CAS 3778-73-2 MFCD00057374-3-(2-Chloroethyl)-2-((2-chloroethyl)amino)-1,3,2-oxazaphosphinane 2-oxide 异环磷酰胺 TAO{mole}

3-(2-Chloroethyl)-2-((2-chloroethyl)amino)-1,3,2-oxazaphosphinane 2-oxide 异环磷酰胺

CAS 3778-73-2 MFCD00057374

化学结构图

SMILES: O=P1(NCCCl)OCCCN1CCCl

化学属性

Mol. Formula	C7H15Cl2N2O2P
Mol. Weight	261
Melting Point	48 ºC
Appearance	本品为白色结晶状粉末，无臭，无味，在水中易溶，乙醇中易溶，丙酮中略溶，氯仿中溶解。

别名和识别编码

Chemical Name	3-(2-Chloroethyl)-2-((2-chloroethyl)amino)-1,3,2-oxazaphosphinane 2-oxide
CAS Number	3778-73-2
Synonym	2H-1,3,2-Oxazaphosphorin-2-amine, N,3-bis[2-chloroethyl]tetrahydro-, 2-ox 3-(2-Chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide Holoxan I-Pho Ifex N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide Ifomide MJF 9325 Mitoxana N,3-B N,3-Bis N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide N,N-Bis(beta-chloroethyl)-amino-N',O-propylene-phosphoric acid ester N-(2-Chloroethyl)-N'-(2-chloroethyl)-N',O-propylenephosphoric acid diamide NSC 109724 NSC-1097 Z4942 cyfos holoxan1000 ifosfamide (INN)
MDL Number	MFCD00057374
EC Number	223-237-3
Chemical Name Translation	异环磷酰胺
Wiswesser Line Notation	T6NPOTJ AM2G BO B2G
Beilstein Registry Number	0611835
PubChem Substance ID	3690
InChI	InChI=1S/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12)
LabNetwork Molecule ID	LN00222241

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产品应用

A cytostatic agent, related structurally to cyclophosphamide.

安全信息

GHS Symbol

WGK Germany3

Precautionary statements

P201 Obtain special instructions before use. 使用前获取专门指示。
P280 Wear protective gloves/protective clothing/eye protection/face protection. 戴防护手套/防护服/眼睛的保护物/面部保护物。
P301+P310
P305+P351+P338
P308+P313

Hazard statements

H319 Causes serious eye irritation 严重刺激眼睛
H301 Toxic if swallowed 吞食有毒
H350 May cause cancer 可能致癌
H360 May damage fertility or the unborn child 可能对生育能力或未出生婴儿造成伤害
H340 May cause genetic defects 可能导致遗传性缺陷

RTECSRP6050000

Signal word Danger

Personal Protective Equipment Eyeshields, Faceshields, Gloves, type P2 (EN 143) respirator cartridges

Safety Statements

S26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advice 眼睛接触后，立即用大量水冲洗并征求医生意见；
S45 In case of accident or if you feel unwell seek medical advice immediately (show the label where possible) 发生事故时或感觉不适时，立即求医（可能时出示标签）；

Hazard Codes 6.1 T

Risk Statements

R25 Toxic if swallowed 吞咽有毒
R36 Irritating to eyes 刺激眼睛

Packing GroupIII

Hazard Class6.1(b)

Storage condition 2-8°C

UN Number 2811

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Intraperitoneal
SPECIES OBSERVED        : Rodent - rat
DOSE/DURATION           : 940 mg/kg/1Y-I
TOXIC EFFECTS :
   Tumorigenic - Carcinogenic by RTECS criteria
   Skin and Appendages - tumors
   Reproductive - Tumorigenic effects - uterine tumors
REFERENCE :
   NCITR* National Cancer Institute Carcinogenesis Technical Report Series.
   (Bethesda, MD)  No.0-205. For publisher information, see NTPTR*.
   Volume(issue)/page/year: NCI-TR-32,1977

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Intraperitoneal
SPECIES OBSERVED        : Rodent - mouse
DOSE/DURATION           : 450 mg/kg/8W-I
TOXIC EFFECTS :
   Tumorigenic - neoplastic by RTECS criteria
   Lungs, Thorax, or Respiration - tumors
REFERENCE :
   CNREA8 Cancer Research. (Public Ledger Building, Suit 816, 6th & Chestnut
   Sts., Philadelphia, PA 19106)  V.1-    1941-  Volume(issue)/page/year:
   33,3069,1973

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Subcutaneous
SPECIES OBSERVED        : Rodent - mouse
DOSE/DURATION           : 2600 mg/kg/65W-I
TOXIC EFFECTS :
   Tumorigenic - Carcinogenic by RTECS criteria
   Tumorigenic - tumors at site of application
REFERENCE :
   ARZNAD Arzneimittel-Forschung. Drug Research.  (Editio Cantor Verlag,
   Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.)  V.1-    1951-
   Volume(issue)/page/year: 29,483,1979

TYPE OF TEST            : TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE       : Intraperitoneal
SPECIES OBSERVED        : Rodent - mouse
DOSE/DURATION           : 3120 mg/kg/1Y-I
TOXIC EFFECTS :
   Tumorigenic - Carcinogenic by RTECS criteria
   Blood - lymphoma, including Hodgkin's disease
REFERENCE :
   NCITR* National Cancer Institute Carcinogenesis Technical Report Series.
   (Bethesda, MD)  No.0-205.

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Oral
SPECIES OBSERVED        : Human
DOSE/DURATION           : 150 mg/

TYPE OF TEST            : LDLo - Lowest published lethal dose
ROUTE OF EXPOSURE       : Intraperitoneal
SPECIES OBSERVED        : Mammal - cat
DOSE/DURATION           : 100 mg/kg
TOXIC EFFECTS :
   Behavioral - ataxia
   Lungs, Thorax, or Respiration - dyspnea
   Nutritional and Gross Metabolic - body temperature decrease
REFERENCE :
   KSRNAM Kiso to Rinsho.  Clinical Report.  (Yubunsha Co., Ltd., 1-5, Kanda
   Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan)  V.1-    1960-
   Volume(issue)/page/year: 16,431,1982

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Oral
SPECIES OBSERVED        : Human
DOSE/DURATION           : 100 mg/kg
TOXIC EFFECTS :
   Blood - leukopenia
   Blood - thrombocytopenia
REFERENCE :
   CCYPBY Cancer Chemotherapy Reports, Part 3.  (Washington, DC)  V.1-6,
   1968-75.  For publisher information, see CTRRDO.  Volume(issue)/page/year:
   3,33,1972

TYPE OF TEST            : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE       : Oral
SPECIES OBSERVED        : Rodent - mouse
DOSE/DURATION           : 1005 mg/kg
TOXIC EFFECTS :
   Sense Organs and Special Senses (Eye) - lacrimation
   Behavioral - ataxia
   Lungs, Thorax, or Respiration - dyspnea
REFERENCE :
   KSRNAM Kiso to Rinsho.  Clinical Report.  (Yubunsha Co., Ltd., 1-5, Kanda
   Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan)  V.1-    1960-
   Volume(issue)/page/year: 16,431,1982

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Intravenous
SPECIES OBSERVED        : Human - woman
DOSE/DURATION           : 218 mg/kg
TOXIC EFFECTS :
   Brain and Coverings - demyelination
   Brain and Coverings - changes in surface EEG
REFERENCE :
   JTCTDW Jo

TYPE OF TEST            : Mutation test systems - not otherwise specified
TEST SYSTEM             : Bird - chicken Cells - not otherwise specified
DOSE/DURATION           : 5 mg/kg
REFERENCE :
   MUREAV Mutation Research.  (Elsevier Science Pub. B.V., POB 211, 1000 AE
   Amsterdam, Netherlands) V.1-    1964-  Volume(issue)/page/year: 268,115,1992

TYPE OF TEST            : Cytogenetic analysis
TEST SYSTEM             : Human Leukocyte
DOSE/DURATION           : 130 mg/L
REFERENCE :
   HUMAA7 Humangenetik.  (Heidelberg, Fed. Rep. Ger.)  V.1-30, 1964-75.  For
   publisher information, s

TYPE OF TEST            : Sex chromosome loss and nondisjunction
ROUTE OF EXPOSURE       : Oral
TEST SYSTEM             : Insect - Drosophila melanogaster
DOSE/DURATION           : 2 mmol/L/24H
REFERENCE :
   MUREAV Mutation Research.  (Elsevier Science Pub. B.V., POB 211, 1000 AE
   Amsterdam, Netherlands) V.1-

TYPE OF TEST            : DNA damage
TEST SYSTEM             : Mammal - species unspecified Lymphocyte
DOSE/DURATION           : 5600 umol/L
REFERENCE :
   JPMSAE Journal of Pharmaceutical Sciences.  (American Pharmaceutical Assoc.,
   2215 Constitution Ave., NW, Washington, DC 20037)  V.50-    1961-
   Volume(issue)/page/year: 61,2009,1972

TYPE OF TEST            : Sperm Morphology
ROUTE OF EXPOSURE       : Intraperitoneal
TEST SYSTEM             : Rodent - mouse
DOSE/DURATION           : 500 mg/kg/5D (Intermittent)
REFERENCE :
   MUREAV Mutation Research.  (Elsevier Science Pub. B.V., POB 211, 1000 AE
   Amsterdam, Netherlands) V.1-    1964-  Volume(issue)/page/year: 201,113,1988

TYPE OF TEST            : Mutation in microorganisms
TEST SYSTEM             : Bacteria - Salmonella typhimurium
DOSE/DURATION           : 400 ug/plate
REFERENCE :
   TCMUD8 Teratogenesis, Carcinogenesis, and Mutagenesis.  (Alan R. Liss, Inc.,
   41 E. 11th St., New York, NY 10003)  V.1-

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Intravenous
SPECIES OBSERVED        : Rodent - rat
DOSE                    : 260 mg/kg
SEX/DURATION            : female 17-21 day(s) after conception
                          lactating female 21 day(s) post-birth
TOXIC EFFECTS :
   Reproductive - Specific Developmental Abnormalities - urogenital system
   Reproductive - Effects on Newborn - behavioral
REFERENCE :
   KSRNAM Kiso to Rinsho.  Clinical Report.  (Yubunsha Co., Ltd., 1-5, Kanda
   Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan)  V.1-    1960-
   Volume(issue)/page/year:

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Intraperitoneal
SPECIES OBSERVED        : Rodent - mouse
DOSE                    : 20 mg/kg
SEX/DURATION            : female 11 day(s) after conception
TOXIC EFFECTS :
   Reproductive - Fertility - post-implantation mortality (e.g. dead and/or
   resorbed implants per total number of implants)
   Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured
   before birth)
REFERENCE :
   PSEBAA Proceedings of the Society for Experimental Biology and Medicine.
   (Academic Press, Inc., 1 E. First St., Duluth, MN 55802)  V.1-    1903/04-
   Volume(issue)/page/year: 143,965,1973

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Intraperitoneal
SPECIES OBSERVED        : Rodent - rat
DOSE                    : 300 mg/kg
SEX/DURATION            : female 30 day(s) pre-mating
TOXIC EFFECTS :
   Reproductive - Maternal Effects - ovaries, fallopian tubes
REFERENCE :
   KSRNAM Kiso to Rinsho.  Clinical Report.  (Yubunsha Co., Ltd., 1-5, Kanda
   Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan)  V.1-    1960-
   Volume(issue)/page/year: 16,439,1982

TYPE OF TEST            : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE       : Int

其他信息

国内市场情况:由于异环磷酰胺类产品在价格上要比环磷酰胺类产品高出许多，因此在生产环磷酰胺得不到回报的时候，国内几大主要生产环磷酰胺的企业纷纷改换生产线，生产异环磷酰胺。异环磷酰胺是环磷酰胺类衍生物，体外无活性，但在体内却对多种转移性肿瘤有明显抑制作用，可治疗骨及软组织肉瘤、非小细胞肺癌、乳腺癌、头颈部癌、子宫颈癌、食管癌等，1993年在国内正式面世。据了解，目前异环磷酰胺原料药的市场价为8000多元／公斤，制剂类在的18次降价之后，由原来的216元／支，降到每支180多元，企业利润空间有所降低，但相比环磷酰胺而言，依然能获得相对丰厚的回报。在去年医院42种抗肿瘤用药金额的排名中，异环磷酰胺名列13位，在2003年全球抗肿瘤药销售额领先的14个品种中，异环磷酰胺以0.8亿美元位列11位，市场
用途一:抗癌药物。
禁忌症与注意事项:禁忌症严重骨髓抑制患者、对本品过敏者、妊娠及哺乳期妇女禁用。注意事项（1）本品的代谢产物对尿路有刺激性，应用时应鼓励患者多饮水，大剂量应用时应水化、利尿，同时给予尿路保护剂美司钠。（2）低白蛋白血症、肝肾功能不全、骨髓抑制及育龄期妇女慎用。（3）本品水溶液不稳定，须现配现用。（4）用药期间应定期检查白细胞，血小板和肝肾功能测定。孕妇及哺乳期妇女用药:有致突变、致畸胎作用，可造成胎儿死亡或先天畸形，妊娠妇女禁用。本品可在乳汁中排出，在开始用药时必须中止哺乳。
药物相互作用:（1）先前应用顺铂患者，可加重异环磷酰胺的骨髓抑制、神经毒性和肾毒性。（2）同时使用抗凝血药物，可能导致出血危险。（3）同时使用降血糖药，可增强降血糖作用。（4）与其他细胞毒药物联合应用时，应酌情减量。贮藏:遮光，密闭，在30℃以下保存。包装:（1）0.5g （2）1.0g
异环磷酰胺说明书（注射用）:性状:本品为白色结晶或结晶性粉末。药品类别:烷化剂类抗肿瘤药药理毒理:本品在体外无抗癌活性，进入体内被肝脏或肿瘤内存在的磷酰胺酶或磷酸酶水解，变为活化作用型的磷酰胺氮芥而起作用。其作用机制为与DNA发生交叉联结，抑制DNA的合成，也可干扰RNA的功能，属细胞周期非特异性药物。本品抗瘤谱广，对多种肿瘤有抑制作用。药代动力学:按体表面积一次静注3.8～5.0g/m2，血药浓度呈双相，终末半衰期为15小时；按体表面积一次静注1.6～2.4g/m2，血药浓度呈单相，半衰期为7小时。可经肝降解，活性代谢产物仅少量通过血脑屏障。经肾脏排出70%～80%；按体表面积一次静注5.0g/m2 时， 61%以原形排出；按体表面积一次静注1.2～2.4g/m2 时，仅12%～18%以原形排出。适应症:适用于睾丸癌、卵巢癌、乳腺癌、肉瘤、恶性淋巴瘤和肺癌等。用法用量:单药治疗静脉注射按体表面积每次1.2～2.5g/m2，连续5日为一疗程。联合用药静脉注射按体表面积每次1.2～2.0g/m2，连续5日为一疗程。每一疗程间隙3～4周。500～600mg/m2。不良反应:（1）骨髓抑制：白细胞减少较血小板减少为常见，最低值在用药后1～2周，多在2～3周后恢复。对肝功有影响。胃肠道反应：包括食欲减退、恶心及呕吐，一般停药1～3天即可消失。（2）泌尿道反应：可致出血性膀胱炎，表现为排尿困难、尿频和尿痛、可在给药后几小时或几周内出现，通常在停药后几天内消失。（3）中枢神经系统毒性：与剂量有关，通常表现为焦虑不安、神情慌乱、幻觉和乏等。少见晕厥、癫痫样发作甚至昏迷。（4）少见的有一过性无症状肝肾功能异常；若高剂量用药可因肾毒性产生代谢性酸中毒。罕见心脏和肺毒性。（5）其他反应尚包括脱发、恶心和呕吐等。注射部位可产生静脉炎。（6）长期用药可产生免疫抑制、垂体功能低下、不育症和继发性肿瘤。
国内市场情况:由于异环磷酰胺类产品在价格上要比环磷酰胺类产品高出许多，因此在生产环磷酰胺得不到回报的时候，国内几大主要生产环磷酰胺的企业纷纷改换生产线，生产异环磷酰胺。异环磷酰胺是环磷酰胺类衍生物，体外无活性，但在体内却对多种转移性肿瘤有明显抑制作用，可治疗骨及软组织肉瘤、非小细胞肺癌、乳腺癌、头颈部癌、子宫颈癌、食管癌等，1993年在国内正式面世。据了解，目前异环磷酰胺原料药的市场价为8000多元／公斤，制剂类在的18次降价之后，由原来的216元／支，降到每支180多元，企业利润空间有
Sigma Aldrich:3778-73-2(sigmaaldrich)