源类抗肿瘤药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 长春花生物碱
• 中文名称: 长春新碱
• 中文别名: 長春新鹼；长春新碱(22-氧代长春花碱)
• 英文名称: Vincristine
• 英文别名: Citomid；methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(13S,15R,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-8-formyl-10-hydroxy-5-methoxy-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
• CAS: 57-22-7
• 化学式: C₄₆H₅₆N₄O₁₀
• 分子量: 824.971
• InChiKey: OGWKCGZFUXNPDA-CFWMRBGOSA-N

物化性质

• 熔点：
  211-216 ºC
• 比旋光度：
  D25 +17°; D25 +26.2° (ethylene chloride)
• 沸点：
  761.92°C (rough estimate)
• 密度：
  1.1539 (rough estimate)
• 溶解度：
  溶于氯仿、二氯甲烷、乙酸乙酯、DMSO、丙酮等。
• 物理描述：
  Vincristine appears as a white crystalline solid. Melting point 218°C. Used as an antineoplastic.
• 颜色/状态：
  Blades from methanol
• 稳定性/保质期：

  STERILE SOLN IN EITHER H2O OR PHYSIOLOGICAL SALINE STORED IN REFRIGERATOR FOR UP TO 2 WK WITHOUT SIGNIFICANT LOSS OF POTENCY

• 旋光度：
  Specific optical rotation: +17 deg at 25 °C/D; +26.2 deg at 25 °C/D (ethylene chloride); max absorption (ethanol): 220, 255, 296 nm (log molar absorptivity = 4.65, 4.21, 4.18)
• 分解：
  When heated to decomposition it emits toxic fumes of oxides of nitrogen.
• 解离常数：
  pKa: 5.0, 7.4 in 33% dimethylformamide

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  60
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  171
• 氢给体数：
  3
• 氢受体数：
  12

ADMET

代谢

肝脏。细胞色素P450酶系的CYP3A亚家族促进了长春新碱的代谢。

Hepatic. Cytochrome P450 isoenzymes of the CYP3A subfamily facilitate the metabolism of vincristine.

来源:DrugBank

代谢

静脉注射... (3)H长春新碱后，72小时内，69%的放射性活性在粪便中回收，12%在尿液中回收。大约一半...以代谢物的形式存在，其紫外光谱表明长春新碱二聚体是完整的。胆瘘患者表现出完整的药物（46.5%）和代谢物（53.5%）的广泛胆汁排泄。观察结果表明，胆汁-粪便途径...在排泄中占主导地位...。

After iv administration of ... (3)H vincristine, 69% of radioactivity was recovered in feces and 12% in urine over 72 hr period. Approx half ... was in form of metabolites, whose UV spectrum suggested that vincristine dimer was intact. Patients with biliary fistula showed extensive biliary excretion of intact drug (46.5%) & of metabolites (53.5%). Observations suggest that biliary-fecal route ... predominate in excretion ... .

来源:Hazardous Substances Data Bank (HSDB)

代谢

长春新碱的代谢命运尚未明确确定；该药物似乎被广泛代谢，可能在肝脏中，但代谢程度尚不清楚，因为该药物在体内也显然会分解。

The metabolic fate of vincristine has not been clearly determined; the drug appears to be extensively metabolized, probably in the liver, but the extent of metabolism is not clear since the drug also apparently undergoes decomposition in vivo.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的总结：大多数来源认为，在母体抗肿瘤药物治疗期间，母乳喂养是禁忌的。由于长春新碱的半衰期较长，治疗结束后恢复母乳喂养可能是不切实际的。化疗可能会不利地影响母乳的 normal microbiome 和化学成分。 ◉ 对哺乳婴儿的影响：在一项研究中，一名4个月大的婴儿在母亲接受了连续6周，每周一次的800毫克环磷酰胺静脉注射、2毫克长春新碱静脉注射和每天30毫克泼尼松龙口服的最后一次治疗后9天，出现了中性粒细胞减少症，这很可能是由于环磷酰胺引起的。中性粒细胞减少症持续了至少12天，并伴随着短暂的腹泻。长春新碱对中性粒细胞减少症的影响无法确定。 一名女性在怀孕27周时被诊断出患有B细胞淋巴瘤。在34周4天时诱导分娩，并在分娩后第二天开始使用标准的利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松治疗方案，剂量未明确说明，每21天一个周期。她在每个周期的前10天泵奶并丢弃，给婴儿喂食捐赠的奶，然后在下一个治疗周期前的剩余10天母乳喂养婴儿。母乳喂养暂停的10天是根据长春新碱大约3个半衰期来确定的。在完成4个周期的化疗后，她的婴儿据报道是健康且没有出现任何并发症。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It is probably impractical to resume breastfeeding after vincristine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. ◉ Effects in Breastfed Infants:In a 4-month-old, neutropenia was probably caused by cyclophosphamide in a mother 9 days after the last of 6 weekly doses of 800 mg cyclophosphamide intravenously, 2 mg vincristine intravenously and daily doses of 30 mg of prednisolone orally. Neutropenia persisted at least 12 days and was accompanied by a brief episode of diarrhea. The contribution of vincristine to the neutropenia cannot be determined. A woman was diagnosed with B-cell lymphoma at 27 weeks of pregnancy. Labor was induced at 34 4/7 weeks and treatment was begun with a standard regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in unspecified doses on a 21-day cycle, starting on day 2 postpartum. She pumped and discarded her milk and fed her infant donor milk for the first 10 days of each cycle and then breastfed her infant for the remaining 10 days before the next treatment cycle. The 10-day period of breastfeeding abstinence was determined by using about 3 half-lives of vincristine. After completion of 4 cycles of chemotherapy, her infant was reportedly healthy and developing without any complications. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

硫酸长春新碱与伊曲康唑（已知是代谢途径的抑制剂）同时给药据报道会导致神经肌肉副作用更早出现和/或增加严重程度（参见不良反应）。这种相互作用被认为与抑制长春新碱的代谢有关。

Concurrent administration of vincristine sulfate with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or an increased severity of neuromuscular side effects (see Adverse Reactions). This interaction is presumed to be related to inhibition of the metabolism of vincristine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

口服或静脉注射苯妥英钠与包括硫酸长春新碱在内的抗肿瘤化疗方案的联合给药已被报道会降低抗惊厥药的血液水平并增加癫痫发作活动。剂量调整应基于连续的血液水平监测。硫酸长春新碱对此相互作用的贡献尚不确定。这种相互作用可能是因为苯妥英钠的吸收减少以及其代谢和排泄速率的增加。

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vincristine sulfate has been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vincristine sulfate to this interaction is not certain. The interaction may result from reduced absorption of phenytoin and an increase in the rate of its metabolism and elimination.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

牛脑神经节苷脂对长春新碱神经毒性的影响在10天鸡胚背根神经节细胞的离体培养中进行了研究。药物的作用通过计算具有神经突起的细胞数量或单个具有神经突起的细胞中神经突起的总长度来量化。长春新碱（1至1000 pg/mL）的给药抑制了细胞的神经突起生长，而神经节苷脂（10至1000 ug/mL）以浓度依赖性的方式对抗这种抑制作用。电子显微镜揭示了长春新碱诱导神经突起中的微管碎片化和纵向错位，并显示了神经节苷脂对这种损害作用的防护。结果表明，外源性给予神经节苷脂可以减轻长春新碱在体外的神经毒性。

The effects of bovine brain gangliosides on the neurotoxicity of vincristine were investigated in dissociated cultures of dorsal root ganglion cells from 10 day chick embryos. The effects of the drugs were quantified as the numbers of neurite bearing cells or total neurite length in individual neurite bearing cells. The administration of vincristine (1 to 1000 pg/mL) inhibited neurite outgrowth from the cells, whereas gangliosides (10 to 1000 ug/mL) protected them against this inhibition in a concentration dependent manner. Electron microscopy revealed vincristine induced fragmentation and longitudinal disorientation of microtubules in neurites and showed the protection by gangliosides against such damaging effects. Results show that exogenous administration of gangliosides attenuates the neurotoxicity of vincristine in vitro.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

长春新碱已显示出能够克服P388白血病对长春碱的获得性耐药性，无论是在体外还是体内。为了研究这种作用的特异性，研究了在慢性淋巴细胞白血病患者淋巴细胞、T-急性淋巴细胞白血病细胞系（GM 3639）和8名正常健康志愿者的外周血淋巴细胞中添加长春新碱对长春碱细胞毒性的影响。使用差染细胞毒性分析，证明了1 uM浓度的长春新碱在0.04-0.25 ug/L的浓度下增强了长春碱对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性。然而，对抗对照组的外周血淋巴细胞并未观察到细胞毒性的增强。数据显示长春新碱优先增强了对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性，但对淋巴细胞没有观察到细胞毒性的增强。

Verapamil has been shown to overcome acquired drug resistance to vincristine in P388 leukemia both in vitro and in vivo. To study the selectivity of this action, the effect of addition of verapamil on the cytotoxicity of vincristine was studied using lymphocytes from eight patients with chronic lymphocytic leukemia, lymphoblasts from a T-acute lymphoblastic leukemia cell line (GM 3639), and peripheral blood lymphocytes from eight normal healthy volunteers. Using the differential staining cytotoxicity assay, it was demonstrated that verapamil at 1 uM concentration potentiated the in vitro cytotoxicity of vincristine on chronic lymphocytic leukemia and GM 3639 cells in concentrations of 0.04-0.25 ug/L. There was however, no enhancement of cytotoxicity noted against the control peripheral blood lymphocytes. The data demonstrate that verapamil preferentially enhances the in vitro cytotoxicity of vincristine on chronic lymphocytic leukemia and GM 3639 cells but no enhancement of cytotoxicity is seen against peripheral blood lymphocytes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 消除途径

肝脏是人类和动物的主要排泄器官。注射的硫酸长春碱剂量的80%通过粪便排出。10-20%通过尿液排出。

The liver is the major excretory organ in humans and animals. 80% of an injected dose of vincristine sulfate is excreted via feces. 10 - 20% is excreted via urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在注射后的15到30分钟内，超过90%的药物从血液中分布到组织中，在那里它紧密但不是不可逆地结合。

Within 15 to 30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not irreversibly, bound.

来源:DrugBank

吸收、分配和排泄

中枢神经系统白血病在接受长春新碱治疗并处于血液学缓解期的患者中的发展被解释为证据表明...长春新碱...穿透血脑屏障的能力较差。长春新碱...可以以比静脉给药大几倍的剂量注入肿瘤的动脉血液供应中，而毒性相当；因此，局部摄取或破坏非常迅速。长春花生物碱似乎主要通过肝脏排泄进入胆汁。

Development of CNS leukemia in patients receiving vincristine and in hematological remission has been interpreted as evidence that ... /vincristine/ penetrates blood-brain barrier poorly. Vincristine ... can be infused into arterial blood supply of tumors in doses several times larger than those that can be admistered iv with comparable toxicity; thus either local uptake or destruction is very rapid. Vinca alkaloids appear to be excreted primarily by liver into bile.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

注射后的头几个小时内，狗和猴子的尿排泄量都很低。在两者中，药物分布到了大多数组织中，但浓度最高的部位是肺、肾、脾、胰腺和肝脏。在猴子中，长春新碱及其代谢物迅速从血浆进入脑脊液，形成低浓度的药物，这种状态持续了数天。

Urinary excretion ... over first few hr after injection was ... low in dogs and monkeys. In both ... the drug was distributed to most tissues, but highest concentrations ... found in lung, kidney, spleen, pancreas and liver. In monkeys, vincristine and its metabolites rapidly entered cerebrospinal fluid from plasma to form low concentrations of drug, which persisted for several days.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫酸长春新碱从胃肠道的吸收是不可预测的。在肾功能和肝功能正常的患者中，快速静脉注射2毫克剂量的硫酸长春新碱后，血药浓度会立即达到大约0.19-0.89微摩尔/升的峰值，并且药物会迅速从血液中清除。当使用相同剂量的药物时，与快速静脉注射相比，连续静脉输注的血药浓度-时间曲线下面积有所增加。

Vincristine sulfate is unpredictably absorbed from the Gl tract. Following rapid iv injection of a 2 mg dose of vincristine in patients with normal renal and hepatic function, peak serum drug concentrations of approximately 0.19-0.89 uM occur immediately and the drug is rapidly cleared from serum. The area under the serum vincristine concentration time curve has been shown to be increased following continuous iv infusion compared with rapid iv injection of the drug when comparable doses are administered.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品运输编号：
  UN 1544
• 包装等级：
  II
• 危险类别：
  6.1(a)

制备方法与用途

理化性质

长春新碱（Vincristine, Oncovin, VCR）是从夹竹桃科植物长春花中提取出的生物碱。它具有显著的抗肿瘤作用，目前作为临床抗肿瘤药物使用。在甲醇中重结晶时形成针状结晶，熔点为211～216℃，比旋光度+42°（氯仿）。

长春新碱、长春碱是长春花中具有抗肿瘤活性的二聚吲哚类生物碱，在抗击癌症方面表现出显著疗效。

发现历史

加拿大医生罗伯特·诺布尔（Robert Noble）是一位研究糖尿病的医学家。他的哥哥克拉克·诺布尔（Clark Noble，对发现胰岛素做出了巨大贡献）听说“牙买加人将长春花当作茶来治疗糖尿病”，并将这一消息告知了罗伯特，并寄了一些样品给他。和大多数药物学家一样，罗伯特也是通过民间医学获取信息，然后经过科学验证，分离出有效的化合物以开发新药。

通过给小白鼠和兔子注射长春花提取液，他们发现长春花并不能降低血糖浓度。然而令人惊讶的是，灭菌的长春花提取液却导致了小白鼠肝脏和肾脏脓肿。进一步研究揭示，长春花提取液破坏了小白鼠的免疫系统，并直接损害了脊髓造血细胞，从而降低了血液中负责免疫的能力。

敏锐的罗伯特很快意识到，这种成分可以杀死白细胞。因此，他认为长春花对治疗白血病具有潜在疗效。白血病是由骨髓异常导致不正常白血球大量繁殖所致。

在敏锐地认识到长春花可能对白血病有潜在疗效后，罗伯特邀请了化学家查尔斯·比尔（Charles Beer）加入研究团队，共同着手分离长春花中的特殊成分。1958年，他们最终得到一个具有活性的生物碱，并命名为长春新碱（Vinblastine）。后来与美国著名医药公司Eli Lilly合作研发，成功推出抗癌药物——长春新碱，其疗效比长春花碱更好，是治疗白血病的首选化疗药物，特别对急性淋巴性白血病、霍奇金氏淋巴瘤等癌症有显著效果。

药理作用

长春新碱能抗癌，疗效比长春碱约高10倍。它可用于治疗急性淋巴细胞性白血病，对其他急性白血病、何杰金氏病、淋巴肉瘤、网状细胞肉瘤和乳腺癌也有一定疗效。长春新碱与长春花碱（Vinblastine）、泛洛洛新及泛洛洗汀等一起存在于蔓长春花中的生物碱具有使细胞分裂（有丝分裂）在中期停止的作用，这类似于化疗药物的效果。

适应症

• 急性白血病，尤其是儿童急性白血病
• 恶性淋巴瘤
• 生殖细胞肿瘤
• 小细胞肺癌、尤文肉瘤、肾母细胞瘤、神经母细胞瘤
• 乳腺癌、慢性淋巴细胞白血病、消化道癌、黑色素瘤及多发性骨髓瘤等

典型不良反应

• 骨髓功能抑制
• 消化道反应
• 神经系统毒性：四肢麻木、腱反射迟钝或消失、外周神经炎、便秘、麻痹性肠梗阻、运动神经和感受神经及脑神经症状
• 血栓性静脉炎，注射时漏至血管外可造成局部坏死

化学性质

长春新碱是白色结晶体，易溶于甲醇、乙醇、DMSO等有机溶剂。

用途

天然植物抗肿瘤药，用于治疗急性白血病和恶性淋巴瘤、小细胞肺癌及乳腺癌。

反应信息

• 作为反应物：
  描述：

  长春新碱 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 甲醇 为溶剂， 反应 48.0h， 以70%的产率得到desacetylvincristine
  参考文献：
  名称：

  Folate–Vinca Alkaloid Conjugates for Cancer Therapy: A Structure–Activity Relationship

  摘要：

  Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted.

  DOI：

  10.1021/bc400441s
• 作为产物：
  描述：

  硫酸长春新碱 在 sodium carbonate 作用下， 以 甲醇 、 氯仿 、 水 为溶剂， 以98%的产率得到长春新碱
  参考文献：
  名称：

  WO2007/98091

  摘要：

  公开号：

文献信息

• METHODS AND SYSTEMS FOR DESIGNING AND/OR CHARACTERIZING SOLUBLE LIPIDATED LIGAND AGENTS
  申请人：TUFTS MEDICAL CENTER

  公开号：US20160052982A1

  公开（公告）日：2016-02-25

  The present application provides methods for preparing soluble lipidated ligand agents comprising a ligand entity and a lipid entity, and in some embodiments, provides relevant parameters of each of these components, thereby enabling appropriate selection of components to assemble active agents for any given target of interest.

  本申请提供了制备可溶性脂质化配体药剂的方法，包括配体实体和脂质实体，并在某些实施例中提供了这些组分的相关参数，从而使得能够适当选择组分来组装出针对任何感兴趣的靶点的活性药剂。
• BLOCK COPOLYMERS FOR STABLE MICELLES
  申请人：Intezyne Technologies, Inc.

  公开号：US20130280306A1

  公开（公告）日：2013-10-24

  The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same. Compositions herein are useful for drug-delivery applications.

  本发明涉及聚合物化学领域，更具体地说是涉及多区块共聚物以及包含相同的多区块共聚物胶束。本发明的组合物适用于药物输送应用。
• Biosynthesis of the Indole Alkaloids. Cell-free Systems fromCatharanthus roseus Plants
  作者：James P. Kutney、Lewis S. L. Choi、Toshio Honda、Norman G. Lewis、Toshitsugu Sato、Kenneth L. Stuart、Brian R. Worth

  DOI：10.1002/hlca.19820650716

  日期：1982.11.3

  Cell-free systems from Catharanthus roseus plants are utilized for various studies relating to the biosynthesis of indole alkaloids. Tryptamine (5) and secologanin (6), two fundamental building units, are shown to be incorporated into the alkaloid vindoline (7). In another study, catharanthine (18) and vindoline (7) are utilized by this enzyme system and coupled to the important bisindole biointermediate

  长春花植物的无细胞系统被用于与吲哚生物碱的生物合成有关的各种研究。两种形式的基本构建单元-色胺（5）和secologanin（6）已显示已掺入生物碱长春花碱（7）中。在另一项研究中，该酶系统利用了catharanthine （18）和vindoline（7），并与重要的双吲哚生物中间体3'，4'-anhydrovinblastine1 （17）偶联。后者又被引入并转化为天然生物碱亮氨酸（8），凯瑟琳（9）和长春碱（10），从而提供有关这些复杂分子生物合成的信息。高压液相色谱法对酶混合物的分析揭示了参与18和7偶联的酶。
• Hypoxia-Activated Anti-Cancer Agents
  申请人：Matteucci Mark

  公开号：US20080132458A1

  公开（公告）日：2008-06-05

  Prodrugs of cyclic anthracyclin toxins comprising a hypoxia-activated trigger and are disclosed. In addition, methods of treating cancer using the compounds of the invention are disclosed.

  环蒽毒素的前药包括一个缺氧活化触发器，并且已经披露。此外，还披露了使用该发明化合物治疗癌症的方法。
• COMBINATIONS OF PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND CHEMOTHERAPEUTIC AGENTS FOR THE TREATMENT OF HEMATOPOIETIC MALIGNANCIES
  申请人：Ebens, JR. Allen J.

  公开号：US20100233164A1

  公开（公告）日：2010-09-16

  Combinations of PI3K inhibitor compounds having Formula I and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hematopoietic malignancies. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  具有I式的PI3K抑制剂化合物及其立体异构体、几何异构体、互变异构体、代谢产物和药学上可接受的盐的组合物，可用于治疗造血恶性肿瘤。本文披露了使用这种组合物在哺乳动物细胞中进行体外、体内和原位诊断、预防或治疗此类疾病或相关病理条件的方法。