78110-38-0 Usage
Description
Aztreonam is the first member of the monobactam class of antibiotics, characterized by its high β-lactamase stability and moderately good activity against gram-negative aerobes. It is a synthetic monocyclic β-lactam antibiotic that inhibits mucopeptide synthesis in the bacterial cell wall, blocking peptidoglycan crosslinking. Aztreonam is effective against a range of gram-negative bacteria but is inactive against gram-positive bacteria.
Uses
Used in Medical Industry:
Aztreonam is used as an antibiotic for treating infections caused by sensitive gram-negative bacteria, including pneumonia, pleurisy, abdominal infections, biliary tract infections, bone and joint infections, skin and soft tissue inflammation, and urinary tract infections. It is particularly effective for sepsis cases where the microorganism is not sensitive to penicillins, cephalosporins, aminoglycosides, and other drugs, due to its good resistance to enzyme performance.
Used as an Antiserotonin:
In some applications, Aztreonam is used as an antiserotonergic agent, although its primary use remains as an antibiotic for gram-negative bacterial infections.
Outline
Aztreonam is a novel kind ofβ-lactam antibiotics belonging to monobactams. In 1978 it was first discovered from the culture brot of New Jersey soil purple bacterium Chromobacterium violaceum, it has been obtained with synthesis method.
Mechanism
Aztreonam belongs to bacteria fungicides. It can quickly go through the outer membrane of Gram-negative aerobic bacteria wall, while it has a high affinity with the penicillin-binding protein 3 (PBP-3) . By acting on the PBP-3 and inhibiting synthesis of bacterial cell wall , it leads to cell lysis and death.
Aztreonam has a narrow antimicrobial spectrum, it only has antibacterial effect on aerobic gram-negative bacilli , such as E. coli, Klebsiella, Serratia spp, Proteus mirabilis, indole-positive Proteus, Citrobacter, influenza addicted blood coli, Pseudomonas aeruginosa and other Pseudomonas, some Enterobacter, Neisseria gonorrhoeae. The product is highly stable to β-lactamase produced by many bacteria .it is inactive in Gram-positive bacteria and anaerobic bacteria . Aztreonam compared with ceftazidime, gentamicin, it effect on aerogenes, and Enterobacter cloacae is higher than ceftazidime, but lower than gentamicin; the effect on Pseudomonas aeruginosa is lower than ceftazidime , and similar to gentamicin .
indications
It is mainly used for the treatment of infections caused by susceptible strains which include the respiratory system, urinary, reproductive system infections (including acute gonorrhea), intra-abdominal infections, skin and soft tissue infections, before surgery preventing infections, other serious infections, such as sepsis.
Precautions
1.contraindication: patients allergic to the products or having a history of allergy on lidocaine and other local anesthetics or having anaphylactic shock on other β-lactam drugs are banned.
2. caution following:
It does not exist cross-allergic reactions between aztreonam and penicillins, but people having allergy body and allergic to penicillins, cephalosporins should take caution.
renal dysfunction patients should take caution.
aztreonam does not have toxicity for liver , but the patients having impaired liver function should observe the dynamic changes. It has been reported that in patients with alcoholic cirrhosis , the total clearance of the products can be reduced by 20-25%.
pregnant and lactating women, infants and young children should use with caution.
3. The impact of drugs on clinical outcomes:
direct anti-human globulin test (Coombs test) can be positive.
there may be a temporary increase of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and serum creatinine values after medication among a few patients, part thromboplastin time (PTT) and prothrombin time (PT) may be extended.
adverse reactions are skin symptoms such as skin rashes, purpura, pruritus (approximately 2%); gastrointestinal symptoms such as diarrhea, nausea, vomiting, taste changes, jaundice, and drug-induced hepatitis (approximately 2%); local irritation such as thrombophlebitis. Injection site swelling (approximately 2.4%); there are other neurological symptoms, vaginitis, oral lesions, fatigue, dizziness, and bleeding.
4. Long-term medication should pay attention to monitoring of liver, kidney and hematopoietic system.
The above information is edited by the lookchem of Tian Ye.
production method
Threonine for raw materials,chloride resulting from the chlorination forms an amide through ammonolysis, protect α-amino with benzyl chloroformate,esterifyβ-hydroxy with methanesulfonyl chloride , the amide group is sulfonated with sulfuric acid tetrabutylammonium , then it is cyclized to generate azetidine derivative in the potassium bicarbonate, then after hydrogen and Deprotection, produce 3-amino-2-methyl-4-oxo-1-sulfo-N oxetane.
Afetr dehydration amidation of side chains Azetidine derivative and thiazole derivatives obtained in the above, hydrolyse to deprotect and to obtain aztreonam.
Acute toxicity
Intraperitoneal-rat LD50: 2549 mg/kg; intraperitoneal-Mouse LD50: 2897 mg/kg.
Flammability and hazard characteristics
Combustible; combustion produces toxic fumes of nitrogen oxides and sulfur oxides.
Originator
Squibb (USA)
Manufacturing Process
This mixture was sterilized for 15 minutes at 121°C at 15 lbs/inch2 steam
pressure prior to use. The fermentation flasks were incubated at 25°C for 40
to 45 hours on a of rotary shaker. A 250 liter batch of Agrobacterium
radiobacter A.T.C.C. No. 31700 is fermented in a 100 gallon steel vessel with
a media and operating conditions described below. Culture of Agrobacterium
radiobacter grown out on agar slants, pH 7.3 consisted of yeast extract (1 g),
beef extract (1 g), NZ amine A (2 g), glucose (10 g), agar (15 g) in 1000 ml
distilled water. Loopful of surface growth from agar slant was used as the
source of incolumn. Medium of oatmeal (20 g), tomato paste (20 g) tapped
water to 1000 ml, pH 7, was sterilized for 15 min at 121°C at 15 lbs/inch2
steam pressure prior to use. 100 ml of the medium, containing incolumn is
incubated at 25°C for about 24 hours on a rotary shaker. It was added to a
mixture of yeast extract (5 g), glucose (10 g) in 1 L distilled water and
incubated for about 42 hours at 25°C in 100 gallon stainless steel
fermentation vessel.
During incubation, the broth is agitated at 155 r.p.m. and aerated at rate of
10.0 cubic feet per minute. An antifoam agent (Ucon LB625, Union Carbide)
was added as needed. The fermentation beer was adjusted to pH 4 with
aqueous HCl and calls separated by centrifugation. The supernatante (200 L) was extracted with 40 L of 0.05 m cetyldimethylbenzyl ammonium chloride in
dichloromethane and extract concentrated in vacuo to 5.5 L. The concentrate
was then extracted with solution of 177 g of sodium thiocyanate in 2 L of
water, adjusting the mixture of pH 4.35 with phosphoric acid. The aqueous
extract was concentrated in vacuo to 465 ml and added to 1840 ml of
methanol. Solids are filtrated yielded 194 g of crude solid product. It was
dissolved and chromatographed on a 5x106.5 cm column of Sephadex G-10
three times and after concentrating in vacuo gave 3.5 g of crude antibiotic
M53 (azetreonam) which was chromatographed at first on QAE Sephadex A-
25 (liner gradient, prepared from 2.5 L of water and 2.5 L of 0.25 M sodium
nitrate). Then the residue (fractions 26-75) gave M53 (natrium salt) after
evaporation. It was triturated with methanol and the souble fraction, 0.40 g
was chromatographed on a 2.5x20 cm column of Diaion HP20AG, eluting at 2
ml per minute with water and collecting 20 ml fractions. Fractions 26-75 gave
51.9 mg of antibiotic M53 (sodium salt).
Therapeutic Function
Antibiotic
Antimicrobial activity
Concentrations (mg/L) inhibiting
50% of other organisms are: Aeromonas spp., 0.1;Acinetobacter spp., 16; Mor. catarrhalis, 0.1; Burkholderia cepacia,
2; and Yersinia spp., 0.1. Synergy has been shown with gentamicin,
tobramycin and amikacin against 52–89% of strains of Ps.
aeruginosa and gentamicin-resistant Gram-negative bacteria.
Biochem/physiol Actions
Aztreonam is a monobactam antibiotic used primarily to treat gram-negative bacterial infections. It is an older compound being re-examined as a therapeutic agent because of increasing carbapenem resistance in aerobic Gram-negative bacilli and because aztreonam is stable to Ambler class B metallo-β-lactamases. It is used alone or more commonly in combination with β-lactamase inhibitors such as avibactim.
Pharmacokinetics
Cmax 1 g intravenous: 90 mg/L end infusion
1 g intramuscular: 46 mg/L after 1 h
Plasma half-life: 1.7 h
Volume of distribution: 0.18 L/kg
Plasma protein binding: 56%
Absorption and distribution
Oral bioavailability is less than 1%. Peak concentrations
above the median MIC for most Gram-negative pathogens
are achieved in most tissues and body fluids after 1 g intramuscular
or intravenous doses.
Metabolism and excretion
It is not extensively metabolized, the most prominent product,
resulting from opening the β-lactam ring, being scarcely
detectable in the serum and accounting for about 6% of the
dose in the urine and 3% in the feces.
It is predominantly eliminated in the urine, where 58–72%
appears within 8 h. Less than 12% is eliminated unchanged in
the feces, suggesting low biliary excretion.
Clinical Use
Urinary tract infections, including pyelonephritis and cystitis
Lower respiratory tract infections, including pneumonia and bronchitis
caused by Gram-negative bacilli
Septicemia
Skin and skin structure infections, including postoperative wounds, ulcers
and burns
Intra-abdominal infections, including peritonitis
Gynecological infections, including endometritis and pelvic cellulitis
Side effects
Local reactions occasionally occur at the injection site.
Systemic reactions include diarrhea, nausea and/or vomiting
and rash (1–1.3%). Neutropenia was seen in 11.3% of the
pediatric patients younger than 2 years. Pseudomembranous
colitis has been reported.
There are no reactions in patients with immunoglobulin E
(IgE) antibodies to benzylpenicillin or penicillin moieties. It
is rarely cross-reactive with other β-lactam antibiotics and is
weakly immunogenic.
Safety Profile
Moderately toxic by severalroutes. An experimental teratogen. Other experimentalreproductive effects. When heated to decomposition itemits toxic fumes of NOx and SOx.
Synthesis
Aztreonam, (Z)-2[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]cabamoyl]methylen]amino]oxy]-2-methylpropionoic acid (32.1.4.9), is synthesized
from tert-butyloxycarbonylthreonine, which is reacted with O-benzylhydroxylamine in the presence of dicyclohexylcarbodimide and 1-hydroxybenzotriazole, to form the benzyl hydroxamide
derivative (32.1.4.1). This product undergoes a reaction with triphenylphosphine and ethyl
azodicarboxylate, which results in the cyclodehydration of the product to (3S-trans)-N-benzyloxy-3-tert-butyloxycarbonylamino-4-methyl-azetidinone (32.1.4.2). Debenzylating this by
hydrogen reduction using a palladium on carbon catalyst forms (3S-trans)-N-hydroxy-3-tertbutyloxycarbonyl-amino-4-methyl-azetidinone (32.1.4.3). The hydroxyl group in this compound is removed by reducing it with titanium trichloride, which forms azetidinone (32.1.4.4).
Removing the tert-butyloxycarbonyl protection using trifluoroacetic acid and subsequent acylation of the resulting product with the benzyl chloroformate gives (3S-trans)-benzyloxycarbonylamino-4-methylazetidinone (32.1.4.5). Sulfonating this product with a mixture of sulfur trioxide and dimethylformamide gives the corresponding N-sulfonic acid. Turning the resulting Nsulfonic acid into a potassium salt by reacting it with potassium hydrophosphate, followed by
replacing the potassium cation with a tetrabutylammonium cation by reacting it with tetrabutylammonium sulfate gives the product (32.1.4.6). Reducing this with hydrogen using a palladium
on carbon catalyst gives 3-amino-4-methyl-monobactamic acid (32.1.4.7). Acylating this with
(Z) 2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino] 4-thiazoleacetic acid
in the presence of dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole gives the diphenylmethyl ester of the desired aztreonam (32.1.4.8), which is hydrolyzed to aztreonam (32.1.4.9)
using trifluoroacetic acid.It is believed that the methyl group at position 4 increases the stability of the beta-lactam
ring with respect to most beta-lactamases, and at the same time it does not induce formation of beta-lactamase as cephalosporins and imipenems do.
Veterinary Drugs and Treatments
Aztreonam is a monobactam antibiotic that may be considered for
use in small animals for treating serious infections caused by a wide
variety of aerobic and facultative gram-negative bacteria, including
strains of Citrobacter, Enterobacter, E. coli, Klebsiella, Proteus,
Pseudomonas and Serratia. The drug exhibits good penetration into
most tissues and low toxic potential and may be of benefit in treating
infections when an aminoglycoside or a fluoroquinolone are either
ineffective or are relatively contraindicated. Any consideration for
using aztreonam must be tempered with the knowledge that little clinical experience or research findings have been published with
regard to target species.
Aztreonam has also been used to treat pet fish (koi) infected
with Aeromonas salmonocida.
Drug interactions
Potentially hazardous interactions with other drugs
Possibly enhanced anticoagulant effect of coumarins.
Metabolism
Aztreonam is not extensively metabolised. The principal
metabolite, SQ-26992, is inactive and is formed by
opening of the beta-lactam ring; it has a much longer
half-life than the parent compound.
Aztreonam is excreted as unchanged drug with only small
quantities of metabolites, mainly in the urine, by renal
tubular secretion and glomerular filtration. Only small
amounts of unchanged drug and metabolites are excreted
in the faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 78110-38-0 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,8,1,1 and 0 respectively; the second part has 2 digits, 3 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 78110-38:
(7*7)+(6*8)+(5*1)+(4*1)+(3*0)+(2*3)+(1*8)=120
120 % 10 = 0
So 78110-38-0 is a valid CAS Registry Number.
78110-38-0Relevant articles and documents
Novel crystal form of compound for treating bacterial infection and preparation method thereof
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Paragraph 0038, (2021/04/14)
The invention belongs to the field of medicines, and discloses a new crystal form of a compound for treating bacterial infection and a preparation method thereof. Specifically, the invention discloses a new crystal form of an aztreonam compound and a preparation method thereof. The novel aztreonam crystal form disclosed by the invention is different from the prior art, and an X-ray powder diffraction pattern measured by using Cu-K alpha rays is as shown in Figure 1. According to the invention, the pH value is adjusted in sections after the purified water is added, so that the problem that triethylamine easily exceeds the standard is solved, and meanwhile, the novel aztreonam crystal form with good stability, low solvent residue and low impurity content is prepared and is suitable for industrial mass production.
An improved method for the synthesis of Aztreonam
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Paragraph 0029, (2017/01/05)
The invention provides an improved synthetic method of aztreonam. According to the improved synthetic method, alpha-(2-aminothiazole-4-yl)-alpha-[(tert-butoxycarbonyl)-propoxyimino)] acetic acid mercaptobenzothiazole ester, and (2S, 3S) 3-amino-2-methyl-4-oxoazetidine sulfonic acid are taken as reaction intermediates; an organic amine is used as a catalyst; and a mixed acid water solution of formic acid and an organic acid is used for removing tertiary butyl protecting group so as to obtain aztreonam. Separation of the intermediates is not necessary, operation is simple and convenient, deprotection method is mild, yield is high, and product purity is high.
PROCESS FOR MAKING AZTREONAM
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Page/Page column 7, (2008/06/13)
A simplified process for the one-pot preparation of aztreonam, using azetidine and TAEM as starting materials, without the intermediary separation of t-butyl-aztreonam is provided.
