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Isophosphamide(CAS No. 3778-73-2)

Isophosphamide C7H15Cl2N2O2P (cas 3778-73-2) Molecular Structure

3778-73-2 Structure

Identification and Related Records

【Name】
Isophosphamide
【CAS Registry number】
3778-73-2
【Synonyms】
2H-1,3,2-Oxazaphosphorine,3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-, 2-oxide (8CI)
3-(2-Chloroethyl)-2-(2-chloroethylamino)tetrahydro-2H-1,3,2-oxaazaphosphorin2-oxide
A 4942
Asta Z 4942
Cyfos
Holoxan
Holoxan 1000
Ifex
Ifomide
Ifosfamid
Ifosfamide
MJF 9325
Mitoxana
NSC 109724
Naxamide
Z 4942
Ifosfamide
【EINECS(EC#)】
223-237-3
【Molecular Formula】
C7H15Cl2N2O2P (Products with the same molecular formula)
【Molecular Weight】
261.09
【Inchi】
InChI=1/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12)
【Canonical SMILES】
C1CN(P(=O)(OC1)NCCCl)CCCl
【MOL File】
3778-73-2.mol

Chemical and Physical Properties

【Appearance】
Crystalline Solid
【Density】
1.33 g/cm3
【Melting Point】
48℃
【Boiling Point】
336.1 °C at 760 mmHg
【Flash Point】
157.1 °C
【Solubilities】
Soluble in water
【Color/Form】
Crystals from anhyd ether
White crystalline powder
【Storage temp】
2-8°C
【Computed Properties】
Molecular Weight:261.085961 [g/mol]
Molecular Formula:C7H15Cl2N2O2P
XLogP3:0.9
H-Bond Donor:1
H-Bond Acceptor:4
Rotatable Bond Count:5
Tautomer Count:2
Exact Mass:260.02482
MonoIsotopic Mass:260.02482
Topological Polar Surface Area:41.6
Heavy Atom Count:14
Formal Charge:0
Complexity:218
Isotope Atom Count:0
Defined Atom Stereocenter Count:0
Undefined Atom Stereocenter Count:1
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Ring Count:1
Effective Rotor Count:6
Conformer Sampling RMSD:0.6
CID Conformer Count:360

Safety and Handling

【Hazard Codes】
T: Toxic;
【Risk Statements】
R25
【Safety Statements 】
26-45
【HazardClass】
6.1(b)
【PackingGroup 】
III
【Transport】
3249
【Octanol/Water Partition Coefficient】
log Kow = 0.86
【Disposal Methods】
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Use and Manufacturing

【Use and Manufacturing】
Methods of Manufacturing

Prepn: FR 1530962 (1968 to Asta), C.A. 71, 49998m (1979); H. Arnold et al., US 3732349 (1973 to Asta).
Production: monoethanolamine + phosphorus oxychloride + 3-(2-chloroethyl)aminopropanol hydrochloride (alcohol chlorination/dehydrochlorination/dehydrochlorination)
Consumption Patterns

An amount consumed of 290 kg/yr was calculated for Germany.
【Usage】
A cytostatic agent, related structurally to cyclophosphamide

Biomedical Effects and Toxicity

【Pharmacological Action】
- A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)
【Therapeutic Uses】
Ifosfamide currently is approved for use in combination with other drugs for germ cell testicular cancer & is widely used to treat pediatric & adult sarcomas. Clinical trials also have shown ifosfamide to be active against carcinomas of the cervix & lung & against lymphomas. It is a common component of high-dose chemotherapy regimens with bone marrow or stem cell rescue; in these regimens, in total doses of 12-14 g/sq m, it may cause severe neurological toxicity, including coma & death. This toxicity is thought to result form a metabolite, chloracetaldehyde. In addition to hemorrhagic cystitis, ifosfamide causes nausea, vomiting, anorexia, leukopenia, nephrotoxicity, & CNS disturbances (especially somnolence & confusion).
Ifosfamide is indicated, in combination with other antineoplastic agents and a prophylactic agent against hemorrhagic cystitis (such as mesna), for treatment of germ cell testicular tumors. /Included in US product labeling/
Ifosfamide is indicated as reasonable medical therapy for treatment of head and neck carcinoma. (Evidence rating: IIID) /NOT included in US product labeling/
Ifosfamide is used for treatment of soft-tissue sarcomas, Ewing's sarcoma, and Hodgkin's and non-Hodgkin's lymphomas. /NOT included in US product labeling/
Ifosfamide is indicated for treatment of breast carcinomas, cervical carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, ovarian epithelial carcinoma, acute lymphocytic leukemia, neuroblastoma, and osteosarcoma. /NOT included in US product labeling/
Ifosfamide, in combination therapy, is considered reasonable medical therapy at some point in the management of germ cell ovarian tumors. (Evidence rating: IIID). /NOT included in US product labeling/
Ifosfamide, alone and in combination with other chemotherapeutic agents, is considered reasonable medical therapy at some point in the management of bladder carcinoma (Evidence rating: IIID) and edometrial carcinoma (Evidence rating IIIA). /NOT included in US product labeling/
Ifosfamide is indicated, alone or in combination with other chemotherapeutic agents, as second-line therapy for the treatment of Wilms' tumor in patients who have not responded to or whose disease has progressed during previous treatment (Evidence rating: IIID). /NOT included in US product labeling/
... A Phase 1 trial was conducted in patients with estrogen negative receptors (ER) or hormone refractory metastatic breast cancer to determine the maximum tolerated dose (MTD) of ifosfamide with a fixed dose of doxorubicin. A secondary objective was to determine the efficacy of the combination in metastatic breast cancer. ... Fifteen patients were entered in the study in cohorts of three patients at each dose level of ifosfamide. The dose of doxorubicin was fixed at 45 mg/m2. Five different dose levels of ifosfamide were tested ranging from dose level 1 of 1.5 gms/m2 day 1-3 to level V at 2.5 gms/m2 day 1-3. ... Dose escalation of ifosfamide was stopped at 2.5 gms/m2. The MTD of ifosfamide was 2.25 gms/m2 day 1-3 in combination with doxorubicin. All patients in the study were assessable for toxicity. Neutropenia and thrombocytopenia were the major dose limiting toxicities. Other toxicities included anemia, confusion and hematuria. Objective responses were documented in 11 of 15 patients (73.3%). Median time to treatment failure (TTF) was 13 months. Median overall survival (OS) was 18 months. ... The combination of ifosfamide and doxorubicin was a practical well tolerated regimen. There was substantial evidence of clinical activity in this phase I trial. This combination should be further evaluated, as an attractive alternative to taxanes for patients in developing countries where cost effectiveness is important. [Aziz Z, et al; J Pak Med Assoc 51 (11): 400-405 (2001)]
【Biomedical Effects and Toxicity】
Renal excretion & t1/2 are dose & schedule dependent. 60-80% recovered as unchanged drug or metabolite in urine within 72 hr after admin.
The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m(2)/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (+/-sem) in vitro and in vivo erythrocyte (e)-plasma (p) partition coefficients (P(e/p)) were 0.75+/-0.01 and 0.81+/-0.03, 0.62+/-0.09 and 0.73+/-0.05, 0.76+/-0.10 and 0.93+/-0.05 and 1.38+/-0.04 and 0.98+/-0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUC(e/p)) were 0.96+/-0.03, 0.87+/-0.07, 0.98+/-0.06 and 1.34+/-0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic-pharmacodynamic studies. [Kerbusch T, et al; Biopharm Drug Dispos 22 (3): 99-108 (2001)] PubMed Abstract
... To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours. ... Pharmacokinetic assessment followed by model fitting. Patients: The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m2 in 1 or 3 hours on 1, 2 or 3 days. ... A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy-ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. ... Population values (mean +/- standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/h/m2 and 20.6 +/- 1.6 L/m2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h2/m2. The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0.0083 m2/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. ... We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling. [Kerbusch T, et al; Clin Pharmacokinet 40 (8): 615-625 (2001)] PubMed Abstract
... The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. ... Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling. ... The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population. [Kerbusch T, et al; Eur J Clin Pharmacol 57 (6-7): 467-477 (2001)] PubMed Abstract
The stereoselective pharmacokinetics of ifosfamide (IF) were investigated in male and female Sprague-Dawley rats. Following intravenous administration of IF deuterium-labeled pseudoracemates into rats at 40 mg/kg, IF enantiomers and their metabolites, 4-hydroxyIF (HOIF), N2-dechloroethylIF (N2D), N3-dechloroethylIF (N3D), and isophosphoramide mustard (IPM) were quantitated in plasma and urine using gas chromatographic-mass spectrometry techniques with appropriately deuterium-labeled analogs as the internal standards. In addition, the intrinsic clearances of IF isomers in rat liver microsomes were estimated by the in vitro metabolism study. Following drug administration in male rats, (R)-IF exhibited a lower area under the curve value and a shorter half-life of 34.2 minutes than (S)-IF, which gave a half-life of 41.8 minutes. In female rats, the half-lives of (R)- and (S)-IF were found to be 62.1 and 75.1 minutes, respectively, significantly longer than those in male rats. No change in volume of distribution or renal clearance for IF enantiomers in all rats was observed, and the protein binding value was low, with no enantioselectivity. Both in vitro and in vivo studies showed that metabolism of (R)-IF proceeded in favor of the 4-hydroxylation pathway, whereas (S)-IF preferentially underwent N2- and N3-dechloroethylation. The observed stereoselectivity and gender difference in pharmacokinetics of IF in the rat are mainly attributed to its stereoselective metabolism.
Active metabolites cross the blood-brain barrier to only a limited extent.

Environmental Fate and Exposure Potential

【Environmental Fate/Exposure Summary】
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 70(SRC), determined from a log Kow of 0.86(2) and a regression-derived equation(3), indicates that ifosfamide is expected to have high mobility in soil(SRC). Volatilization of ifosfamide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Ifosfamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-5 mm Hg(SRC), determined from a fragment constant method(5). Ifosfamide has been shown to be non-biodegradable in laboratory-scale sewage treatment studies(6), therefore biodegration in soil may not be an important environmental fate process(SRC).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 70(SRC), determined from a log Kow of 0.86(2) and a regression-derived equation(3), indicates that ifosfamide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Ifosfamide may hydrolyze as indicated by a neutral hydrolysis calculated half-life for analogous cyclophosphamide at 25 deg C of 41 days(8). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Ifosfamide has been shown to be non-biodegradable in laboratory-scale sewage treatment studies(7), therefore biodegration in water may not be an important environmental fate process(SRC).
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ifosfamide, which has an estimated vapor pressure of 3.0X10-5 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase ifosfamide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 9 hrs(SRC), calculated from its rate constant of 4.3X10-11 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure estimation method(3). Particulate-phase ifosfamide may be removed from the air by wet and dry deposition(SRC).

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