111406-87-2 Usage
Uses
Used in Pharmaceutical Industry:
Zileuton is used as an inhibitor of 5-lipoxygenase, the initial enzyme in the biosynthesis of leukotrienes from Arachidonic Acid, for the management of chronic asthma. It is particularly effective in reducing the formation of leukotrienes LTB4, LTC4, LDT, and LTE4, which play a significant role in asthma and other inflammatory conditions.
Used in Asthma Treatment:
Zileuton is used as an antiasthmatic drug for the prophylaxis and chronic treatment of asthma. It has been shown to significantly attenuate asthmatic response to cold dry air, inhibit exercise-induced bronchoconstriction, and attenuate induced bronchospasms. Additionally, it has anti-inflammatory effects, such as a decrease in edema, mucus production, and cellular infiltration, and a bronchodilatory effect within 2 hours, increasing spirometry results by 18%.
Used in Gastrointestinal Treatment:
Zileuton is also used as a gastric acid secretion inhibitor, helping to reduce the production of gastric acid and providing relief from conditions related to excess stomach acid, such as heartburn and gastroesophageal reflux disease (GERD).
Brand Name:
Zyflo (Sensus) is the brand name under which Zileuton is marketed. It was launched in the US for chronic asthma treatment and can be prepared in three steps from 2-acetylbenzo[b]thiophene. Zyflo is a reversible direct inhibitor of 5-lipoxygenase that is orally-active and has no effect on myeloperoxidase activity, neutrophil degranulation, mast cell histamine release, or phospholipase A2 activities. It does not inhibit cyclooxygenase, as evidenced by the formation of TXB2.
References
[1] A Rossi, C Pergola, A Koeberle, M Hoffmann, F Dehm, P Bramanti, S Cuzzocrea, O Werz and L Sautebin, The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages, British Journal of Pharmacology, 2010, col. 161, 555-570
[2] SE Wenzel and AK Kamada, Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma, Ann Pharmacother., 1996, vol. 30, 858-864
References
1) Carter et al. (1991), 5-Lipoxygense inhibitory activity of zileuton; J. Pharmacol. Exp. Ther. 256 929
2) Rossi et al. (2010), The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages; Br. J. Pharmacol. 161 555
Originator
Abbott (US)
Manufacturing Process
N-Hydroxy-N-(1-benzo[b]thien-2-ylethyl) acetamide
1. 2-Acetyl benzo[b]thiophene.Method a. Benzo[b]thiophene (10 g, 75 mmole) was dissolved in THF (50 ml)
and cooled to -78°C. n-Butyl lithium (28 ml, 2.7 M in hexanes) was added.
The mixture was stirred for 15 minutes and N,O-dimethyl acetohydroxamic
acid was added. Following an additional 30 minutes of stirring, the reaction
was quenched at -78°C with ethanol and 2 N HCl solution and extracted into
ether. The solvent was removed in vacuo and the residue chromatographed on
silica gel eluting with 20% ether in pentane to yield 6.9 g of the desired
product as a white solid.Method b. To a solution of benzo[b]thiophene (10.0 g, 75 mmole) in THF (50
ml) was added n-butyl lithium (33 ml, 2.5 M in hexanes) at -70°C under N 2 .
The mixture, containing a white precipitate, was stirred at 70°C for 1 hour.
Acetaldehyde (4.6 ml, 82 mmole) was added dropwise. After a few minutes
the reaction was quenched with saturated NH 4 Cl solution. The layers were
separated, the organic layer dried over MgSO4, filtered, and evaporated to
give a white solid (10 g) which was used directly for the next step.
The alcohol prepared as described above (1.0 g) in acetone (50 ml) was
cooled to 5°C and Jones Reagent was added dropwise until the orange yellow
color persisted (1.4 ml). The reaction mixture was diluted with water and the
desired product precipitated. It was collected by filtration to give 0.85 g.2. 2-Acetyl benzo[b]thiophene oxime.
2-Acetyl benzo[b]thiophene (5 g, 28.4 mmole), prepared as described in step
1 above, and hydroxylamine hydrochloride (3.0 g, 42.6 mmole) were
dissolved in a mixture of ethanol (50 ml) and pyridine (50 ml) and allowed to
stir at room temperature for 2 hours. Most of the solvent was removed in
vacuo and the residue dissolved in ether. After washing with 2 N HCl (100 ml),
the solution was dried over MgSO 4 and evaporated. A white crystalline solid was obtained and was carried on without further purification. An alternative
work-up may also be used. The reaction mixture was diluted with water (300
ml) and the product precipitated. It was filtered off and dried in vacuo.3. 1-Benzo[b]thien-2-ylethyl hydroxylamine. The oxime prepared as in step 2
above (3.5 g, 18.5 mmole) was dissolved in ethanol (25 ml) and cooled to
0°C. Borane pyridine complex (3.7 ml, 37 mmole) was added via syringe
under nitrogen followed 10 minutes later by 20% HCl in ethanol (30 ml).
Within 30 minutes the reaction was complete and was brought to pH 9 with
the addition of solid sodium carbonate or 2 N NaOH. The mixture was
extracted into ether and dried over MgSO 4 . After evaporation a white solid
(3.0 g) was obtained. This was carried on without further purification.
N-Hydroxy-N-(1-benzo[b]thien-2-ylethyl)ureaMethod A. 1-Benzo[b]thien-2-yl ethyl hydroxyl amine prepared as described
above, step 3 (2.0 g, 10 mmole), was refluxed for 30 minutes with
trimethylsilyl isocyanate (1.65, 14.2 mmole) in dioxane (30 ml). The reaction
mixture was then washed with saturated NH 4 Cl solution, dried with MgSO 4 ,
and evaporated.
Method B. 1-Benzo[b]thien-2-yl ethyl hydroxyl amine prepared as described in
step 3, was dissolved in toluene (100 ml) and HCl gas was bubbled through
the mixture at a moderate rate for about 4 minutes. The solution was then
heated to reflux and phosgene was bubbled through for another 4 minutes.
After an additional one hour reflux, the mixture was allowed to cool to room
temperature and then added to excess cold ammonium hydroxide solution.
The precipitate was collected and recrystallized. Melting point: 157°-158°C.
NMR (300 MHz), and mass spectrum confirmed the structure of the prepared
compound.
Therapeutic Function
Antiallergic, Antiinflammatory
Biological Activity
Orally active 5-lipoxygenase (5-LOX) inhibitor that inhibits LTB 4 synthesis (IC 50 values are 0.56, 2.3 and 2.6 μ M in dog, rat and human blood respectively). Inhibits antigen-induced contraction of tracheal strips in vitro (IC 50 = 6 μ M) and exhibits antiasthmatic activity in vivo . Also weakly inhibits CYP1A2 (K i = 66 - 98 μ M).
Biochem/physiol Actions
Zileuton is an anti-asthmatic, an inhibitor of 5-lipoxygenase; the initial enzyme in the biosynthesis of leukotrienes from arachidonic acid.
Check Digit Verification of cas no
The CAS Registry Mumber 111406-87-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,1,4,0 and 6 respectively; the second part has 2 digits, 8 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 111406-87:
(8*1)+(7*1)+(6*1)+(5*4)+(4*0)+(3*6)+(2*8)+(1*7)=82
82 % 10 = 2
So 111406-87-2 is a valid CAS Registry Number.
InChI:InChI=1/C11H12N2O2S/c1-7(13(15)11(12)14)10-6-8-4-2-3-5-9(8)16-10/h2-7,15H,1H3,(H2,12,14)
111406-87-2Relevant articles and documents
Hydroxyurea derivatives of irofulven with improved antitumor efficacy
Staake, Michael D.,Kashinatham, Alisala,McMorris, Trevor C.,Estes, Leita A.,Kelner, Michael J.
, p. 1836 - 1838 (2016)
Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven.
Acid-catalyzed addition of N-hydroxyurea to 1-aryl alcohol derivatives: A new synthesis of Zileuton
Copp,Fohey,Lannoye
, p. 3081 - 3086 (2001)
A highly efficient synthesis of Zileuton is described in which the key step involves a site-specific alkylation of hydroxyurea under acid catalysis. Various aryl alcohol electrophiles were tested and the reaction was found to be highly substrate-specific, favoring benzothiophene and benzofuran-based alcohols.
Process for the Preparation of Zileuton
-
Paragraph 0117, (2017/01/19)
The invention discloses a process for the preparation of Zileuton of formula I by employing acetic acid-1-benzo[b]thiophen-2-yl-ethyl-ester of formula-III as an intermediate.
IMPROVED PROCESS FOR THE PREPARATION OF (±)-1-(1-BENZO[B]THIEN-2-YLETHYL)-1-HYDROXYUREA
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Page/Page column 20, (2011/04/24)
The present invention relates to an improved process for the preparation of (±)-1-(I -Benzo[b]thien-2-ylethyl)-1-hydroxyurea compound of formula 1.
A PROCESS FOR THE PREPARATION OF N-(1-BENZO[B]THIEN-2-YLETHYL)-N-HYDROXYUREA
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Page/Page column 7-8, (2010/04/03)
A method of preparation of N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea of formula (I) with the use of a reaction of l-(benzo[b]thien-2-yl)-ethanol of formula (II) with hydroxyurea of formula (III) in organic solvents, organic acids, their mixtures or in mixtures thereof with water, being catalyzed by strongly acidic cation exchangers or various hydrogen sulphates.
PROCESS FOR THE PREPARATION OF ZILEUTON
-
Page/Page column 4, (2009/12/05)
Process for preparing a compound of formula (I), or a salt thereof, comprising reacting of a compound of formula (II) wherein X and R are as herein defined; with a compound of formula (III) [in-line-formulae]NH2OZ??(III)[/in-line-formulae] wherein Z is a hydroxy protecting group, in presence of a catalyst, to obtain a compound of formula (IV), or a salt thereof, removing the hydroxyl protecting group to obtain a compound of formula (V), or a salt thereof; converting a compound of formula (V), or a salt thereof, into a compound of formula (I), or a salt thereof; and, if desired, converting a compound of formula (I) into a salt thereof, or vice versa.
Reactions of in situ generated N-Boc nitrones with aromatic and heteroaromatic Grignard reagents: Application to the synthesis of zileuton
Guinchard, Xavier,Denis, Jean-Noel
, p. 2028 - 2031 (2008/09/19)
(Chemical Equation Presented) A new class of α-aromatic-N- hydroxylamines has been prepared by reaction of tert-butyl (phenylsulfonyl) alkyl-N-hydroxycarbamates with aromatic and heteroaromatic Grignard reagents. Reactions proceed via a base-assisted elimination of the phenylsulfonyl group leading to N-Boc nitrones. This methodology has been applied to the synthesis of zileuton.
Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a lipoxygenase inhibitor for treatment of asthma or chronic obstructive pulmonary disease
-
, (2008/06/13)
A pharmaceutical or veterinary composition, comprises a first active agent selected from a dehydroepiandrosterone and/or dehydroepiandrosterone-sulfate, or a salt thereof, and a second active agent comprising a lipoxygenase inhibitor for the treatment of asthma, chronic obstructive pulmonary disease, or other respiratory diseases. The composition is provided in various formulations and in the form of a kit. The products of this patent are applied to the prophylaxis and treatment of asthma, chronic obstructive pulmonary disease, or other respiratory diseases.
Synthesis and isolation of N-(aryl or heteroaryl)-alkyl-N-hydroxyurea
-
, (2008/06/13)
The present invention provides a simple, 1-step process for preparing a N-(aryl or heteroaryl)-hydroxyurea comprising reacting the corresponding alcohol, ester or ether with hydroxyurea and acid. This reaction is particularly useful for preparing a benzo[b]thienyl substituted N-hydroxyurea of formula: from compound 1: by reacting compound 1 with hydroxyurea and acid. R1 is selected from the group consisting of hydrogen, 1-6 carbon alkyl, 1-6 carbon alkoxy, and halogen; R2 is an 1-4 carbon alkyl; and R3 is selected from the group consisting of hydrogen, acyl, methyl, ethyl and mixtures thereof. Additional steps to isolate the pure bulk product follow.
Process for producing amine-boranes
-
, (2008/06/13)
The invention provides a method for producing amine-boranes which are highly stable and substantially free of colour. According to the invention, amine is reacted with an alkali metal borohydride in a weakly acidic aqueous medium to produce an amine-borane containing reaction mixture which is stabilized by a strong base.
