| Identification | More | [Name]
Demeclocycline hydrochloride | [CAS]
64-73-3 | [Synonyms]
7-chloro-4-dimethylamino-3,6,10,12,12a-pentahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxamide hydrochloride
7-CHLORO-6-DEMETHYLTETRACYCLINE HYDROCHLORIDE
DEMECLOCYCLINE
DEMECLOCYCLINE HYDROCHLORIDE
6,10,12,12a-pentahydroxy-1,11-dioxo-ydro-monohydrochloride
declomycinhydrochloride
demethylchlorotetracyclinehydrochloride
demethylchlortetracyclinehydrochloride
detravis
DEMECLOCYCLINE HYDROCHLORIDE*CRYSTALLINE
DEMECLOCYCLIN HYDROCHLORIDE HEMI-HYDRAT
DemeclocyclineHcl
[4S-(4a,4aa,5aa,6b,12aa)]-7-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-1,11-dioxo-2-naphthacenecarboxamide Monohydrochloride
6-Demethyl-7-chlorotetracycline Hydrochlorid
chlorodemethyltetracyclin hydrochloride
2-Naphthacenecarboxamide, 7-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-1,11-dioxo-, monohydrochloride (8CI)
2-Naphthacenecarboxamide, 7-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-1,11-dioxo-, monohydrochloride, (4S,4aS,5aS,6S,12aS)-
2-Naphthacenecarboxamide, 7-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-1,11-dioxo-, monohydrochloride, [4S-(4α,4aα,5aα,6β,12aα)]-
6-Demethyl-7-chlorotetracycline hydrochloride
7-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride | [EINECS(EC#)]
200-592-2 | [Molecular Formula]
C21H21ClN2O8 | [MDL Number]
MFCD00864922 | [Molecular Weight]
464.85 | [MOL File]
64-73-3.mol |
| Chemical Properties | Back Directory | [Appearance]
Yellow Solid | [Melting point ]
>245°C (dec.) | [storage temp. ]
−20°C
| [solubility ]
H2O: 20 mg/mL, clear, very deep greenish yellow
| [form ]
powder
| [pka]
pKa 3.3 (Uncertain) | [color ]
Light Yellow to Yellow | [Water Solubility ]
Soluble in water. | [Usage]
An antibiotic related to tetracycline and produced by streptomyces aureofaciens. Because it is excreted more slowly than tetracycline, it maintains effective blood levels for longer periods of time | [Merck ]
13,2905 | [BRN ]
5705221 | [Major Application]
clinical testing | [InChIKey]
GVSJQNRGSCOSNJ-KBHRXELFSA-N | [SMILES]
O[C@@]12C(C(C(=O)N)=C(O)[C@@H](N(C)C)[C@]1([H])C[C@]1([H])[C@@H](C3C(=CC=C(O)C=3C(=O)C1=C2O)Cl)O)=O.Cl |&1:1,9,13,16,18,r| | [CAS DataBase Reference]
64-73-3(CAS DataBase Reference) | [EPA Substance Registry System]
2-Naphthacenecarboxamide, 7-chloro-4-(dimethylamino)-4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-1,11-dioxo-, hydrochloride (1:1), (4S,4aS,5aS,6S,12aS)- (64-73-3) |
| Hazard Information | Back Directory | [Description]
Demeclocycline lacks the C-6-methyl of tetracycline and is produced by a genetically altered strain of
Streptomyces aureofaciens. Because it is a secondary alcohol, it is more chemically stable than tetracycline
against dehydration. Food and milk co-consumption decrease absorption by half, although it is 60 to 80%
absorbed by fasting adults. It is the tetracycline most highly associated with phototoxicity and has been
shown to produce dose-dependent, reversible diabetes insipidus with extended use. | [Chemical Properties]
Yellow Solid | [Originator]
Declomycin,Lederle,US,1959 | [Uses]
An antibiotic related to tetracycline and produced by streptomyces aureofaciens. Because it is excreted more slowly than tetracycline, it maintains effective blood levels for longer periods of time | [Uses]
Antibacterial;Ribosomal protein synthesis inhibitor | [Uses]
Demeclocycline hydrochloride is a salt prepared from demeclocycline taking advantage of the basic dimethylamino group which protonates and readily forms a salt in hydrochloric acid solutions. The hydrochloride is the preferred formulation for pharmaceutical applications. Like all tetracyclines, demeclocycline shows broad spectrum antibacterial and antiprotozoan activity and acts by binding to the 30S and 50S ribosomal subunits, blocking protein synthesis. | [Definition]
ChEBI: The hydrochloride salt of demeclocycline. A tetracycline antibiotic, it is used (mainly as the hydrochloride) for the treatment of Lyme disease, acne and bronchitis, as well as for hyponatraemia (low blood sodium concentration) due to the syndrome of inapp
opriate antidiuretic hormone (SIADH) where fluid restriction alone has been ineffective. | [Manufacturing Process]
According to US Patent 2,878,289, a suitable medium for the preparation of
inocula for the fermentation may be prepared with the following substances.
The pH of the medium thus prepared is about 6.8. An 8 ml portion is
measured into an 8 inch Brewer tube and sterilized at 120°C for 20 minutes.
The sterilized medium is then inoculated with 0.5 ml of an aqueous spore
suspension of a strain of S. aureofaciens capable of producing
chlorodemethyltetracycline, such as S-604, containing approximately 40-60
million spores per milliliter. The inoculated medium is incubated for 24 hours
at 28°C on a reciprocating shaker operated at 110 cycles per minute.
A suitable fermentation medium contains water and a source of assimilable
carbon and nitrogen and essential mineral salts. A typical medium suitable for
production of chlorodemethyltetracycline is as follows:
A suitable fermentation medium contains water and a source of assimilable
carbon and nitrogen and essential mineral salts. A typical medium suitable for
production of chlorodemethyltetracycline is as follows:
Ten percent of the resulting inoculum is then transferred to a 250 ml
Erlenmeyer flask containing 50 ml of the medium employed above and the
flask agitated a further 72 hours under the same conditions. One ml of the
resulting inoculum is then employed for the inoculation of 10 ml of an
aqueous medium containing, per 1,000 ml, 30 grams extraction process
soybean meal, 1 gram sodium chloride, 50 grams glucose and 7 grams
calcium carbonate, in a 1" x 6" test tube.
In addition, 1 mg of sterile S-2-hydroxyethyl-DL-homocysteine is added to the
tube and the tube is shaken on a rotary shaker at 280 cycles per minute at
25°C for seven days. The contents of the tube were then acidified to pH 2 by
the addition of sulfuric acid and centrifuged. Examination of the supernatant
liquid by paper chromatography employing the methods of Bohonos et al,
Antibiotics Annual (1953-4, page 49),demonstrates the presence of 7-chloro6-demethyltetracycline,7-chlorotetracycline and tetracycline. | [Brand name]
Declomycin (Lederle). | [Therapeutic Function]
Antibacterial
| [Antimicrobial activity]
Occasional strains of viridans streptococci,
N. gonorrhoeae and H. influenzae are more susceptible than to tetracycline.
It is the most active tetracycline against Brucella spp. | [General Description]
Demeclocycline, 7-chloro-6-demethyltetracycline (Declomycin),was isolated in 1957 by McCormick et al. from amutant strain of S. aureofaciens. Chemically, it is 7-chloro-4-(dimethylamino)1,4,4a,5,5a,6, 11, 12a-octahydro-3, 6, 10, 12,12a-pentahydroxy1, 11-dioxo2-naphthacenecarboxamide.Thus, it differs from chlortetracycline only in the absence ofthe methyl group on C-6.
Demeclocycline is a yellow, crystalline powder that isodorless and bitter. It is sparingly soluble in water. A 1% solutionhas a pH of about 4.8. It has an antibiotic spectrumlike that of other tetracyclines, but it is slightly more activethan the others against most of the microorganisms forwhich they are used. This, together with its slower rate ofelimination through the kidneys, makes demeclocycline aseffective as the other tetracyclines, at about three fifths ofthe dose. Like the other tetracyclines, it may cause infrequentphotosensitivity reactions that produce erythema afterexposure to sunlight. Demeclocycline may produce this reactionsomewhat more frequently than the other tetracyclines.The incidence of discoloration and mottling of theteeth in youths from demeclocycline appears to be as low asthat from other tetracyclines. | [Pharmaceutical Applications]
6-Demethyl-7-chlortetracycline. A fermentation product of a
mutant strain of Streptomyces aureofaciens formulated as the
hydrochloride for oral administration. | [Biochem/physiol Actions]
Used to study mechanisms of bacterial protein synthesis inhibition at the level of the 30S subunit and aminoacy-tRNA A-site binding. | [Pharmacokinetics]
Oral absorption： 60–70%
Cmax 300 mg oral：2 mg/L after 3–6 h
Plasma half-life：c.12 h
Volume of distribution：c.1.7 L/kg
Plasma protein binding：90%
Absorption
It is promptly yet incompletely absorbed by mouth, giving
mean peak plasma levels after a single dose that are slightly
higher than those produced by oxytetracycline and chlortetracycline,
but lower than those achieved by tetracycline.
However, with repeat dosing, steady-state concentrations
exceed those for tetracycline. Simultaneous administration of
antacids markedly depresses blood levels.
Distribution and excretion
It is widely distributed, achieving concentrations in pleural
exudates
similar to those of blood. CSF penetration is
poor, especially in the absence of inflammation. Biliary
concentrations
are 20–30 times higher than those of plasma, and 40–50% of the drug can be recovered from feces. The
other route of elimination is via glomerular filtration without
reabsorption and accumulation occurs in renal failure. | [Clinical Use]
It has been extensively used in the management of the syndrome
of inappropriate ADH secretion in a dose of at least
1.2 g per day; therapeutic response may take several days, but
is superior to that of lithium. It has also found occasional use
in patients with water retention as a result of congestive cardiac
failure and in those with alcoholic cirrhosis and water
and electrolyte retention. | [Side effects]
Untoward reactions, notably gastrointestinal intolerance,
are generally those typical of the group. Occasional
patients develop transient steatorrhea.
Of particular note is the occurrence of nephrogenic diabetes
insipidus with development of vasopressin-resistant polyuria.
The effect is dose dependent and occurs with daily doses
in excess of 1.2 g. The drug inhibits activation of adenylate
cyclase and protein kinase, which are both important in the
interaction of antidiuretic hormone (ADH) with receptors
within the renal tubule, thus decreasing the effect of ADH on
the kidney. As a result, it has found a place in the treatment of
inappropriate ADH secretion.
Renal failure may occur, particularly if prescribed for those
with advanced liver cirrhosis. The mechanism is uncertain but
may in part be related to the antianabolic effect of the tetracyclines
as well as a direct toxic effect.
Photosensitivity may be severe and accompanied by vesiculation,
edema and onycholysis. It is largely restricted to exposed
skin; patients should avoid prolonged exposure to sunlight. | [Synthesis]
Demeclocycline, 7-chloro-4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahdroxy-1,11-dioxo-2-napthacencarboxamide (32.3.4), is produced
by a mutant strain of S. aureofaciens, in which the mechanism of transferring methyl groups
is disrupted, and thus demeclocycline or demethylchlorotetracycline differs from chlorotetracycline, oxytetracycline, and tetracycline in the absence of a methyl group at C6 of the
hydronaphthacene system. As a result, an antibiotic is synthesized that is more resistant to
acids and bases in comparison with the methyl homologs. | [Drug interactions]
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced anticoagulant
effect of coumarins and phenindione.
Oestrogens: possibly reduced contraceptive effects of
oestrogens (risk probably small).
Retinoids: possible increased risk of benign
intracranial hypertension, avoid. | [Metabolism]
Demeclocycline hydrochloride, like other tetracyclines,
is concentrated in the liver, where it is metabolised
and excreted into the bile. It is found in much higher
concentrations in the bile compared with the blood.
Following a single 150 mg dose of demeclocycline
hydrochloride in normal volunteers, 44% (n = 8) was
excreted in urine and 13% and 46%, respectively, were
excreted in faeces in two patients within 96 hours as
active drug. | [storage]
Store at -20°C | [Purification Methods]
Crystallise the salt from EtOH/Et2O or H2O and dry it in air [McCormick et al. J Am Chem Soc 79 4561 1957, Dobrynin et al. Tetrahedron Lett 901 1962]. [Beilstein 14 IV 2625.] |
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