环磷酰胺 | 50-18-0

• 物质功能分类: 生物化工 - 抑制剂 - 免疫抑制剂
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 环磷酰胺
• 中文别名: P-[N,N-双(beta-氯乙基)]-1-氧-3-氮-2-磷杂环己烷-P-氧化物
• 英文名称: cyclophosphamide
• 英文别名: Cyclophosphamid；2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide；endoxan；CPA；CYP；N,N-bis(2-chloroethyl)-2-oxo-1,3,2λ5-oxazaphosphinan-2-amine
• CAS: 50-18-0
• 化学式: C₇H₁₅Cl₂N₂O₂P
• mdl: MFCD00005978
• 分子量: 261.088
• InChiKey: CMSMOCZEIVJLDB-UHFFFAOYSA-N

物化性质

• 熔点：
  41-45°C
• 沸点：
  336.1±52.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)
• 溶解度：
  温和加热和超声波下，水中≥11.85 mg/mL； DMSO 中≥13.05 mg/mL；乙醇中≥50.8 mg/mL
• 物理描述：
  Cyclophosphamide is a fine white crystalline powder. Odorless with a slightly bitter taste. Melting point 41-45°C. A 2% solution has pH of 4 to 6. Used medicinally as an antineoplastic agent.
• 颜色/状态：
  LIQUEFIES ON LOSS OF ITS WATER OF CRYSTALLIZATION
• 气味：
  Odorless
• 味道：
  Slightly bitter
• 闪点：
  113 °C c.c.
• 蒸汽压力：
  Vapor pressure, Pa at 25 °C: 0.006 (calculated)
• 稳定性/保质期：
  Constitute solns should be used within 24 hr if stored at room temp or within 6 days if stored under refrigeration. When constituted with sterile water for injection or paraben-preserved bacteriostatic water for injection to a concn of 21 mg/ml, <1.5% cyclophosphamide decomposition will occur within 8 hr at 24-27 °C & within 6 days at 5 °C.
• 分解：
  When heated to decomposition it emits highly toxic fumes of /phosphorus oxides, nitrogen oxides, & hydrogen chloride/.

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

新陈代谢和活化发生在肝脏。75%的药物由细胞色素P450同种物激活，包括CYP2A6、2B6、3A4、3A5、2C9、2C18和2C19。CYP2B6同种物是具有最高4-羟基酶活性的酶。环磷酰胺经历活化最终形成活性代谢物，包括磷酰亚胺芥和丙烯醛。环磷酰胺似乎能诱导其自身的代谢，这导致清除率整体增加，4-羟基代谢物的形成增加，以及重复给药后t1/2值缩短。

Metabolism and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19. The CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration.

来源:DrugBank

代谢

环磷酰胺通过肝脏细胞色素P450系统激活。环磷酰胺首先转化为4-羟基环磷酰胺，它与环状同分异构体醛磷酰胺处于稳态。体外研究使用人肝微粒体和克隆的P450异构酶已经显示，环磷酰胺通过P450异构酶的CYP2B组激活。4-羟基环磷酰胺可能会在肝脏或肿瘤组织中，也可能通过其他酶，被醛氧化酶进一步氧化，产生代谢物羧基磷酰胺和4-酮基环磷酰胺，这两种代谢物都不具有显著的生物活性。这些次要反应似乎将肝脏损伤降至最低，而大量的活性代谢物，如4-羟基环磷酰胺及其同分异构体醛磷酰胺，则通过循环系统输送到靶点。在肿瘤细胞中，醛磷酰胺会自发裂解，生成等量的磷酰亚胺芥和丙烯醛。前者被认为是抗肿瘤效果的原因。后者可能是环磷酰胺治疗期间出现的血尿性膀胱炎的原因。通过静脉注射美司钠（一种易于在尿液酸环境中与丙烯醛反应的巯基化合物），可以降低膀胱炎的强度或预防其发生。静脉给药后，尿液中未改变的环磷酰胺的回收量最小。口服给药后1小时达到血浆中的最大浓度，血浆中的半衰期约为7小时。

... /Cyclophosphamide/ is activated by the hepatic cytochrome P450 system. Cyclophosphamide is first converted to 4-hydroxycyclophosphamide, which is in a steady state with the acyclic tautomer aldophosphamide. In vitro studies with human liver microsones & cloned P450 isoenzymes have shown that cyclophosphamide is activated by the CYP2B group of P450 isoenzymes... . 4-hydroxycyclophosphamide may be oxidized further by aldehyde oxidase either in liver or in tumor tissue & perhaps by other enzymes, yielding the metabolites carboxyphosphamide & 4-ketocyclophsphamide, neither of which possesses significant biological activity. It appears that hepatic damage is minimized by theses secondary reactions, whereas significantl amoutns of the active metabolies, such as 4-hydroxycyclophosphamide & its tautomer, aldophosphamed, are transported to the target sites by the circulatory system. In tumor cells, the aldophosphamide cleaves spontaneously, generating stoichiometric amounts of phosphoramide mustard & acrolein. The former is believed to be responsible for antitumor effects. The latter cmpd may be responsible for the hemorrhagic cystitis seen during therapy with cyclophosphamide. Cystitis can be reduced in intensity or prevented by the pareneteral admin of mesna, a sulfhydryl cmpd that reacts readily with acrolein in the acid environment of the urinary tract. ... Urinary & fecal recovery of unchanged cyclophosphamide is minimal after iv admin. Maximal concns in plasma are achieved 1 hr after oral admin, & the half-life in plasma is about 7 hr.

来源:Hazardous Substances Data Bank (HSDB)

代谢

绵羊口服环磷酰胺。在收集的尿液中，观察到2种代谢物，并鉴定为O-(2-羧基乙基)-N,N-双(2-氯乙基)磷酰亚胺酸酯和2-(双(2-氯乙基)氨基)四氢-2H-1,3,2-氧氮杂磷酰2,4-二氧化物（4-酮环磷酰胺）。

SHEEP WERE ORALLY DOSED WITH CYCLOPHOSPHAMIDE. IN COLLECTED URINE, 2 METABOLITES WERE OBSERVED AND CHARACTERIZED AS O-(2-CARBOXYETHYL)-N,N-BIS (2-CHLOROETHYL)PHOSPHORODIAMIDATE & 2-(BIS (2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZOPHOSPHORINE 2,4-DIOXIDE (4-KETOCYCLOPHOSPHAMIDE).

来源:Hazardous Substances Data Bank (HSDB)

代谢

一个具有强大烷基化和细胞毒性的反应性代谢物，N,N-双-(2-氯乙基)磷酰亚胺酸，最近从环磷酰胺的氧化产物和小鼠肝脏微染色质中被分离出来。

A REACTIVE METABOLITE, N,N-BIS-(2-CHLOROETHYL)PHOSPHORODIAMIDIC ACID, WHICH POSSESSES POTENT ALKYLATING & CYTOTOXIC PROPERTIES, HAS RECENTLY BEEN ISOLATED FROM THE OXYGENATION PRODUCTS OF CYCLOPHOSPHAMIDE AND MOUSE LIVER MICROCHROMOSOMES.

来源:Hazardous Substances Data Bank (HSDB)

代谢

环磷酰胺口服吸收良好，口服后约一小时血药浓度达到峰值。该药物也可以静脉给药。这种药物在肝脏中代谢为细胞毒代谢物，4-羟基环磷酰胺，它与无环构象异构体，aldophosphamide，处于平衡状态。尽管这些代谢物的大部分被进一步氧化成无活性产物，但一些aldophosphamide会转化为phophoramidemustard，它与DNA发生烷基化反应，并生成丙烯醛。

Cyclophosphamide is well absorbed orally, and peak plasma levels appear about one hour after oral use. It is also administered intravenously. This drug is metabolized in the liver to the cytotoxic metabolite, 4-hydroxycyclophosphamide, which is in equilibrium with the acyclic tautomer, aldophosphamide. Although the major fraction of these metabolites is oxidized further to inactive products, some aldophosphamide is converted to phophoramidemustard, which alkylates DNA, and to acrolein.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

烷基化剂通过三种不同的机制发挥作用：1）将烷基团附着到DNA碱基上，导致DNA在修复酶试图替换被烷基化的碱基时被切碎，阻止受影响的DNA进行DNA合成和RNA转录；2）通过形成交联（DNA中原子之间的键）造成DNA损伤，阻止DNA分离以进行合成或转录；3）诱导核苷酸错配，导致突变。

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

轻度和暂时性的血清转氨酶水平升高在多达43%的使用环磷酰胺治疗的癌症患者中发现。这些异常通常是无需剂量调整的无症状和暂时的。酶水平升高在高剂量和静脉治疗中更为常见。在某些情况下，显著的升高可能需要调整剂量或停止使用环磷酰胺（案例3）。 从标准剂量的环磷酰胺引起的临床上明显的肝损伤是不常见的，但已经发表了几例急性肝损伤伴黄疸的病例报告（案例1和2）。发病时间通常在开始使用环磷酰胺后的2到8周内，血清酶水平升高的模式是肝细胞型。免疫过敏和自身免疫特征是不常见的。在大多数情况下，损伤是自限性的，在停止使用后1到3个月内解决；然而，也有致命的案例报道。重新接触后复发的描述也已经提出。 作为癌症化疗或与全身照射或白消安联合使用作为造血干细胞移植前的骨髓清除治疗的高剂量环磷酰胺可以诱导门脉阻塞性综合征（静脉闭塞性疾病），这可能导致严重的急性肝衰竭和死亡。损伤的发病通常在骨髓清除后的10到20天内，其特点是突然出现的腹痛、体重增加、腹水、血清转氨酶水平（和乳酸脱氢酶）显著升高，随后出现黄疸和肝功能障碍。门脉阻塞性综合征的严重程度可以从短暂、自限性的损伤到急性肝衰竭不等。诊断通常基于肝脏压痛和肿大、体重增加、腹水和黄疸的临床特征。肝活检是诊断性的，但在造血干细胞移植后由于严重的血小板减少而常常被禁忌。 可能性评分：B（高度可能是临床上明显肝损伤的原因）。

Mild and transient elevations in serum aminotransferase levels are found in up to 43% of patients with cancer who are treated with cyclophosphamide. The abnormalities are generally asymptomatic and transient and do not require dose modification. Enzyme elevations are more common with higher doses and with intravenous therapy. In some instances, marked elevations arise warranting dose modification or discontinuation of cyclophosphamide (Case 3). Clinically apparent liver injury from standard doses of cyclophosphamide is uncommon, but several case reports of acute liver injury with jaundice have been published (Cases 1 and 2). The onset is within 2 to 8 weeks of starting cyclophosphamide and the pattern of serum enzyme elevations is hepatocellular. Immunoallergic and autoimmune features are uncommon. The injury in most cases is self-limited and resolves within 1 to 3 months of stopping; however, fatal instances have been reported. Recurrence on reexposure has been described. High doses of cyclophosphamide given as chemotherapy of cancer or as myeloablative therapy in combination of total body irradiation or busulfan in preparation for hematopoietic cell transplantation can induce sinusoidal obstruction syndrome (veno-occlusive disease), which can be severe leading to acute liver failure and death. The onset of injury is usually within 10 to 20 days of the myeloablation and is characterized by a sudden onset of abdominal pain, weight gain, ascites, marked increase in serum aminotransferase levels (and lactic dehydrogenase), and subsequent jaundice and hepatic dysfunction. The severity of sinusoidal obstruction syndrome varies from a transient, self limited injury to acute liver failure. The diagnosis is usually based on clinical features of tenderness and enlargement of the liver, weight gain, ascites and jaundice. Liver biopsy is diagnostic but often contraindicated, because of severe thrombocytopenia after hematopoietic cell transplantation. Likelihood score: B (highly likely cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

环磷酰胺

Compound:cyclophosphamide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：5

Severity Grade:5

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，血药浓度峰值出现在1小时。

After oral administration, peak concentrations occur at one hour.

来源:DrugBank

吸收、分配和排泄

• 消除途径

环磷酰胺主要通过代谢物的形式消除。10-20%以原形从尿液中排出，4%在静脉给药后随胆汁排出。

Cyclophosphamide is eliminated primarily in the form of metabolites. 10-20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.

来源:DrugBank

吸收、分配和排泄

• 分布容积

30-50升

30-50 L

来源:DrugBank

吸收、分配和排泄

• 清除

总体清除率 = 63 ± 7.6 升/千克。

Total body clearance = 63 ± 7.6 L/kg.

来源:DrugBank

吸收、分配和排泄

环磷酰胺口服吸收良好。

Cyclophosphamide is well absorbed orally.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 安全说明：
  S22,S24/25
• 危险品运输编号：
  UN 1851
• RTECS号：
  RP5950000
• 海关编码：
  2924299090
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 储存条件：
  | 室温，惰性气体环境中 |

SDS

Name:	Cyclophosphamide monohydrate 97% Material Safety Data Sheet
Synonym:	N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide monohydrate; 2-[Bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazophosphorine 2-oxide monohydrate; Cancer research tool
CAS:	50-18-0

Section 1 - Chemical Product MSDS Name:Cyclophosphamide monohydrate 97% Material Safety Data Sheet
Synonym:N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide monohydrate; 2-[Bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazophosphorine 2-oxide monohydrate; Cancer research tool

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
50-18-0	Cyclophosphamide monohydrate	97	unlisted

Hazard Symbols: T
Risk Phrases: 25 41 45 46 48/23/24/25 61

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Toxic if swallowed. Risk of serious damage to eyes. May cause cancer. May cause heritable genetic damage. Toxic : danger of serious damage to health by prolonged exposure through inhalation, contact with skin and if swallowed. May cause harm to the unborn child.
Potential Health Effects
Eye:
Causes severe eye irritation and possible injury.
Skin:
May cause skin irritation. May be harmful if absorbed through the skin.
Ingestion:
May cause irritation of the digestive tract. Poison by ingestion.
May cause nausea and vomiting.
Inhalation:
May cause respiratory tract irritation. May be harmful if inhaled.
May cause nausea and possible vomiting.
Chronic:
May cause cancer in humans. May cause reproductive and fetal effects.

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Section 4 - FIRST AID MEASURES
Eyes: Immediately flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid immediately.
Skin:
Get medical aid immediately. Immediately flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes.
Ingestion:
Get medical aid immediately. Wash mouth out with water.
Inhalation:
Get medical aid immediately. Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen.
Notes to Physician:
Treat symptomatically and supportively.

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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. Will burn if involved in a fire. This material in sufficient quantity and reduced particle size is capable of creating a dust explosion.
Extinguishing Media:
Use water spray, dry chemical, carbon dioxide, or chemical foam.

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Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container. Avoid generating dusty conditions. Provide ventilation.

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Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Minimize dust generation and accumulation. Do not get in eyes, on skin, or on clothing. Take precautionary measures against static discharges. Do not breathe dust. Use only with adequate ventilation.
Storage:
Store in a cool, dry place. Store in a tightly closed container.
Keep under an argon blanket.

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Facilities storing or utilizing this material should be equipped with an eyewash facility and a safety shower. Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 50-18-0: CAS# 6055-19-2: 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.

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Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Solid
Color: white to almost white
Odor: odorless
pH: 4 - 6 (2% aq soln)
Vapor Pressure: 0.000033 HPa @ 20 deg C
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 49 - 53 deg C
Autoignition Temperature: Not available.
Flash Point: > 112 deg C (> 233.60 deg F)
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature: 90 deg C
Solubility in water: 40 g/l water
Specific Gravity/Density:
Molecular Formula: C7H15Cl2N2O2P.H2O
Molecular Weight: 279.09

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable at room temperature in closed containers under normal storage and handling conditions. Exothermic decomposition at 90C (Method VDI 2263).
Conditions to Avoid:
Dust generation, excess heat.
Incompatibilities with Other Materials:
Strong oxidizing agents, acids, bases.
Hazardous Decomposition Products:
Hydrogen chloride, nitrogen oxides, phosphine, carbon monoxide, oxides of phosphorus, carbon dioxide.
Hazardous Polymerization: Has not been reported.

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 50-18-0: RP5950000 CAS# 6055-19-2: RP6157750 LD50/LC50:
CAS# 50-18-0: Oral, mouse: LD50 = 137 mg/kg; Oral, rat: LD50 = 100 mg/kg.
CAS# 6055-19-2: Oral, mouse: LD50 = 350 mg/kg; Oral, rat: LD50 = 94 mg/kg.
Primary irritative effect to the eyes: Corrosive, rabbit, OECD 405.
Carcinogenicity:
Cyclophosphamide (anhydrous form) - California: carcinogen, initial date 2/27/87 NTP: Known carcinogen IARC: Group 1 carcinogen Cyclophosphamide monohydrate - California: carcinogen, initial date 2/27/87 IARC: Group 1 carcinogen Other:
See actual entry in RTECS for complete information.

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Section 12 - ECOLOGICAL INFORMATION
Other No information available.

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

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Section 14 - TRANSPORT INFORMATION

IATA
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.*
Hazard Class: 6.1
UN Number: 2811
Packing Group: III
IMO
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing Group: III
RID/ADR
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing group: III
USA RQ: CAS# 50-18-0: 10 lb final RQ; 4.54 kg final RQ

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: T
Risk Phrases:
R 45 May cause cancer.
R 46 May cause heritable genetic damage.
R 61 May cause harm to the unborn child.
R 25 Toxic if swallowed.
R 41 Risk of serious damage to eyes.
R 48/23/24/25 Toxic : danger of serious damage to
health by prolonged exposure through inhalation,
contact with skin and if swallowed.
Safety Phrases:
S 53 Avoid exposure - obtain special instructions
before use.
S 15 Keep away from heat.
S 26 In case of contact with eyes, rinse immediately
with plenty of water and seek medical advice.
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# 50-18-0: No information available.
CAS# 6055-19-2: 3
Canada
CAS# 50-18-0 is listed on Canada's DSL List.
CAS# 50-18-0 is not listed on Canada's Ingredient Disclosure List.
CAS# 6055-19-2 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 50-18-0 is not listed on the TSCA inventory.
It is for research and development use only.
CAS# 6055-19-2 is not listed on the TSCA inventory.
It is for research and development use only.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

烷化剂类抗肿瘤药——环磷酰胺 一、概述

环磷酰胺是一种最常用的烷化剂类抗肿瘤药。常温下为白色结晶或结晶性粉末（失去结晶水即液化），在室温中稳定，溶于水但溶解度不大。其水溶液不稳定，在溶解后应短期内使用；易溶于乙醇。环磷酰胺由Arnold和Bourseaux于1958年首次合成，这种化合物及其衍生物的合成是基于之前抗癌药物结构和作用的研究。

环磷酰胺主要用于肿瘤免疫。进入人体内后，在肝微粒体酶催化下分解释出烷化作用很强的氯乙基磷酰胺(或称磷酰胺氮芥)，从而对多种肿瘤产生细胞毒作用，抑制其生长。近年来，它因证实有免疫抑制作用而被用于治疗自身免疫性疾病，已取得明显疗效。

二、作用机制

环磷酰胺（简称CTX）为细胞周期非特异性细胞毒药物，但对G2期(DNA合成后期)作用更为强烈。它的主要免疫抑制机制如下：

1. 减少T及B淋巴细胞：使T和B淋巴细胞绝对数目减少，早期对B淋巴细胞影响更明显。
2. 抑制淋巴细胞反应：明显抑制淋巴细胞对特异性抗原刺激后的母细胞转化。对有丝分裂素刺激的抑制作用不如对特异性抗原。
3. 抑制抗体反应及皮肤迟缓变态反应：降低升高的免疫球蛋白水平，长期使用（几年）后可能出现低丙球蛋白血症。
4. 选择性抑制B淋巴细胞功能：减少某些B淋巴细胞自发产生免疫球蛋白，并抑制一般的有丝分裂原受刺激后的免疫球蛋白产生。

环磷酰胺在代谢前并无细胞毒作用。其活化必须依赖肝细胞微粒体酶系统中的细胞色素P450氧化形成4-羟基环磷酰胺，开环后再变成活性很强的磷酰胺氮芥，从而发挥细胞毒作用。

三、适应症

适用于治疗恶性淋巴瘤、多发性骨髓瘤、淋巴细胞白血病、宫颈癌、前列腺癌、结肠癌、支气管癌、神经母细、卵巢癌、乳癌、各种肉瘤及肺癌等。也可用于类风湿关节炎、儿童肾病综合征以及自身免疫疾病的治疗。

四、用法用量 1. 环磷酰胺片：50mg 2. 注射用环磷酰胺：

• 100mg
• 200mg

成人常用量：

• 口服每日按体重2~3mg/kg。
• 静脉注射每次4mg/kg，每日或隔日一次。或每次600~1200mg，每7~10日一次。

小儿常用量：

• 口服每日按体重2~6mg/kg。
• 静脉注射每次2—6mg/kg，每日或隔日一次。或每次10~15mg/kg，每周一次，以氯化钠注射液20ml稀释后缓慢注射。

3. 其他用法：

• 抗肿瘤：口服，一次50mg，一日3次；静注，一次每平方米400-600mg，每周一次，总量8g左右为一疗程。也可肌注，剂量同静注。动脉内注射，每次100-500mg，鞘内注射，每次20-40mg，每周1次。
• 免疫抑制：静脉注射，初始剂量3~6mg/kg，维持剂量1.2～3mg/(kg·d)。

五、副作用

1. 胃肠道反应：能引起恶心、呕吐和食欲减退。可给予胃动力药如多潘立酮。
2. 骨髓抑制：需定期化验血常规检查。
3. 出血性膀胱炎：国外报道较为常见，可在治疗期间多饮水以稀释药物浓度。
4. 卵巢功能损害：可能影响生育能力。在有要求生育的年轻病人中使用要慎重。
5. 免疫抑制和肿瘤风险增加：长期应用可能导致继发性肿瘤，但发生率较低。

环磷酰胺作为一种广谱抗肿瘤药，在临床治疗多种肿瘤时表现出显著效果，但也需注意其可能带来的副作用。

反应信息

• 作为反应物：
  描述：

  环磷酰胺 在 sodium hypochlorite 作用下， 以 氯仿 为溶剂， 反应 18.0h， 以87%的产率得到3-chlorocyclophosphamide
  参考文献：
  名称：

  3-卤代环磷酰胺及其类似化合物作为新型抗癌“前药”的合成与评价

  摘要：

  由三氟甲基次萤石，次氯酸钠和溴与抗癌药环磷酰胺反应制得3-氟，3-氯和3-溴环磷酰胺。用次氯酸钠处理顺式和反式-4-苯基环磷酰胺和5，6-苯并环磷酰胺分别得到顺式和反式3-氯-4-苯基环磷酰胺和3-氯-5，6-苯并环磷酰胺。31 P-NMR光谱用于研究这些化合物的反应性：与小鼠肝切片一起孵育时，氟衍生物被还原为环磷酰胺，巯基诱导的3-卤代环磷酰胺还原的反应级数Br约等于Cl，与环磷酰胺对小鼠L-1210和P-388癌症的治疗效果相比，3-氟-和3-氯环磷酰胺的活性较低，尽管氟衍生物比3-氯化合物更有效。分别由（S）-和（R）-环磷酰胺制得的3-氯环磷酰胺的各个R和S对映体在P-388测试系统中的治疗活性无明显差异。

  DOI：

  10.1002/jps.2600720622
• 作为产物：
  描述：

  (2-Oxo-2λ5-[1,3,2]oxazaphosphinan-2-yl)-bis-(2-trimethylsilanyloxy-ethyl)-amine 在 磺酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 25.0h， 生成 环磷酰胺
  参考文献：
  名称：

  A New Method for the Preparation of Ifosfamide and Cyclophosphamide

  摘要：

  2-氯-3-(2-氯乙基)-四氢-2H-1,3,2-氧杂磷杂环戊烷-2-氧化物1和2-氯-四氢-2H-1,3,2-氧杂磷杂环戊烷-2-氧化物2与2-(三甲基硅氧基)乙胺3和双-[2-(三甲基硅氧基)乙基]胺4分别反应，得到类似于异环磷酰胺和环磷酰胺的三甲基硅基化合物5和6。5和6与2-氯-1,3,5-三甲基-1,3,5-三氮杂-2-磷杂环己烷-4,6-二酮7反应，生成二磷化合物8和9，可以通过与亚硫酰氯处理转化为异环磷酰胺11和环磷酰胺12。这种合成表明，可以避免烷基化剂2-氯乙基铵盐和双-(2-氯乙基)铵盐，并且氯原子可以在合成11和12的最终反应步骤中引入。

  DOI：

  10.1515/znb-1997-0810

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。
• Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
  申请人：——

  公开号：US20020143182A1

  公开（公告）日：2002-10-03

  The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): 1 wherein: (a) m is an integer 0 or 1; (b) R 12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar 3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar 4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R 5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.

  该发明涉及某些对治疗癌症和其他疾病有用的杂环化合物，其具有以下式（I）： 1 其中： (a) m是整数0或1； (b) R12是烷基，取代烷基，环烷基，取代环烷基，杂环基，取代杂环基，杂芳基，取代杂芳基，芳基或取代芳基残基； (c) Ar3是芳基，取代芳基，杂芳基或取代杂芳基残基； (d) Ar4是芳基，取代芳基，杂芳基或取代杂芳基残基； (e) R5是氢，羟基，烷基或取代烷基； (f) - - - - - 代表存在或不存在的键；以及 (g) W、X、Y和Z独立或一起是C(O)、C(S)、S、O或NH；或其药学上可接受的盐。
• [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。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。

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