Demeclocycline hydrochloride Chemical Properties

Melting point:

>245°C (dec.)

storage temp. 

Sealed in dry,Store in freezer, under -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.

Merck 

13,2905

BRN 

5705221

InChIKey

GVSJQNRGSCOSNJ-KBHRXELFSA-N

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)

Safety Information

Hazard Codes 

Xi

Risk Statements 

43

Safety Statements 

36/37

WGK Germany 

2

RTECS 

QI7700000

F 

8-10-21

HS Code 

29413020

Toxicity

LD50 orally in rats: 2372 mg/kg (Goldenthal)

MSDS

• Language:English Provider:SigmaAldrich

Demeclocycline hydrochloride Usage And Synthesis

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%
C_max 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.

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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