3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2λ5-oxazaphosphinan-2-one

• ChemBase ID: 1052
• Molecular Formular: C7H15Cl2N2O2P
• Molecular Mass: 261.085961
• Monoisotopic Mass: 260.02481972
• SMILES: ClCCN1P(=O)(OCCC1)NCCCl
• Canonical SMILES: ClCCNP1(=O)OCCCN1CCCl
• InChI: InChI=1S/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12)
• InChIKey: HOMGKSMUEGBAAB-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2λ^5-oxazaphosphinan-2-one; 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2$l^{5}-oxazaphosphinan-2-one; (2S)-3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2λ^5-oxazaphosphinan-2-one
• IUPAC Traditional name: ifosfamide; (2S)-3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2λ^5-oxazaphosphinan-2-one
• Brand Name: Cyfos; Holoxan 1000; IFEX; Ifex/Mesnex Kit; Ifosfamide/Mesna Kit; Isoendoxan; Mitoxana; Naxamide
• Synonyms: N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide; Ifosfamide; Asta Z 4942; Ifosfamid; Ifosfamide Sterile; Ifsofamide; Iphosphamid; Iphosphamide; Isophosphamide; Isofosfamide; I-Phosphamide; Ifosphamide; Ifosfamide; Mitoxana; Ifex; (S)-3-(2-chloroethyl)-2-((2-chloroethyl)amino)-1,3,2-oxazaphosphinane 2-oxide; Dexifosfamide; N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-Oxide; A 4942; Cyfos; Holoxan; Ifomide; MJF 9325; NSC 109724; Naxamide; Isophosphamide

Database IDs

• CAS Number: 66849-34-1; 3778-73-2
• EC Number: 223-237-3
• MDL Number: MFCD00057374
• PubChem SID: 160964515; 46508335
• PubChem CID: 3690

CALCULATED PROPERTIES

JChem

• Acid pKa: 13.238064
• H Acceptors: 2
• H Donor: 1
• LogD (pH = 5.5): 0.09654586
• LogD (pH = 7.4): 0.096547104
• Log P: 0.096547686
• Molar Refractivity: 58.4781 cm^3
• Polarizability: 23.373835 Å^3
• Polar Surface Area: 41.57 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 0.57
• LOG S: -1.24
• Solubility (Water): 1.50e+01 g/l

PROPERTIES

Physical Property

• Solubility: 3780 mg/L; DMSO; Methanol; Water
• Apperance: White to Off-White Solid
• Melting Point: 39-41°C
• Hydrophobicity(logP): 0.8

Safety Information

• Storage Condition: -20°C; -20°C Freezer, Under Inert Atmosphere
• RTECS: RP6050000
• European Hazard Symbols: Toxic (T)
• UN Number: 2811
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: 3
• Risk Statements: 25-36
• Safety Statements: 26-45
• GHS Pictograms: GHS06
• GHS Signal Word: Danger
• GHS Hazard statements: H301-H319
• GHS Precautionary statements: P301 + P310-P305 + P351 + P338
• Personal Protective Equipment: Eyeshields, Faceshields, Gloves, type P2 (EN 143) respirator cartridges
• RID/ADR: UN 2811 6.1/PG 3
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: DNA/RNA synthesis
• Mechanism of Action: Alkylating agent in cancer therapy

Product Information

• Purity: ≥98%; 97%
• Salt Data: Free Base
• Application(s): Antileukaemic; Antineoplastic; Immunosuppressant
• Shipped in: wet ice
• Empirical Formula (Hill Notation): C7H15Cl2N2O2P

DETAILS

DrugBank - DB01181

• Drug Groups: approved
• Description: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [PubChem]
• Indication: Used as a component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer. Also used as a component of various chemotherapeutic regimens for the treatment of cervical cancer, as well as in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas. Other indications include treatment of osteosarcoma, bladder cancer, ovarian cancer. small cell lung cancer, and non-Hodgkin's lymphoma.
• Pharmacology: Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation. It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA. Ifosfamide is cycle-phase nonspecific.
• Toxicity: LD₅₀ (mouse) = 390-1005 mg/kg, LD₅₀ (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).
• Affected Organisms: Humans and other mammals
• Biotransformation: Primarily hepatic
• Half Life: 7-15 hours
• Protein Binding: Minimal
• Elimination: Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.
• References: Furlanut M, Franceschi L: Pharmacology of ifosfamide. Oncology. 2003;65 Suppl 2:2-6. [Pubmed] ; Fleming RA: An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy. 1997 Sep-Oct;17(5 Pt 2):146S-154S. [Pubmed] ; Wagner T: Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet. 1994 Jun;26(6):439-56. [Pubmed] ; Allen LM, Creaven PJ, Nelson RL: Studies on the human pharmacokinetics of isophosphamide (NSC-109724). Cancer Treat Rep. 1976 Apr;60(4):451-8. [Pubmed] ; Brade WP, Herdrich K, Varini M: Ifosfamide--pharmacology, safety and therapeutic potential. Cancer Treat Rev. 1985 Mar;12(1):1-47. [Pubmed] ; Zalupski M, Baker LH: Ifosfamide. J Natl Cancer Inst. 1988 Jun 15;80(8):556-66. [Pubmed] ; Willits I, Price L, Parry A, Tilby MJ, Ford D, Cholerton S, Pearson AD, Boddy AV: Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer. Br J Cancer. 2005 May 9;92(9):1626-35. [Pubmed] ; Lokiec F: Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention. Ann Oncol. 2006 May;17 Suppl 4:iv33-6. [Pubmed] ; Schoenike SE, Dana WJ: Ifosfamide and mesna. Clin Pharm. 1990 Mar;9(3):179-91. [Pubmed] ; Dechant KL, Brogden RN, Pilkington T, Faulds D: Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs. 1991 Sep;42(3):428-67. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1302

Research Area: Cancer
Biological Activity:
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer. It is given as a treatment for a variety of cancers. [1]

Sigma Aldrich - I4909

Biochem/physiol Actions
Ifosfamide is a nitrogen mustard compound that is a structural isomer of cyclophosphamide. Ifosfamide is a prodrug that must be transformed by cytochrome P450 to the biologically active component. It is used as an antineoplastic agent in cancer chemotherapy, but ifosfamide is more likely to cause renal toxicity than cyclophosphamide.

Toronto Research Chemicals - I265000

A cytostatic agent, related structurally to cyclophosphamide.

REFERENCES

• Fleming RA: An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy. 1997 Sep-Oct;17(5 Pt 2):146S-154S. Pubmed
• Wagner T: Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet. 1994 Jun;26(6):439-56. Pubmed
• Allen LM, Creaven PJ, Nelson RL: Studies on the human pharmacokinetics of isophosphamide (NSC-109724). Cancer Treat Rep. 1976 Apr;60(4):451-8. Pubmed
• Brade WP, Herdrich K, Varini M: Ifosfamide--pharmacology, safety and therapeutic potential. Cancer Treat Rev. 1985 Mar;12(1):1-47. Pubmed
• Zalupski M, Baker LH: Ifosfamide. J Natl Cancer Inst. 1988 Jun 15;80(8):556-66. Pubmed
• Willits I, Price L, Parry A, Tilby MJ, Ford D, Cholerton S, Pearson AD, Boddy AV: Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer. Br J Cancer. 2005 May 9;92(9):1626-35. Pubmed
• Lokiec F: Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention. Ann Oncol. 2006 May;17 Suppl 4:iv33-6. Pubmed
• Schoenike SE, Dana WJ: Ifosfamide and mesna. Clin Pharm. 1990 Mar;9(3):179-91. Pubmed
• Dechant KL, Brogden RN, Pilkington T, Faulds D: Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs. 1991 Sep;42(3):428-67. Pubmed
• Furlanut M, Franceschi L: Pharmacology of ifosfamide. Oncology. 2003;65 Suppl 2:2-6. Pubmed
• http://en.wikipedia.org/wiki/Ifosfamide
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