Sunday 31 August 2014

Idarubicin hydrochloride


 

 

Idarubicin hydrochloride 

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

 

Idarubicin /ˌdəˈrbɨsɪn/ 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).
Idarubicin ball-and-stick.png

UV – spectrum

Conditions : Concentration – 1 mg / 100 ml
SOLVENT DESIGNATION SCHEDULEMETHANOL
WATER
0.1 M HCL
0.1M NAOH
The absorption maximum481 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
-
ε11100
9540
43600
10400
9620
39700
10400
9620
39400
-

IR – spectrum

WAVELENGTH (ΜM)
WAVENUMBER (CM -1 )

Brief background information

SALTATCFORMULAMMCAS
-L01DB0626 H 27 NO 9497.50 g / mol58957-92-9
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,
Figure imgf000003_0003
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)
  1. SYNTHESIS A)
    • US 4,471,052 (ADRIA; 9.11.1984; APPL. 18.1.1982).
SYNTHESIS OF B)
  1. 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

COUNTRYTRADE NAMEMANUFACTURER
GermanyZavedosPharmacia
France- “-Pfizer
United Kingdom- “-Pharmacia
Italy- “-Pharmacia & Upjohn
JapanIdamitsinPfizer
UkraineZavedosActavis Italy SpA, Italy
IdalekCJSC “Biolik”, Ukraine
ZavedosPfizer Іtaliya Srl, Іtaliya
RubidiumNGO “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:
Idamycin PFS®  (idarubicin hydrochloride) Structural Formula Illustration
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 NameIdarubicin 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
SynonymIdamycin; Zavedos
Formula Wt.533.96
Melting Point183oC-185oC
Purity98%
SolubilitySoluble in water and methanol.
Store Temp-20oC
ReferencesGanzina, 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
Idarubicin.svg
Idarubicin ball-and-stick.png
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.COMmonograph
MEDLINEPLUSa691004
PREGNANCY CAT.(US)
LEGAL STATUS-only (US)
PHARMACOKINETIC DATA
PROTEIN BINDING97%
HALF-LIFE22 hours
IDENTIFIERS
CAS NUMBER58957-92-9 Yes
ATC CODEL01DB06
PUBCHEMCID 42890
DRUGBANKDB01177
CHEMSPIDER39117 Yes
UNIIZRP63D75JW Yes
KEGGD08062 Yes
CHEBICHEBI:42068 Yes
CHEMBLCHEMBL1117 Yes
SYNONYMS9-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
FORMULAC26H27NO9 
MOL. MASS497.494 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).
    • 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

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 2525633eidem, 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.

Thursday 28 August 2014

GSK receives FDA approval for Promacta

paolo-cropped
Dr Paolo Paoletti, president, Oncology, GSK


GlaxoSmithKline (GSK) announced that the USFDA has approved a supplemental New Drug Application (sNDA) for the once-daily use of Promacta (eltrombopag) in patients with severe aplastic anaemia (SAA), who have had an insufficient response to immunosuppressive - 


Tuesday 26 August 2014

Situation Analysis of R & D Activities: An Empirical Study in Iranian Pharmaceutical Companies

Volume & Issue: Volume 11, Issue 4, Autumn 2012, Page 999-1290

 

Situation Analysis of R & D Activities: An Empirical Study in Iranian Pharmaceutical Companies




Hamid Reza Rasekh; Gholamhossein Mehralian; Abbas Ali Vatankhah-MohammadabadiPage 1013-1025

http://ijpr.sbmu.ac.ir/volume_51.html
 

 
 



FDA Gives Insys Pharmaceutical Cannabidiol Orphan Status

Insys Therapeutics Inc., a specialty pharmaceutical company that is developing and commercializing innovative drugs and novel drug delivery systems, announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to its pharmaceutical cannabidiol (CBD) for the treatment of glioblastoma multiforme (GBM), the most common and most aggressive malignant primary brain tumor in humans.
 

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Iroko Pharmaceuticals Gains FDA Approval of Zorvolex for Management of Osteoarthritis Pain



Iroko Pharmaceuticals Gains FDA Approval of Zorvolex for Management of Osteoarthritis Pain

 
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August 25, 2014 — Iroko Pharmaceuticals, LLC, a global specialty pharmaceutical company dedicated to advancing the science of analgesia, announced today the United States Food and Drug Administration (FDA) has approved Zorvolex (diclofenac) capsules, a nonsteroidal anti-inflammatory drug (NSAID), for the management of osteoarthritis pain. This marks the second indication for Zorvolex, approved by FDA in October 2013 for the treatment of mild to moderate acute pain in adults1.
 

“Given the dose-related adverse events associated with NSAIDs as a class and the widespread use of NSAIDs for osteoarthritis, we are delighted to gain approval for our first SoluMatrix® NSAID for the management of osteoarthritis pain,” said Dr. Clarence Young, Chief Medical Officer of Iroko Pharmaceuticals. “Iroko has already made great strides to help fill the need for low dose NSAID options in patients with acute pain and we are continuing to expand our portfolio to also address chronic pain indications.”
 


Zorvolex was developed to align with recommendations from FDA and several professional medical organizations that NSAIDs be used at the lowest effective dose for the shortest possible duration consistent with individual patient treatment goals2. Zorvolex is the first FDA-approved low dose NSAID developed using proprietary SoluMatrix Fine Particle Technology™ and is now available by prescription. Zorvolex contains diclofenac as submicron particles that are approximately 20 times smaller than their original size. The reduction in particle size provides an increased surface area, leading to faster dissolution.
 

“Expanding the use of Zorvolex beyond acute pain to osteoarthritis pain, a chronic condition, is a testament to Iroko’s continued commitment to developing a low dose NSAID portfolio to address a broad range of unmet patient needs,” said John Vavricka, President and CEO of Iroko Pharmaceuticals. “This second approval for Zorvolex continues to lay the groundwork for our future portfolio, which utilizes a new approach to pain management.”
 
The approval of Zorvolex for the management of osteoarthritis pain was supported by data from a 12-week, multi-center, randomized, double-blind, parallel-group, placebo-controlled trial that enrolled 305 patients, aged 41-90 years, with osteoarthritis of the hip or knee. Half of the patients were between the ages of 61-90. Participants were randomized to Zorvolex 35mg three times daily or 35mg twice daily, or placebo3. The Supplemental New Drug Application (sNDA) also included data from a 12-month open-label safety study that enrolled 602 patients1.
“NSAIDs continue to be an integral part of the management for osteoarthritis, the most common type of arthritis4, and their use is likely to increase as the U.S. population continues to age and the incidence of osteoarthritis rises5,” said Dr. Roy Altman, Professor of Medicine in Rheumatology at UCLA. “The approval of Zorvolex is a welcome and meaningful advance and is the first SoluMatrix® NSAID option approved by the FDA for osteoarthritis pain.”
 

About Iroko Pharmaceuticals, LLC

Iroko is a global specialty pharmaceutical company, based in Philadelphia, dedicated to advancing the science of analgesia. The company develops and globally commercializes pharmaceutical products.
Iroko is at the forefront of the development of SoluMatrix® NSAIDs – new low dose drug products based on existing NSAIDs – using iCeutica Inc.’s proprietary SoluMatrix Fine Particle Technology™ exclusively licensed to Iroko for NSAIDs. Zorvolex is the first SoluMatrix® NSAID and is available in pharmacies; a second was approved by FDA in February 2014. For more information, visit www.iroko.com.