220620-09-7 Usage
Uses
Used in Pharmaceutical Industry:
Tigecycline is used as an anti-infective agent for the treatment of complicated skin and skin structure infections caused by susceptible organisms, including E. coli, E. faecalis, S. aureus (methicillin-susceptible and methicillin-resistant isolates), S. pyogenes, and B. fragilis, among others. It is also indicated for complicated intra-abdominal infections caused by strains of Clostridium, Enterobacter, Klebsiella, and Bacteroides.
Used in Antineoplastic Applications:
Tigecycline is used as an antineoplastic agent, demonstrating activity against a broad range of Gram-positive and Gram-negative bacteria, including tetracycline-resistant organisms. It is particularly effective against drug-resistant bacteria such as Staphylococcus aureus and Acinetobacter baumannii.
Used in Research and Development:
Tigecycline is used as a research tool to study the mechanisms of bacterial resistance and the development of new antibiotics to combat drug-resistant infections. Its unique mechanism of action and resistance to common resistance mechanisms make it a valuable asset in the fight against antibiotic resistance.
Indications and Usage
Tigecycline is also called 9-tert-glycylaminomycetine or diclofenac, and it is a new type of venous injection antibiotic with broad-spectrum activities. It is a type of 9-tert-glycylaminomycetine derivative and is the first glycylcine antibiotic.
Tigecycline can serve as a second option after failed first-line treatment for multi-drug resistant bacteria, and it is also a new treatment option for patients who are allergic to penicillin or intolerable to other drugs. It can treat patients 18 years old or above with complex skin and skin structure infections or complex abdominal infections such as complex appendicitis, burn infections, abdominal abscesses, deep soft tissue infections, and ulcer infections.
Mechanisms of Action
Tigecycline’s mechanisms of action are similar to those of tetracycline antibiotics, which are binding with bacterial 30S ribosomes to prevent transfer RNA from entering, making it impossible for amino acids to form peptide chains, thus preventing bacterial protein synthesis and limiting bacterial growth. However, tigecycline’s ability to bind with ribosomes is 5 times that of other tetracycline antibiotics, which means that tetracycline’s anti-drug resistance ability is stronger. Tigecycline’s structure is similar to that of minocycline, but tigecycline’s antibacterial activity is much stronger, and bacteria are less likely to develop resistance to it compared to other tetracycline drugs, and it can also act on the methicillin-resistant Staphylococcus aureus. Tigecycline’s antifungal spectrum includes gram-positive bacteria, gram-negative bacteria and anaerobic bacteria. In vitro experiments and clinical trials showed that tigecycline is sensitive to some aerobic gram-negative bacteria (such as Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae and Klebsiella pneumoniae, Acinetobacter baumannii, Aeromonas hydrophila, Citrobacter Enterobacteriaceae, hemorrhagic Pasteurella, Serratia marcescens, and Stenotrophomonas maltophilia). Pseudomonas auruginosa is resistant to tigecycline.
Adverse reaction
The most common adverse effects are nausea and vomiting, which usually happens in the first 1-2 days of treatment and are mild to moderate in intensity. In a positive drug control clinical trial, 35% percent of complex skin and skin structure infection patients using tigecycline experienced nausea, and 20% experienced vomiting; vancomycin/aztreonam use caused 8.9% nausea and 4.2% vomiting. 25.3% of complex abdominal infection patients using tigecycline experienced nausea, and 19.5% experienced vomiting; vancomycin/aztreonam caused 20.5% nausea and 15.3% vomiting.
Antimicrobial activity
It is as potent as, or more potent than,
earlier tetracyclines and activity is retained against strains
expressing acquired tetracycline resistance determinants. It
displays better activity than tetracycline, doxycycline or
minocycline against Streptococcus spp. and against Enterococcus
faecalis and E. faecium. Among Gram-negative organisms it
displays improved activity against Citrobacter freundii,
Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae,
Salmonella spp., Serratia marcescens and Shigella spp. The
spectrum includes rapidly growing mycobacteria. Ps. aeruginosa,
Pr. mirabilis, other Proteus spp. and some strains of
Corynebacterium jeikeium are resistant. Activity against strains
expressing acquired resistance to earlier tetracyclines is
attributed to failure of the MFS efflux pumps to recognize
tigecycline, and to a novel mechanism of ribosome binding
that permits tigecycline to overcome ribosomal protection
mechanisms.
Comparative susceptibility data for some atypical pathogens
are not available. However, in common with earlier
tetracyclines,
it is active against Chlamydophila and Mycoplasma
spp. and rapidly growing Mycobacteria spp. It is less active
than minocycline or tetracycline against U. urealyticum.
Pharmaceutical Applications
9-T-butylglycylamido-minocycline. A compound of the glycylcycline
class available as a powder for intravenous infusion.
Pharmacokinetics
Cmax 100 mg intravenous infusion (1 h): 0.85–1 mg/L
Plasma half-life: 37–67 h
Volume of distribution: 7–10 L/kg
Plasma protein binding: 68%
Distribution and excretion
It is widely distributed and is concentrated in the gallbladder,
colon and lung. The volume of distribution is dose related and
variable, but is generally greater than that of older tetracyclines.
CSF penetration is poor. Tigecycline is excreted in the
feces and urine predominantly as the unchanged molecule.
The elimination half-life is long (37–67 h). Tigecycline clearance
is decreased by 20% in patients with renal failure. No
dosage adjustments are apparently necessary for tigecycline
in patients with renal impairment.
Clinical Use
Complicated skin and skin structure infections
Complicated intra-abdominal infections
Community-acquired bacterial pneumonia
Recommended principally for the treatment of infections with
multiresistant organisms.
Side effects
Side effects typical of the group, including nausea, vomiting,
diarrhea and headache, occur. Occasional cases of pancreatitis,
hypoproteinemia, antibiotic-associated colitis and thrombocytopenia
have also been reported.
Synthesis
It
does not require dosage adjustment in patients with impaired
renal function and is conveniently dosed every 12 hours.
Synthesis of tigecycline started with nitration
of 138 with potassium nitrate and concentrated sulfuric
acid to give 9-nitro derivative 139 in 93 % yield as disulfate
salt, which was hydrogenated over Pd/C in 2-methoxyethanol/
2N sulfuric acid at 40 psi to provide 9-aminominocycline
(140). Finally, 9-aminominocycline (140) is acylated directly
with N-tert-butylglycyl chloride in a 1:5 mixture of acetonitrile
and N, N-dimethylpropyleneurea (DMPU) with anhydrous
sodium carbonate to give tigecycline (XX).
in vitro
tigecycline exihibited good in vitro activities. the range of mic90s was 0.12-0.5 μg/ml for vancomycin-susceptible and -resistant strains of enterococcus faecalis and enterococcus faecium [2]. tigecyclinewas concentrated in cells and eliminated primarily via biliary excretion. diminished renal function didn’t significantly alter its systemic clearance. tigecycline didn’t interfere with common cytochrome p450 enzymes, making pharmacokinetic drug interactions uncommon [3].the tissue penetration of tigecycline was excellent and the compound showed equivalence to imipenem/cilastatin in intra-abdominal infection and to vancomycin plus aztreonam in skin and skin structure infection [4].
in vivo
in an intraperitoneal systemic murine infection model, tigecycline exihibited in vivo activities against gisa, methicillin-susceptible s. aureus and methicillin-resistant s. aureus strains [2]. tigecycline and daptomycin showed similar in vivo efficacies against infections caused by the mssa strain (strain gc 4543) with the ed50s of 0.12 and 0.24 mg/kg, respectively. the ed50s of tigecycline was 0.72 mg/kg [2].
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced anticoagulant
effect of coumarins.
Oestrogens: possibly reduced contraceptive effects of
oestrogens (risk probably small).
Metabolism
Tigecycline is not thought to be extensively metabolised,
although some trace metabolites have been identified
including a glucuronide, an N-acetyl metabolite, and a
tigecycline epimer. Tigecycline is primarily eliminated
(about 60%) via biliary excretion of unchanged drug and
some metabolites.
References
1) Greer (2006)?Tigecycline (Tygacil): the first in the glycylcycline class of antibiotics; Proc. (Bayl. Univ. Med. Cent.)?19?155
2) Peterson (2008)?A review of tigecycline – the first glycylcycline; Int. J. Antimicrob. Agents?32 Suppl 4?S215
3) Skrtic?et al.?(2011)?Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia; Cancer Cell?20?674
4) Jia?et al.?(2016)?Tigecyclin targets nonsmall cell lung cancer through inhibition of mitochondrial function; Fundam. Clin. Pharmacol.?30?297
5) Hu?et al.?(2016)?Antibiotic drug tigecycline inhibits melanoma progression and metastasis in a p21CIP1/Waf1-dependent manner; Oncotarget?7?3171
6) D’Andrea?et al.?(2016)?The mitochondrial translational machinery as a therapeutic target in Myc-driven lymphomas.; Oncotarget?7?72415
7) Chen?et al.?(2019)?Inhibition of mitochondrial translation selectively targets osteosarcoma; Biochem. Biophys. Res. Commun. 515 9
Check Digit Verification of cas no
The CAS Registry Mumber 220620-09-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,2,0,6,2 and 0 respectively; the second part has 2 digits, 0 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 220620-09:
(8*2)+(7*2)+(6*0)+(5*6)+(4*2)+(3*0)+(2*0)+(1*9)=77
77 % 10 = 7
So 220620-09-7 is a valid CAS Registry Number.
InChI:InChI=1/C29H39N5O8/c1-28(2,3)31-11-17(35)32-15-10-16(33(4)5)13-8-12-9-14-21(34(6)7)24(38)20(27(30)41)26(40)29(14,42)25(39)18(12)23(37)19(13)22(15)36/h10,12,14,21,31,36,38-39,42H,8-9,11H2,1-7H3,(H2,30,41)(H,32,35)/t12-,14-,21-,29-/m0/s1
220620-09-7Relevant articles and documents
Synthesis and structure-activity relationship of novel glycylcycline derivatives leading to the discovery of GAR-936
Sum, Phaik-Eng,Petersen, Peter
, p. 1459 - 1462 (1999)
A number of new glycylcyclines were synthesized for structure-activity relationship study. Many of the derivatives exhibit potent, broad spectrum antibacterial activity against both tetracycline susceptible and resistant organisms. GAR-936 (TBG-MINO) shows better activity than the previously reported DMG-MINO and DMG-DMDOT.
Purification method of tigecycline
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Paragraph 0019-0029, (2020/12/08)
The invention discloses a purification method of tigecycline in the technical field of medicinal chemistry. The purification method of tigecycline comprises the following specific steps: S1, adding 9-aminominocycline hydrochloride and N-tert-butylglycyl chloride hydrochloride, and carrying out a reaction under stirring; S2, after the reaction is completed, adding a protective agent, and adjustingthe pH value of the reaction solution to 7.0-7.4 with 14-20% of ammonia water; S3, carrying out chromatography; and S4, collecting the purified desorption solution, drying, filtering to remove the drying agent, and drying under reduced pressure to obtain the tigecycline finished product. The method provided by the invention has the advantages of high yield, good impurity removal effects, low organic solvent consumption, recoverability, simple process and easy control, and is especially suitable for industrial production.
Synthetic method of minocycline and derivative of minocycline
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Paragraph 0026; 0027, (2019/09/13)
The invention relates to a synthetic method of minocycline and substituted minocycline, and especially synthesis of 9-amino minocycline. 9-amino minocycline is an important intermediate of tigecycline, and tigecycline is mostly used for control on multiple resistant bacteria. The raw materials are easily available; the synthetic route is short; reaction conditions are mild; the yield is high; thetechnology is simple; and the synthetic method is suitable for large scale production.
A by to a fund of rapamycin synthesis of tigecycline new method (by machine translation)
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, (2019/07/04)
The invention provides a synthesis of erythromycin by to a fund of tigecycline new method, comprises the following steps: would go to a fund ycin nitration, catalytic reduction, with tert-butyl amine acetyl chloride hydrochloride reaction, further nitration reaction, catalytic reduction, methylation reaction to obtain a crude product such as prostacyclin for canada 6 step reaction can; be the final purification tigecycline. Short reaction steps of this invention, high purity, low cost, non-toxic and the like, is suitable for mass production. (by machine translation)
Preparation method of tigecycline
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Paragraph 0018; 0019; 0026, (2017/07/22)
The invention relates to a preparation method of tigecycline. The preparation method comprises the following steps of condensating N-t-butylglycine with 9-aminosancycline under the action of a compound condensating agent, and making the tigecycline through nitration and reductive methylation. The preparation method is simple and convenient in process; an obtained product is high in yield and high in purity.
PROCESS FOR THE PREPARATION OF TIGECYCLINE
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Page/Page column 14-15, (2010/04/25)
The present invention relates to an improved process for the preparation of tigecycline. The process comprises treating minocycline hydrochloride with nitrating agent at low temperature followed by reduction in presence of catalyst to produce 9-aminominocycline disulphate in granular form. It is then reacted with N-t-butylglycyl chloride hydrochloride at pH below 3 under nitrogen atmosphere to obtain tigecycline.
TIGECYCLINE FORMULATIONS
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, (2010/03/02)
The invention is directed to a frozen pharmaceutical formulation suitable for administration to a subject parenterally, comprising a therapeutically effective amount of tigecycline and an agent selected from the group consisting of lactose, dextrose, glucose, mannose, sucrose, ribose, xylose and a combination thereof, wherein the formulation in a pre-frozen state at about 22° C. or in an unfrozen state at about 22° C. has a pH in the range of from 4.0 to 5.5. Preferably, the formulation is suitable for storage at or below about ?20° C. over a period of at least about 2 months, preferably 6 months, more preferably 26 months. Alternatively, the formulation is suitable for storage at about 22° C. over a period of about 24 hours.
ANTIBIOTIC COMPOUNDS
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Page/Page column 7, (2009/09/05)
The present invention relates to the new crystalline solid form Xl of Tigecycline and a process of preparing the same. Form Xl of Tigecycline is particularly suitable for the isolation of Tigecycline in the last step of the synthesis of Tigecycline. Further the present invention relates to a process of preparing amorphous Tigecycline by spray drying form Xl or another crystalline form of Tigecycline.
PROCESSES FOR PREPARATION OF CRYSTALLINE TIGECYCLINE FORM II
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Page/Page column 10, (2009/07/03)
The present invention provides processes for the preparation of crystalline forms of Tigecycline.
PROCESSES FOR PREPARATION OF 9-HALOACETAMIDOMINOCYCLINES
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Page/Page column 10-11, (2008/12/06)
The present invention provides substantially pure intermediates, 9- haloacetomidominocyclines, and process of preparing them that are useful for the preparation of glycylcyclines, specifically Tigecycline.
