- PYRAZOLYL ACYLSULFONAMIDE DERIVATIVES AS ENDOTHELIN CONVERTING ENZYME INHIBITORS AND USEFUL IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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The invention provides compounds of formula (I),wherein R?1?,R?2? ,R?3? and R?4? are as defined in the specification,processes for preparing such compounds,to pharmaceutical compositions comprising such compounds and to the use of the compounds as active
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Page/Page column 37
(2008/06/13)
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- Suzuki-Miyaura and related cross-couplings in aqueous solvents catalyzed by di(2-pyridyl)methylamine-palladium dichloride complexes
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Di(2-pyridyl)methylamine-based palladium dichloride complexes 4 are versatile catalysts for different types of cross-coupling reactions in water or aqueous solvents under aerobic conditions. The Suzuki-Miyaura reaction of arylboronic acids can be performed with bromoarenes under water reflux using K2CO3 as base or at room temperature or 60°C in aqueous methanol using KOH as base. For aryl chlorides the corresponding cross-couplings with arylboronic acids can be carried out in refluxing water with K2CO3 as base and TBAB as additive to provide biaryls and heterobiaryls. Arylboronic acids react with benzylic chlorides and allylic substrates such as chlorides, acetates or carbonates also in refluxing water with K2CO3 as base or at room temperature in aqueous acetone and KOH as base, to give diarylmethanes and arylpropenes. Trimethylboroxine and alkylboronic acids are coupled with bromo- and chloroarenes under water at reflux with K2CO3 as base and TBAB as additive to furnish methyl- and butylarenes. These cross-couplings have also been performed in shorter times under microwave irradiation. Several important intermediates such as, 4′-methylbiphenyl-2-carbonitrile, 4-biphenylacetic acid, 3-(3-methylphenyl)benzoic acid, 4,5-diphenyl-2-methyl- 3(2H)pyridazinone and 2-(4′-fluorobenzyl)thiophene have been prepared under aqueous and aerobic conditions in good yields.
- Najera, Carmen,Gil-Molto, Juan,Karlstroem, Sofia
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p. 1798 - 1811
(2007/10/03)
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- Substituted arylalkynyl-and heteroarylalkynl-N-hydroxyurea inhibitors of leukotriene biosynthesis
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The invention relates to compounds having activity to inhibit lipoxygenase enzyme activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treating. More particularly, this invention concerns certain substituted arylalkynyl- and ((heteroaryl)alkynyl)-N-hydroxy-ureas which inhibit leukotriene biosynthesis, to pharmaceutical compositions of these compounds and to a method of inhibiting leukotriene biosynthesis.
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- Process for the preparation of methylene compounds and the novel compound 2-(2,4-Dichloro-5-fluorobenzyl)thiophene
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Methylene compounds are preferably prepared by reducing an aluminum halide complex of the formula STR1 in which R1 represents a C6 -C10 -aryl radical which is optionally substituted by 1 to 4 C1 -C4 -alkyl radicals, 1 to 4 fluorine, chlorine and/or bromine atoms, one C1 -C8 -alkoxy group and/or one acetoxy group, or represents a heteroaryl radical which is optionally substituted by one C1 -C4 -alkyl radical and/or one fluorine, chlorine or bromine atom and contains 5 to 10 C atoms and one O or S atom and R2 represents a C1 -C12 -alkyl radical which is optionally substituted by 1 to 5 fluorine, chlorine and/or bromine atoms, independently of R1 represents a radical as defined for R1 and, in the case where R1 =a C6 -C10 -aryl radical which is substituted by 1 to 4 fluorine, chlorine and/or bromine atoms, also represents a furyl or thienyl radical, Y represents fluorine, chlorine or bromine, with an amineborane of the formula STR2 in which R3 represents C1 -C4 -alkyl and R4 represents hydrogen or C1 -C4 -alkyl and/or with sodium borohydride and/or with potassium borohydride. 2-(2,4-Dichloro-5-fluorobenzyl)thiophene is obtainable in this way for the first time.
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- A general, convenient and highly efficient synthesis of diarylmethanes by copper-catalyzed reaction
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Copper-catalyzed reactions of arylmagnesium derivatives with benzyliodides have been developed for the large scale preparation of diarylmethanes. Various diarylmethanes have been prepared in high yield by this reaction, the amount of homocoupled dimers be
- Ku, Yi-Yin,Patel, Ramesh R.,Sawick, David P.
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p. 1949 - 1952
(2007/10/03)
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- Substituted aryl- and heteroarylalkenyl-N-hydroxyurea inhibitors of leukotriene biosynthesis
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Compounds of the structure STR1 wherein Z is selected from optionally substituted thienyl, thiazolyl, oxazolyl and furyl are potent inhibitors of lipoxygenase enzymes and thus inhibit the biosynthesis of leukotrienes. These compounds are useful in the treatment or amelioration of allergic and inflammatory disease states.
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- Process for the preparation of N-4-[(substituted phenyl)alkylheterocyclic]-N
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A process for preparing a compound of the structure I STR1 where A is oxygen and sulfur and R1 is selected from the group consisting of hydrogen, halogen, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, and trifluoromethyl, and R2 is alkyl of one to four carbon atoms, comprising coupling a compound of formula II: STR2 where X is bromine or iodine, with an N-hydroxyurea compound of formula III: STR3 in the presence of a palladium catalyst followed by reaction of the product thus formed with an alkali metal isocyante. The compounds of formula I are inhibitors of the enzyme 5-lipoxygenase and are thus useful as therapeutic agents for the treatment of allergic and inflammatory disease conditions.
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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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- Benzylation via Tandem Grignard Reaction - Iodotrimethylsilane (TMSI) Mediated Reduction
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A method has been developed which allows for the large scale preparation of biarylmethanes.This method involves the initial formation of biarylmethanols via reaction of aryl Grignards with carbonyl compounds followed by a subsequent reduction with iodotrimethylsilane (TMSI).A number of improvements over existing literature procedures are reported as well as previously unobserved dimerizations.Studies reveal that as few as 3 equiv of TMSI will give complete reduction in most cases where either of the substituents are not heteroaromatic.Mono-substituted alkanols react with TMSI to afford the corresponding iodides.A mechanistic study of the TMSI reduction is also reported.
- Stoner, Eric J.,Cothron, Darlene A.,Balmer, Mary K.,Roden, Brian A.
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p. 11043 - 11062
(2007/10/02)
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- [(SUBSTITUTED) PHENYALKYL]FURYLALKYNYL-AND [SUBSTITUTED)PHENYALKYL]THIENYLALKYNYL-N-HYDROXYUREA INHIBITORS OR LEUKOTRIENE BIOSYNTHESIS
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The present invention relates to compounds of the formula and the pharmaceutically acceptable salts thereof wherein Z is selected from optionally substituted phenyl, furyl, thienyl or thiazolyl; which inhibits leukotriene biosynthesis and is useful in the treatment of inflammatory disease states; also disclosed are leukotriene biosynthesis inhibiting compositions and a method for inhibiting 5-lipoxygenase activity and leukotriene biosynthesis
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