74-55-5 Usage
Indications
Ethambutol is a water-soluble, heat-stable compound
that acts by inhibition of arabinosyl transferase enzymes
that are involved in cell wall biosynthesis. Nearly
all strains of M. tuberculosis and M. kansasii and most
strains of Mycobacterium avium-intracellulare are sensitive
to ethambutol. Drug resistance relates to point mutations
in the gene (EmbB) that encodes the arabinosyl
transferases that are involved in mycobacterial cell wall
synthesis.
Therapeutic Function
Antitubercular
Antimicrobial activity
Ethambutol is active against several species of mycobacteria
and nocardiae. MICs on solid media are: M. tuberculosis
0.5–2 mg/L; M. kansasii 1–4 mg/L; other slowly growing
mycobacteria 2–8 mg/L; rapidly growing pathogens 2–16
mg/L; Nocardia spp. 8–32 mg/L.
Resistance is uncommon and is a multistep process due to
mutations in the embA, embB and embC gene cluster. A mutation
in codon 306 of the embB gene predisposes to the development
of resistance to a range of antituberculosis agents,
possibly by affecting cell-wall permeability.
Pharmaceutical Applications
A synthetic ethylenediamine derivative formulated as the
dihydrochloride for oral administration. The dry powder is
very soluble and stable.
Mechanism of action
The mechanism of action of EMB remains unknown, although mounting evidence suggests a specific site of action for EMB. It has been known for some time that EMB affects mycobacterial cell wall synthesis; however, the complicated nature of the mycobacterial cell wall has made pinpointing the site of action difficult. In addition to the peptidoglycan portion of the cell wall, the mycobacterium have a unique outer envelop consisting of arabinofuranose and galactose (AG), which is covalently attached to the peptidoglycan and an intercalated framework of lipoarabinomannan (LAM) . The AG portion of the cell wall is highly branched and contains distinct segments of galactan and distinct segments of arabinan. At various locations within the arabinan segments (terminal and penultimate), the mycolic acids are attached to the C-5′ position of arabinan. Initially, Takayama et al. reported that EMB inhibited the synthesis of the AG portion of the cell wall. More recently, it has been reported that EMB inhibits the enzymes arabinosyl transferase. One action of arabinosyl transferase is to catalyze the polymerization of D-arabinofuranose, leading to AG. Ethambutol mimics arabinan, resulting in a buildup of the arabinan precursor β-D-arabinofuranosyl- 1-monophosphoryldecaprenol and, as a result, a block of the synthesis of both AG and LAM. The mechanism of resistance to EMB involves a gene overexpression o
Pharmacology
Orally administered ethambutol is well absorbed
(70–80%) from the gut, and peak serum concentrations
are obtained within 2 to 4 hours of drug administration;
it has a half-life of 3 to 4 hours. Ethambutol is widely
distributed in all body fluids, including the cerebrospinal
fluid, even in the absence of inflammation.A
majority of the unchanged drug is excreted in the urine
within 24 hours of ingestion. Up to 15% is excreted in
the urine as an aldehyde and a dicarboxylic acid
metabolite. Ethambutol doses may have to be modified
in patients with renal failure.
Pharmacokinetics
Oral absorption: c. 80%, but some patients absorb it poorly
Cmax 25 mg/kg oral: 2–6 mg/L after 2–3 h
Plasma half-life: 10–15 h
Volume of distribution: >3 L/kg
Plasma protein binding: 20–30%
Absorption is impeded by aluminum hydroxide and alcohol.
It is concentrated in the phagolysosomes of alveolar macrophages.
It does not enter the cerebrospinal fluid (CSF) in
health but CSF levels of 25–40% of the plasma concentration,
with considerable variation between patients, are achieved in
cases of tuberculous meningitis.
Various metabolites are produced, including dialdehyde,
dicarboxylic acid and glucuronide derivatives. Around 50% is
excreted unchanged in the urine, with an additional 10–15%
as metabolites, and 20% is excreted unchanged in feces.
Clinical Use
Tuberculosis (initial intensive phase of short-course therapy)
Other mycobacterioses (M. kansasii, M. xenopi, M. malmoense and the
M. avium complex) (with appropriate additional drugs)
Clinical Use
Ethambutol has replaced aminosalicylic acid as a
first-line antitubercular drug. It is commonly included as
a fourth drug, along with isoniazid, pyrazinamide, and
rifampin, in patients infected with MDR strains. It also
is used in combination in the treatment of M. aviumintracellulare
infection in AIDS patients.
Side effects
The major toxicity associated with ethambutol use is
retrobulbar neuritis impairing visual acuity and redgreen
color discrimination; this side effect is dose related
and reverses slowly once the drug is discontinued.
Mild GI intolerance, allergic reaction, fever, dizziness,
and mental confusion are also possible. Hyperuricemia
is associated with ethambutol use due to a decreased renal
excretion of urates; gouty arthritis may result.
Side effects
The most important side effect is optic neuritis, which may be
irreversible if treatment is not discontinued. This complication
is rare if the higher dose (25 mg/kg) is given for no more
than 2 months. National codes of practice for prevention of
ocular toxicity should be adhered to; in particular, patients
should be advised to stop therapy and seek medical advice if
they notice any change in visual acuity, peripheral vision or
color perception, and the drug should not be given to young
children and others unable to comply with this advice.
Other side effects include gastrointestinal upsets, peripheral
neuritis, arthralgia, nephritis, myocarditis, hyperuricemia,
dermal hypersensitivity and, rarely, thrombocytopenia
and hepatotoxicity.
Synthesis
Ethambutol, (±)-N,N-ethylenbis-(2-aminobutan-1-ol) (34.1.4), is synthesized in several different ways. According to one of them, nitropropane undergoes oxymethylation using formaldehyde, and the nitro group in the resulting 2-nitrobutanol (34.1.2) is reduced by hydrogen to an amino group, making racemic (±) 2-aminobutanol. L (＋) tartaric acid is used to separate (＋) 2-aminobutanol (34.1.3). Reacting this with 1, 2-dichloroethane in the presence of sodium hydroxide gives ethambutol (34.1.4).
An alternative method of synthesis consists of preparing (＋) 2-aminobutanol (34.1.3) by reducing ethyl ester of L-2-aminobutyric acid hydrochloride with hydrogen using simultaneously Raney nickel and platinum oxide catalysts. This gives pure (＋) 2-aminobutanol. Reacting this with 1,2-dichloroethane in the presence of sodium hydroxide gives the desired ethambutol (34.1.4).
The third way of synthesis is very interesting and resembles of the Ritter reaction, but which takes place in the presence of chlorine. This method consists of reacting 1-butene and acetonitrile in the presence of chlorine, which evidently results in the 1,4-addition of chlorine to the product of the Ritter reaction, forming an intermediate dichloride (33.1.5), which is hydrolyzed with water to make N-[1-(chloromethyl)-propyl]-acetamide (33.1.6). Heating this product with hydrochloric acid gives racemic (±) 2-aminobutanol, from which (＋) 2-aminobutanol (34.1.3) is isolated as described above using L (＋) tartaric acid. Reacting this with 1,2-dichloroethane in the presence of sodium hydroxide gives the desired ethambutol (34.1.4)
Check Digit Verification of cas no
The CAS Registry Mumber 74-55-5 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 7 and 4 respectively; the second part has 2 digits, 5 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 74-55:
(4*7)+(3*4)+(2*5)+(1*5)=55
55 % 10 = 5
So 74-55-5 is a valid CAS Registry Number.
InChI:InChI=1/C10H24N2O2/c1-3-9(7-13)11-5-6-12-10(4-2)8-14/h9-14H,3-8H2,1-2H3/t9-,10-/m1/s1
74-55-5Relevant articles and documents
Salts and ionic liquid of the antituberculosis drug S,S-ethambutol
Cherukuvada, Suryanarayan,Nangia, Ashwini
, p. 1752 - 1760 (2013)
A salt screen of the antituberculosis chiral basic drug Ethambutol with protic acids resulted in the formation of several salts and an ionic liquid. The protic salt/ionic liquid product was characterized by spectroscopic (ATR-IR and ss-NMR), thermal (DSC and TGA), and X-ray diffraction. Similar to the marketed Ethambutol dihydrochloride salt of the drug, all the new salts were found to be hygroscopic. Moisture-free conditions of the desiccator and rotavapor gave nonhygroscopic materials in a few cases. X-ray crystal structures of two new salts were determined and that of the Ethambutol base and Ethambutol dihydrochloride salt were redetermined in this work.
Preparation method of ethambutol
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Paragraph 0034-0037, (2020/11/12)
The invention relates to a preparation method of an antituberculosis drug ethambutol. The preparation method specifically comprises the following steps: a, reacting 2-amino-1 butanol with carbonic ester to generate a compound 2, b, reacting the compound 2 with dihalogenated ethane to generate a compound 3, and c, hydrolyzing the compound 3 to generate ethambutol. According to the preparation method of the ethambutol, the adopted raw materials are low in price and easy to obtain, and the method has the advantages of short synthetic route, novel route, high yield and no dangerous process.
Preparation ethylamine butanol and ethylamine hydrochloride butanol
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Paragraph 0047; 0100-0101, (2017/02/28)
The invention provides methods for preparing ethambutol and ethambutol hydrochloride. The method for preparing the ethambutol comprises the step of utilizing (S)-2-aminobutanol and 1,2-dichloroethane to perform condensation reaction to prepare the ethambutol, wherein the condensation reaction is carried out in a low-boiling organic solvent, and HCl produced in the ammonia gas neutralization reaction process is utilized. Through the utilization of the method, the ethambutol of which the yield coefficient is improved can be obtained, so that the ethambutol hydrochloride of which the yield coefficient is improved can be obtained. Besides, the methods are simple in technology, safe, stable, low in cost and super-high in practical value in the industry.
SUBSTITUTED AMINO ALCOHOLS
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Page/Page column 26, (2009/04/24)
Disclosed herein are substituted amino alcohol anti-mycobacterial agents and/or chelation therapy agents of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
Enantioselective synthesis of (S,S)-ethambutol using proline-catalyzed asymmetric α-aminooxylation and α-amination
Kotkar, Shriram P.,Sudalai, Arumugam
, p. 1738 - 1742 (2007/10/03)
An efficient enantioselective synthesis of (S,S)-ethambutol, a tuberculostatic antibiotic, has been achieved in 99% ee via both proline-catalyzed α-aminooxylation and α-amination of n-butyraldehyde as the key step.
Efficient synthesis of (S,S)-ethambutol from L-methionine
Stauffer, Christina S,Datta, Apurba
, p. 9765 - 9767 (2007/10/03)
Starting from readily available amino acid L-methionine, an efficient synthesis of the tuberculostatic agent (S,S)-ethambutol has been developed. The key steps in the synthetic sequence involve: dimerization of methionine methyl ester through oxalyl diamide formation, Raney nickel desulfurization of the terminal thiomethyl groups, and a one-pot exhaustive reduction of the oxalamide and the diester functionalities to afford the desired enantiopure (S,S)-ethambutol in good overall yield.
Dynamic kinetic asymmetric transformation of diene monoepoxides: A practical asymmetric synthesis of vinylglycinol, vigabatrin, and ethambutol
Trost, Barry M.,Bunt, Richard C.,Lemoine, Remy C.,Calkins, Trevor L.
, p. 5968 - 5976 (2007/10/03)
The ability to perform a dynamic kinetic asymmetric transformation (DYKAT) using the palladium-catalyzed asymmetric allylic alkylation (AAA) is explored in the context of butadiene monoepoxide. The versatility of this commercially available, but racemic, four-carbon building block becomes significantly enhanced via conversion of both enantiomers into a single enantiomeric product. The concept is explored in the context of a synthesis of vinylglycinol with phthalimide as the nitrogen source. The success of the project required a new design of the ligand for palladium wherein additional conformational restraints were introduced. Thus, the phthalimide derivative of vinylglycinol was obtained in nearly quantitative yield and had an ee of 98% which, upon crystallization, was enhanced to > 99%. This one-step synthesis of a protected form of vinylglycinol provided short practical syntheses of the title compounds. Vigabatrin requires only four steps, and ethambutol six. The intermediate to the existing synthesis of ethambutol is available in 87% yield in three steps. (R)-Serine derives from oxidative cleavage of the double bond. The reaction of phthalimide and isoprene monoepoxide demonstrates the remarkable ability of the chiral ligands to control both regioselectivity and enantioselectivity and demonstrates the effectiveness of this protocol in creating a quaternary center asymmetrically.
