71-63-6 Usage
Uses
Used in Pharmaceutical Industry:
Digitoxin is used as a cardiotonic drug for the treatment of chronic cardiac insufficiency, tachyarrhythmia form of atrial fibrillation, paroxysmal ciliary arrhythmia, and paroxysmal supraventricular tachycardia. It enhances developed tension and contractile force in electrically stimulated isolated guinea pig left atrial muscle, providing relief from congestive heart failure and reducing myocardial hypertrophy in a rat model of myocardial infarction induced by coronary artery ligation.
Used in Research and Development:
Digitoxin has been used as a labeled drug for binding sites on human serum albumin (HSA) and to test its anti-transmissible gastroenteritis virus (TGEV) activity. It also exhibits cytotoxicity to a panel of 10 human cancer cell lines, including myeloma, lymphoma, and leukemia cancer cells, making it a potential candidate for cancer research and treatment.
Used in Drug Formulation:
Formulations containing digitoxin have been used in the treatment of congestive heart failure and cardiac arrhythmias. The brand name for one such formulation is Crystodigin (Lilly).
Originator
Crystodigin,Lilly
Indications
Digitoxin (Dig) is an FDA approved drug for the treatment of cardiac disease.Digitoxin is used for the treatment of heart failure, especially in people with impaired kidney function. It is also used to treat certain kinds of heart arrhythmia, such as atrial fibrillation.Digoxin is used to treat heart failure and abnormal heart rhythms (arrhythmias). It also helps the heart work better and control heart rate. Digoxin may be used after a heart attack. This medication comes in various forms: tablet, capsule, or pediatric elixir (liquid). It is available under the brand names Lanoxin, Cardoxin, Digitek, Digox, and Lanoxicaps.
Manufacturing Process
1000 g of Digitalis purpurea leaves were moistened thoroughly with a
menstruum consisting of 60% ethyl alcohol and 40% water and were packed
in a percolator with enough of the menstruum to leave a stratum above the
drug. After maceration overnight, the drug was percolated with about 7 liters of the 60%-alcohol menstruum and about 5 liters of percolate or extract were
collected. 400 g of solid lead acetate were added to the percolate and the
mixture was stirred until all the lead acetate had dissolved. After standing for
at least one hour, the copious light green precipitate was centrifuged off and
washed successively with 1000 ml and 500 ml portions of 60% alcohol. The
washings were combined with the filtrate from the centrifuge and most of the
excess lead acetate removed by treatment with a saturated solution of sodium
carbonate monohydrate. The resulting lead carbonate was filtered off, washed
with two 200 ml portions of 60% ethyl alcohol, and the washings combined
with the filtrate. Hydrogen sulfide was then passed through the combined
liquids until no more lead sulfide precipitated. The filtrate and washings
resulting from filtering off the lead sulfide were concentrated in vacuo at or
below 40°C to a volume of 2000 ml and saturated with a salt, such as sodium
chloride, to facilitate subsequent extraction with a water-immiscible organic
solvent. The mixture was extracted five times with 600 ml of a solvent
consisting of two volumes of chloroform and three volumes of amyl ether. The
chloroform-amyl ether solution is extracted with about four 400 ml portions of
a 10% solution of sodium carbonate monohydrate to remove any gitalin that
may have carried through in the process and vegetative extractive material.
After drying over anhydrous sodium sulfate and filtering, the chloroform-amyl
ether solution was concentrated in vacuo at 75°-85°C to a volume of about 25
ml. After cooling to room temperature, the concentrate was mixed with about
four volumes of petroleum ether and allowed to stand for about one hour at
room temperature. The dark colored, amorphous precipitate was filtered and
washed with petroleum ether to ensure that all fat had been removed. The
precipitate was dissolved in 100 ml of dilute alcohol (1:1) and the slight
precipitate remaining after thorough agitation was filtered off. The filtrate was
made slightly alkaline with 10% ammonia water and 10 g of solid lead acetate
were dissolved therein with agitation. The light brown precipitate, which
formed, was centrifuged off and washed with two 50 ml portions of dilute
alcohol. Excess lead acetate was removed by passage of hydrogen sulfide
through the solution until no more lead sulfide precipitated. The filtrate and
washings resulting from removal of the lead sulfide was concentrated below
40°C. After making slightly alkaline with ammonia water, the concentrate was
extracted with three 50 ml portions of chloroform. The chloroform extract of
digitoxin was dried over anhydrous sodium sulfate. After filtering and washing
the filter with dry chloroform, the chloroform extract was heated on a water
bath to remove the chloroform and the residue was dissolved in 20ml of hot
alcohol at about 60°C., and diluted with hot distilled water at 60°C to an
alcohol concentration of 30%. Upon standing overnight, the digitoxin settled
out as a yellowish orange, mostly amorphous solid together with some needle
and rosette crystals.The digitoxin was filtered off, and dried in a vacuum desiccator over calcium
chloride and then was dissolved In 10 cc. of dry chloroform after which 15 ml
of dry amyl ether was added, followed by 100 ml of petroleum ether. After
standing one hour, the precipitate was filtered off, washed with petroleum
ether, and dried in a vacuum desiccator until all traces of amyl ether were
removed. One 1ml of alcohol for each 25 milligrams of material was added to
the dried precipitate and the mixture was heated on a water-bath at 60°C
until the precipitate had completely dissolved, after which hot distilled water
at 60°C was added to produce an alcohol concentration of 40%. Upon
standing overnight at room temperature the digitoxin came down as almost
completely white crystals. Upon recrystallizing a second time from 40%
alcohol, completely white crystals of digitoxin were obtained. On the basis of the digitalis cat assay, the digitoxin was completely pure and is a prompt and
powerful heart tonic in doses of 25 mg to 1 mg. The crystalline digitoxin is
also substantially stable and may be relied upon by the physician to furnish a
uniform degree of activity of the same kind insofar as the digitoxin is
concerned.
Therapeutic Function
Cardiotonic, Topical venotonic
Health Hazard
Material is bioactive and capable of causing cardiac arrythmias and electrolyte imbalances that may be fatal. Death is due to ventricular fibrillation or cardiac standstill. Material has a high toxicity hazard rating; it may cause death or permanent injury after a very short exposure. It is classified as super toxic; an estimated single lethal dose is 3-10 mg.
Fire Hazard
When heated to decomposition, DIGITOXIN emits acrid smoke and irritating fumes.
Safety Profile
A deadly poison by
most routes. Human systemic effects:
arrhythmias, cardiomyopathy, EKG
changes, nausea or vomiting, paresthesia,
pulse rate increase, thrombocytopenia.
Human reproductive effects by ingestion:
reduced viability of newborn. An eye irritant. When heated to decomposition it
emits acrid smoke and irritating fumes. See
also DIGITALIS.
Purification Methods
Digitoxin crystallises from MeOH, aqueous EtOH with 0.5 to 1 H2O and from H2O as the dihydrate. It also crystallises from CHCl3/Et2O as anhydrous crystals. The hydrate dehydrates at 120o/vacuum. Its solubility is 2.5% in CHCl3, 1.7% in EtOH, 0.25% in EtOAc, and 0.001% in H2O; and has E1cm 202.5 at 219-220nm (50% EtOH). [Stoll et al. Helv Chim Acta 37 1134 1954, Demoen & Janssen J Am Pharm Assoc 42 635 1953, Beilstein 18 IV 1478.]
Mode of action
Digitoxin is a purified cardiac glycoside similar in structure and function to Digoxin. Unlike Digoxin, Digitoxin is eliminated from the body via the liver and not the kidneys. Both drugs are used to treat various heart conditions. Cardiac glycosides bind to a site on the extracellular aspect of the a-subunit of the Na+/K+ ATPase pump in the membranes of heart cells (myocytes). This causes an increase in the level of sodium ions in the myocytes, which then leads to a rise in the level of calcium ions. Digitoxin inhibits the sodium-potassium ATPase in heart muscle cells, resulting in increased force of contractions (positive inotropic), reduced speed of electric conduction (negative dromotropic), increased excitability (positive bathmotropic), and reduced frequency of heartbeat (negative chronotropic).
Check Digit Verification of cas no
The CAS Registry Mumber 71-63-6 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 7 and 1 respectively; the second part has 2 digits, 6 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 71-63:
(4*7)+(3*1)+(2*6)+(1*3)=46
46 % 10 = 6
So 71-63-6 is a valid CAS Registry Number.
InChI:InChI=1/C41H64O13/c1-20-36(46)29(42)16-34(49-20)53-38-22(3)51-35(18-31(38)44)54-37-21(2)50-33(17-30(37)43)52-25-8-11-39(4)24(15-25)6-7-28-27(39)9-12-40(5)26(10-13-41(28,40)47)23-14-32(45)48-19-23/h14,20-22,24-31,33-38,42-44,46-47H,6-13,15-19H2,1-5H3/t20-,21-,22-,24-,25+,26-,27?,28?,29+,30+,31+,33+,34+,35+,36-,37-,38-,39+,40-,41+/m1/s1
71-63-6Relevant articles and documents
Catalytic stereoselective synthesis of β-digitoxosides: Direct synthesis of digitoxin and C1′-epi-digitoxin
Baryal, Kedar N.,Adhikari, Surya,Zhu, Jianglong
, p. 12469 - 12476 (2014/01/17)
A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of β-d-digitoxosides from 6-deoxy-d-allals has been described. This β-selective glycosylation was achieved probably because of the formation of corresponding α-digitoxosides disfavored by 1,3-diaxial interaction. In addition, this method has been successfully applied to the synthesis of digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1′-epi-digitoxin.
Assembly of digitoxin by gold(I)-catalyzed glycosidation of glycosyl o-alkynylbenzoates
Ma, Yuyong,Li, Zhongzhen,Shi, Hefang,Zhang, Jian,Yu, Biao
experimental part, p. 9748 - 9756 (2012/01/04)
Digitoxin, a clinically important cardiac trisaccharide, was assembled efficiently from digitoxigenin and 3,4-di-O-tert-butyldiphenylsilyl-d- digitoxosyl o-cyclopropylethynylbenzoate in 9 steps and 52% overall yield via alternate glycosylation and protecting group manipulation. The present synthesis showcases the advantage of the gold(I)-catalyzed glycosylation protocol in the synthesis of glycoconjugates containing acid-labile 2-deoxysugar linkages.
A direct comparison of the anticancer activities of digitoxin MeON-Neoglycosides and O-Glycosides
Iyer, Anand Krishnan V.,Zhou, Maoquan,Azad, Neelam,Elbaz, Hosam,Wang, Leo,Rogalsky, Derek K.,Rojanasakul, Yon,O'Doherty, George A.,Langenhan, Joseph M.
scheme or table, p. 326 - 330 (2010/12/18)
Digitoxin is a cardiac glycoside currently being investigated for potential use in oncology; however, an investigation of anticancer activity as a function of oligosaccharide chain length has not yet been performed. We generated mono-, di-, and tri-O-digitoxoside derivatives of digitoxin and compared their activities to the corresponding MeON-neoglycosides. Both classes of cardenolide derivatives display comparable oligosaccharide chain length-dependent cytotoxicity toward human cancer cell lines. Further investigation revealed that both classes of compounds induce caspase-9-mediated apoptosis in non-small cell lung cancer cells (NCI-H460). Because O-glycosides and MeON-neoglycosides share a similar mode of action, the convenience of MeON-neoglycosylation could be exploited in future SAR work to rapidly survey large numbers of carbohydrates to prioritize selected O-glycoside candidates for traditional synthesis.
Recent advances in the synthesis of 2-deoxy-glycosides
Hou, Dianjie,Lowary, Todd L.
scheme or table, p. 1911 - 1940 (2010/03/01)
Glycosides of 2-deoxy-sugars, monosaccharides in which the hydroxyl group at C-2 is replaced with a hydrogen atom, occur widely in natural products and therefore have been the subject of intense synthetic activity. The report summarizes recent advances in this area, with a particular focus on work published since an earlier review on the topic, in 2000 (Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385-8417).
De novo approach to 2-deoxy-β-glycosides: Asymmetric syntheses of digoxose and digitoxin
Zhou, Maoquan,O'Doherty, George A.
, p. 2485 - 2493 (2008/02/02)
A highly enantioselective and straightforward route to trisaccharide natural products digoxose and digitoxin has been developed. Key to this approach is the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The first total synthesis of natural product digoxose was accomplished in 19 total steps from achiral 2-acylfuran, and digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8β. This flexible synthetic strategy also allows for the preparation of mono- and disaccharide analogues of digoxose and digitoxin.
A stereoselective synthesis of digitoxin and digitoxigen mono- and bisdigitoxoside from digitoxigenin via a palladium-catalyzed glycosylation
Zhou, Maoquan,O'Doherty, George A.
, p. 4339 - 4342 (2007/10/03)
(Chemical Equation Presented) A convergent and stereocontrolled route to trisaccharide natural product digitoxin has been developed. The route is amenable to the preparation of both the digitoxigen mono- and bisdigitoxoside. This route featured the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The natural product digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8a or 18 steps from achiral acylfuran.
Convergent synthesis of digitoxin: Stereoselective synthesis and glycosylation of the digoxin trisaccharide glycal
McDonald, Frank E.,Subba Reddy
, p. 3653 - 3655 (2007/10/03)
Tungsten-catalyzed alkynol cycloisomerization and iterative acid-catalyzed stereoselective glycosylations form the basis of a revolutionary new strategy for oligosaccharide synthesis. The method has been successfully applied to a highly convergent synthesis of Digitalis 2-deoxyglycosides.
Dicarboxylic acid oxidation products
-
, (2008/06/13)
What is disclosed is a dicarboxylic acid oxidation product of a immunologically reactive mono- or a polysaccharide having vicinal diols.
