Idarubicin hydrochloride

 

 

Idarubicin hydrochloride 

NSC-256439, IMI-30, DMDR, Idamycin, Zavedos

 

Idarubicin /ˌaɪdəˈruːbɨsɪn/ or 4-demethoxydaunorubicin is an anthracyclineantileukemic drug. It inserts itself into DNA and prevents DNA from unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake.[1] Similar to other anthracyclines, it also induces histone eviction fromchromatin.[2]

It belongs to the family of drugs called antitumor antibiotics.

It is currently combined with cytosine arabinoside as a first line treatment ofacute myeloid leukemia.

It is distributed under the trade names Zavedos (UK) and Idamycin (USA).

UV – spectrum

Conditions : Concentration – 1 mg / 100 ml
SOLVENT DESIGNATION SCHEDULE	METHANOL	WATER	0.1 M HCL	0.1M NAOH
The absorption maximum	481 nm, 287 nm, 251 nm	484 nm 289 nm 257 nm	484 nm 289 nm 257 nm	Observed decay
	207 179 816	194 180 743	194 180 738	-
ε	11100 9540 43600	10400 9620 39700	10400 9620 39400	-

IR – spectrum

WAVELENGTH (ΜM)
WAVENUMBER (CM -1 )

Brief background information

SALT	ATC	FORMULA	MM	CAS
-	L01DB06	C 26 H 27 NO 9	497.50 g / mol	58957-92-9

Idarubicin is the 4-demethoxy derivative of daunorubicin. Idarubicin is an antineoplastic agent that has been used to treat various cancers, including those of the breast, lung, stomach, ovaries, and lymph system. Idarubicin is marketed as an intravenous injection of Idarubicin hydrochloride of the formula,

under the brand name IDAMYCIN®. Idarubicin hydrochloride is a red-orange crystalline powder, soluble in water, methanol, and other polar solvents like dimethylformamide. It is practically insoluble in acetone, chloroform, and methylene chloride. Idarubicin hydrochloride has a melting point of 175-180°C, and apH of 5.0-6.5 in a 0.5% w/v solution in water.

Application

• antitumor agent
• anthracycline antibiotic

Classes of substances

• Naftatsenovye antibiotics

Synthesis pathway

PREPARATION
SYNTHESIS A) SYNTHESIS A) US 4,471,052 (ADRIA; 9.11.1984; APPL. 18.1.1982).
SYNTHESIS OF B) SYNTHESIS OF B) DOS 2,525,633 (SOC. FARMACEUTICI; APPL. 06.09.1975; GB -PRIOR. 16.12.1974).  US 4,046,878 (SOC. FARMACEUTICI; 09/06/1977; APPL. 05/22/1975; GB -PRIOR. 12.6.1974).

The reaction of daunomycinone (IX) with AlCl3 in dichloromethane gives 4-demethyldaunomycinone (X), which is ketalized with ethylene glycol as before yielding the dioxolane (XI). The selective sulfonation of (XI) with TsCl, DIEA and DMAP in pyridine affords the 4-tosyloxy derivative (XII), which is treated with 4-methoxybenzylamine (XIII) in pyridine providing the secondary benzylamine (XIV). Elimination of the benzyl protecting group of (XIV) with TFA gives 4-amino-4-demethoxydaunomycinone ethylene ketal (XV), which is deaminated by reaction with TFA, NaNO2 and H3PO2 to give 4-demethoxydaunomycinone (XVI). Finally, this compound is submitted to fermentation with Streptomyces peucetius corneus, S. Peucetius caesius, S. Caeruleus, S. Peucetius , S. Coeruleorubidus, and other chemical or radio-induced mutants thereof.

Mitscher, LA; Lednicer, D. (Pharmacia Corp.); Biosynthesis of simplified anthracyclines US 4471052.

condensation of chiral tetraline (I) with phthalic anhydride (II) by means of AlCl3 at 180 C gives the naphthacenedione (III),  acetyl group which is ketalized with ethylene glycol and p-toluenesulfonic acid yielding the dioxolane (IV). The hydroxylation of (IV) with Br2 and AIBN in CCl4/CHCl3 affords the 4-demethoxy-7-epidaunomycinone (V), which is isomerized with TFA yielding 4-demethoxydaunomycinone (VI) . The condensation of (VI) with the acylated hexopyranosyl chloride (VII) by means of CF3SO3Ag of Br2Hg affords the trifluoroacetylated 4-demethoxydaunomycin (VIII), which is finally deprotected by treated with NaOH  to eliminate the trifluoroacetyl groups

Trade Names

COUNTRY	TRADE NAME	MANUFACTURER
Germany	Zavedos	Pharmacia
France	- “-	Pfizer
United Kingdom	- “-	Pharmacia
Italy	- “-	Pharmacia & Upjohn
Japan	Idamitsin	Pfizer
Ukraine	Zavedos	Actavis Italy SpA, Italy
	Idalek	CJSC “Biolik”, Ukraine
	Zavedos	Pfizer Іtaliya Srl, Іtaliya
	Rubidium	NGO “Lance Farm”, Russia
	other generic drugs

Formulations

• Capsules of 5 mg, 10 mg, 25 mg;
• vial of 5 mg, 10 mg (hydrochloride)

IDAMYCIN PFS Injection contains idarubicin hydrochloride and is a sterile, semi-synthetic, preservative-free solution (PFS) antineoplastic anthracycline for intravenous use. Chemically, idarubicin hydrochloride is 5, 12-Naphthacenedione, 9-acetyl-7-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxyhydrochloride, (7S-cis). The structural formula is as follows:

C26H27NO9•Hcl           M.W 533.96

IDAMYCIN PFS (idarubicin hydrochloride injection) is a sterile, red-orange, isotonic parenteral preservative-free solution, available in 5 mL (5 mg), 10 mL (10 mg) and 20 mL (20 mg) single-use-only vials.

Each mL contains Idarubicin HCL, USP 1 mg and the following inactive ingredients: Glycerin, USP 25 mg and Water for Injection, USP q.s. Hydrochloric Acid, NF is used to adjust the pH to a target of 3.5.

Product Name	Idarubicin Hydrochloride
Chemical Name	(7S,9S)-9-Acetyl-7-[(3-amino-2,3,6-trideoxy-a-L- lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11- trihydroxy-5,12-naphthacenedione hydrochloride
Synonym	Idamycin; Zavedos
Formula Wt.	533.96
Melting Point	183oC-185oC
Purity	≥98%
Solubility	Soluble in water and methanol.
Store Temp	-20oC
References	Ganzina, F., Pacciarini, MA., Di Pietro, N. Invest New Drugs. 4:85-105 (1986). Tsuruo, T., Oh-Hara, T., Sudo, Y., Naito, M. Anticancer Res. 13:357-61 (1993). Belaud-Rotureau, MA., Durrieu, F., Labroille, G. et al Leukemia 14:1266-75 (2000).

IDARUBICIN

SYSTEMATIC (IUPAC) NAME
(1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxo-α-L-lyxo-hexopyranoside
CLINICAL DATA
AHFS/DRUGS.COM	monograph
MEDLINEPLUS	a691004
PREGNANCY CAT.	D (US)
LEGAL STATUS	℞-only (US)
PHARMACOKINETIC DATA
PROTEIN BINDING	97%
HALF-LIFE	22 hours
IDENTIFIERS
CAS NUMBER	58957-92-9
ATC CODE	L01DB06
PUBCHEM	CID 42890
DRUGBANK	DB01177
CHEMSPIDER	39117
UNII	ZRP63D75JW
KEGG	D08062
CHEBI	CHEBI:42068
CHEMBL	CHEMBL1117
SYNONYMS	9-acetyl-7-(4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl)oxy-6,9,11-trihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione
CHEMICAL DATA
FORMULA	C26H27NO9
MOL. MASS	497.494 g/mol

Links

1. Synthesis a)
   • US 4,471,052 (Adria; 9.11.1984; appl. 18.1.1982).
2. Synthesis of b)
   • DOS 2,525,633 (Soc. Farmaceutici; appl. 06.09.1975; GB -prior. 16.12.1974).
   •  US 4,046,878 (Soc. Farmaceutici; 09/06/1977; appl. 05/22/1975;GB -prior. 12.6.1974).
3. • UV and IR Spectra. H.-W. Dibbern, RM Muller, E. Wirbitzki, 2002 ECV
   • NIST / EPA / NIH Mass Spectral Library 2008
   • Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman.Academic Press, 2000.
   • Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

References

1.  Package insert
2.  Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, Nieuwland M, Ovaa H, Rottenberg S, van Tellingen O, Janssen J, Huijgens P, Zwart W, Neefjes J (2013). “Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin”. Nature Communications 4: 1908. doi:10.1038/ncomms2921.PMID 23715267.

External links

• Idarubicin bound to proteins in the PDB

Title: Idarubicin CAS Registry Number: 58957-92-9 CAS Name: (7S,9S)-9-Acetyl-7-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedione Additional Names: (1S,3S)-3-acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-6,11-dioxo-1-naphthacenyl-3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranoside; 4-demethoxydaunomycin; 4-demethoxydaunorubicin; DMDR Manufacturers' Codes: IMI-30; NSC-256439 Molecular Formula: C26H27NO9 Molecular Weight: 497.49 Percent Composition: C 62.77%, H 5.47%, N 2.82%, O 28.94% Literature References: Orally active anthracycline; analog of daunorubicin, q.v. Prepn: B. Patelli et al. DE 2525633; eidem, US4046878 (1976, 1977 both to Soc. Farmac. Ital.); and antitumor activity: F. Arcamone et al., Cancer Treat. Rep. 60, 829 (1976). Total synthesis for larger scale preparation: M. J. Broadhurst et al., Chem. Commun. 1982, 158. Synthesis of optically pure isomers: Y. Kimura et al., Bull. Chem. Soc. Jpn. 59, 423 (1986). Metabolism and biodistribution in rats: G. Zini et al., Cancer Chemother. Pharmacol. 16, 107 (1986). HPLC determn in plasma: S. S. N. De Graaf et al., J. Chromatogr. 491, 501 (1989). Clinical pharmacokinetics: H. C. Gillies et al., Br. J. Clin. Pharmacol. 23, 303 (1987). Clinical evaluation of cardiac toxicity: F. Villani et al., Eur. J. Cancer Clin. Oncol. 25, 13 (1989). Reviews of pharmacology and antitumor efficacy: A. M. Casazza, Cancer Treat. Rep. 63, 835-844 (1979); F. Ganzina et al., Invest. New Drugs 4, 85-105 (1986). Symposium on clinical experience in acute leukemias: Semin. Oncol. 17, Suppl. 2, 1-36 (1989).   Derivative Type: Hydrochloride CAS Registry Number: 57852-57-0 Trademarks: Idamycin (Pharmacia & Upjohn); Zavedos (Pharmacia & Upjohn) Molecular Formula: C26H27NO9.HCl Molecular Weight: 533.95 Percent Composition: C 58.48%, H 5.29%, N 2.62%, O 26.97%, Cl 6.64% Properties: Orange crystalline powder, mp 183-185° (Arcamone); also reported as mp 172-174° (Broadhurst). [a]D20 +205° (c = 0.1 in methanol) (Arcamone); also reported as [a]D20 +188° (c = 0.10 in methanol) (Kimura). Melting point: mp 183-185° (Arcamone); mp 172-174° (Broadhurst) Optical Rotation: [a]D20 +205° (c = 0.1 in methanol) (Arcamone); [a]D20 +188° (c = 0.10 in methanol) (Kimura)   Therap-Cat: Antineoplastic. Keywords: Antineoplastic; Antibiotics and Analogs; Anthracyclines; Topoisomerase II Inhibitor.