- Hydroxyurea derivatives of irofulven with improved antitumor efficacy
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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.
- Staake, Michael D.,Kashinatham, Alisala,McMorris, Trevor C.,Estes, Leita A.,Kelner, Michael J.
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p. 1836 - 1838
(2016/07/27)
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- Process for the Preparation of Zileuton
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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.
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- IMPROVED PROCESS FOR THE PREPARATION OF (±)-1-(1-BENZO[B]THIEN-2-YLETHYL)-1-HYDROXYUREA
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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.
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Page/Page column 20
(2011/04/24)
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- A PROCESS FOR THE PREPARATION OF N-(1-BENZO[B]THIEN-2-YLETHYL)-N-HYDROXYUREA
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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.
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Page/Page column 6
(2010/04/03)
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- PROCESS FOR THE PREPARATION OF ZILEUTON
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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.
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Page/Page column 4
(2009/12/05)
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- Reactions of in situ generated N-Boc nitrones with aromatic and heteroaromatic Grignard reagents: Application to the synthesis of zileuton
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(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.
- Guinchard, Xavier,Denis, Jean-Noel
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p. 2028 - 2031
(2008/09/19)
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- Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a lipoxygenase inhibitor for treatment of asthma or chronic obstructive pulmonary disease
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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.
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- Acid-catalyzed addition of N-hydroxyurea to 1-aryl alcohol derivatives: A new synthesis of Zileuton
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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.
- Copp,Fohey,Lannoye
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p. 3081 - 3086
(2007/10/03)
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- Synthesis and isolation of N-(aryl or heteroaryl)-alkyl-N-hydroxyurea
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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.
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- Process for producing amine-boranes
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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.
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- Process for producing amine-boranes
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A method for producing amine-boranes, specifically pyridine-borane which is highly stable and of good color is described.
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- Substituted 2-ethylbenzo [b] thiophene, process for preparation thereof and use thereof as synthetic intermediate
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The subject of the invention is 2-(1-bromoethyl)benzo[b]thiophene of formula: STR1 as well as a process for the preparation thereof, characterised in that 2-ethylbenzo[b]thiophene is reacted, in a solvent, with a brominating agent in the presence of a free radical initiator, which provides the desired compound, and the use thereof in the preparation of 2-(1-(benzyloxyamino)ethyl)benzo[b]thiophene and of N-hydroxy-N-{1-(benzo[b]thien-2-yl)ethyl}urea. No figure.
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- (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]- N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor
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Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5- lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N- hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]- N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4- fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene- mediated disorders.
- Brooks,Stewart,Basha,Bhatia,Ratajczyk,Martin,Craig,Kolasa,Bouska,Lanni,Harris,Malo,Carter,Bell
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p. 4768 - 4775
(2007/10/03)
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- SYNTHESIS OF SUBSTITUTED HETEROCYCLES. SIMPLE METHOD FOR THE INTRODUCTION OF THE N-HYDROXYUREA FUNCTIONALITY
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A simple method for the introduction of the N-hydroxyurea functionality has been developed.This involves conjugate addition of hydroxylamine to a vinylsulfone substrate.This method was successfully used in a facile synthesis of the 5-lipoxygenase inhibitors, zileuton and A-69412.
- Ku, Yi-Yin,Patel, Ramesh R.,Roden, Brian A.,Sawick, David P.
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p. 6017 - 6020
(2007/10/02)
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- O-substituted N-hydroxyurea derivatives
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The present invention provides compounds useful as intermediates for the preparation of 5-lipoxygenase inhibiting compounds. The intermediates of this invention have the structure STR1 wherein R1 is an O-protecting group selected from the group consisting of STR2 In the above, X is oxygen or sulfur.
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- ADDITION OF ORGANOLITHIUM COMPOUNDS TO N-THP PROTECTED NITRONE
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A novel synthesis of a-branched primary hydroxylamines by addition of organolithium reagents to N-THP protected nitrone is described.
- Basha, Anwer,Ratajczyk, James D.,Brooks, Dee W.
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p. 3783 - 3786
(2007/10/02)
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