191114-48-4 Usage
Description
Telithromycin, also known as Ketek, is a semisynthetic ketolide antibiotic derived from the natural macrolide erythromycin. It is the first marketed ketolide, featuring a C3-ketone instead of the L-cladinose group. Telithromycin is an orally bioavailable macrolide that is classified as a ketolide and differs chemically from the macrolide group of antibacterials. It is characterized by the lack of α-L-cladinose at the 3-position of the erythronolide A ring, resulting in a 3-keto function. The antibiotic is further characterized by imidazolyl and pyridyl rings linked to the macrolide nucleus through a butyl chain. Telithromycin is a pale beige solid and is well tolerated and distributed into pulmonary tissues, bronchial secretions, tonsils, and saliva.
Uses
Used in Pharmaceutical Industry:
Telithromycin is used as an antibiotic for treating respiratory infections. It is effective against common respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes, as well as other atypical pathogens. The 3-keto group confers increased acidic stability and reduced induction of macrolide-lincosamide-streptogramin B resistance that is frequently observed with macrolides.
Telithromycin is used as a first-line treatment for community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute sinusitis, and tonsillitis/pharyngitis. It prevents bacterial protein synthesis by binding to two domains of the 50S subunit of bacterial ribosomes, causing a blockade of protein synthesis. The antibiotic is also believed to inhibit the assembly of ribosomes.
Additionally, Telithromycin is used as a competitive inhibitor and a substrate of CYP3A4. However, unlike several macrolides such as troleandomycin, it does not form a stable inhibitory CYP P-450 Fe2+-nitrosoalkane metabolite complex, which is potentially hepatotoxic. This property makes it a safer option for patients with liver concerns.
Macrolide antibiotics
Telithromycin is recently developed a new kind of macrolide antibiotics. It is the first antibiotic in the family of semi synthetic macrolides, a lincomycin B (MLSB) family. It is also the first ketone lactone antibiotic to be applied to the clinic. It is developed by the French Sanofi Aventis group successfully, with broad-spectrum antimicrobial activity and low resistance selection. It can be a good treatment of Streptococcus pneumoniae and resistant to penicillin and erythromycin, pneumococcal strains, Haemophilus influenzae bacteria and bacteria morahan, The antibacterial effect is stronger than the macrolide antibiotics such as azithromycin.It is mainly used for the treatment of respiratory tract infection, bronchitis, pharyngitis, tonsillitis and pneumonia.The function mechanism of Telithromycin is similar to the that of macrolide antibiotic.Mainly by binding to the 50S subunit of the bacterial ribosome, it inhibits the synthesis of protein and inhibits its translation and assembly. It can also be combined with nucleotides of the 23S ribosome RNA II and V structural region. But the biggest difference is that the binding force of telithromycin on wild-type ribosomes is about 10 times and 6 times stronger than that of erythromycin and clarithromycin. The slight difference in modification of ribosomal structure V region has made the MLSB antibiotic tolerance to bacteria increased by 20 times, making it effective for all drug-resistant strains of macrolide mg/(L?h). Oral administration absorbs well and its bioavailability is about 57%. Food does not affect its absorption. The 70% will be metabolized by CYP3A4 into theyrite alcohol, theyrite acid, N- deoxamide derivative and N- oxpyridine derivative in the liver. T1/2 is 9.81h, and the renal clearance rate was 12.5L/h. There are many ways of excreting: 13% are excreted from the urine in the original form, 3% are excreted from the feces in the original form , and 37% of the metabolites are excreted from the liver.In patients with liver dysfunction, Cmax decreases by about 20%, T1/2 is 1.4 times longer than normal people, and the metabolic rate decreases. The average pharmacokinetic parameters in patients with community acquired pneumonia (CAP) are Cmax 2.89 mg/L, Cmin 0.19 mg/L and AUC 13.9 mg/ (L. H).The US Food and Drug Administration announced on February 12, 2007It should make certain modifications to the drug labels of on the antibiotic telithromycin (also called Kenlike) produced by Sanofi Aventis. It will remove two items of acute bacterial sinusitis and chronic bronchitis in the indications of the drug from the drug instructions. It reminds patients to be careful in using telithromycin.
Antimicrobial activity
The spectrum covers Gram-positive and Gramnegative cocci, Gram-positive bacilli, fastidious Gram-negative bacilli, atypical mycobacteria, M. leprae, H. pylori, anaerobes, T. pallidum, intracellular pathogens and atypical organisms.It exhibits bactericidal activity in vitro against isolates of Str. pneumoniae regardless of the underlying resistance to penicillin G, erythromycin A and other agents. It is 2–4 times more active than clarithromycin against erythromycin A-susceptible isolates of Str. pneumoniae and other streptococci. Against H. influenzae the MIC range is 1–4 mg/L. It also exhibits good in-vitro activity against Coxiella burnetii (MIC 1 mg/L) and various Gram-positive species, including viridans streptococci (MIC ≤0.015–0.25 mg/L), C. diphtheriae (MIC 0.004–0.008 mg/L) and Listeria spp. (MIC 0.03–0.25 mg/L).
Acquired resistance
It retains activity against isolates resistant to erythromycin A. Str. pneumoniae and Str. pyogenes isolates for which the MIC of telithromycin is above the resistance breakpoint of 2 mg/L are presently rare. It is not active against Staph. aureus isolates that owe their resistance to erythromycin to constitutive methylation of adenine 2058 on domain V of the peptidyl transferase loop.
Pharmaceutical Applications
A 14-membered-ring ketolide, obtained by semisynthesis from erythromycin A. Formulated for oral administration.
Pharmacokinetics
Oral absorption :90% Cmax 800 mg oral :1.9–2.27 mg/L (steady state after 2–3 days) Plasma half-life: 10–12 h Volume of distribution :210 LPlasma protein binding:60–70%After oral administration the absolute bioavailability is 57% in both young and elderly subjects. The rate and extent of absorption are not influenced by food. In a study of ascending doses administered to healthy volunteers, peak plasma concentration ranged from 0.8 mg/L (400 mg dose) to 6 mg/L (2400 mg dose). The peak plasma concentration was reached after 1–2 h. The apparent elimination half-lives ranged from 10 to 14 h, with an AUC of 2.6 mg.h/L (400 mg dose) to 43.3 mg.h/L (2400 mg dose). After repeated oral doses the ratios between day 1 and day 10 ranged from 1.3 to 1.5. After once-daily oral dosing with 800 mg, the AUC is 8.25 mg.h/L.
Side effects
It is generally well tolerated. The main adverse event is diarrhea.
Check Digit Verification of cas no
The CAS Registry Mumber 191114-48-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,9,1,1,1 and 4 respectively; the second part has 2 digits, 4 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 191114-48:
(8*1)+(7*9)+(6*1)+(5*1)+(4*1)+(3*4)+(2*4)+(1*8)=114
114 % 10 = 4
So 191114-48-4 is a valid CAS Registry Number.
InChI:InChI=1/C43H65N5O10.C22H19ClO3/c1-12-33-43(8)37(48(41(53)58-43)19-14-13-18-47-23-31(45-24-47)30-16-15-17-44-22-30)27(4)34(49)25(2)21-42(7,54-11)38(28(5)35(50)29(6)39(52)56-33)57-40-36(51)32(46(9)10)20-26(3)55-40;23-16-11-9-14(10-12-16)13-5-7-15(8-6-13)19-20(24)17-3-1-2-4-18(17)21(25)22(19)26/h15-17,22-29,32-33,36-38,40,51H,12-14,18-21H2,1-11H3;1-4,9-13,15,24H,5-8H2/t25-,26-,27-,28+,29-,32+,33+,36-,37-,38-,40+,42-,43-;/m1./s1
191114-48-4Relevant articles and documents
Novel synthesis of telithromycin
Cao, Zhiling,Liu, Bing,Liua, Weiwei,Yao, Guowei,Liu, Wenjie,Wang, Qianqian
, p. 107 - 109 (2013)
A novel synthesis route for telithromycin was developed based on a 11,12-cylic carbonate protection strategy to prevent formation of 9,12-hemiacetal by-product. Through a 11,12-carbonate-6-O-methylerythromycin intermediate, telithromycin was synthesised from 6-O-methylerythromycin in five steps with 33% overall yield.
PROCESS FOR THE PRODUCTION OF TELITHROMYCIN
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Page/Page column 10; 17-18, (2009/05/28)
The present invention relates to a process for the preparation of erythromysin derivatives, in particular telithromycin of formula (I) and its pharmaceutically acceptable salts, providing the isolated intermediates in crystalline form of superior stability and purity.
NOVEL PROCESS FOR THE PREPARATION OF TELITHROMYCIN
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Page/Page column 22, (2010/11/30)
The present invention relates to the process for the preparation of compounds of formula (I) or its pharmaceutically acceptable salts wherein, (R) is a.