- SPIROPIPERIDINE COMPOUND AND MEDICINAL USE THEREOF
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The present invention relates to a CXCR3 antagonist comprising a compound represented by formula (I) (wherein all the symbols have the same meaning as defined in the description), a salt thereof, a quaternary ammonium salt thereof, an N-oxide form thereof or a solvate thereof, or a prodrug thereof. This antagonist is useful as a preventive, therapeutic and/or progression-suppressing agent for a CXCR3-mediated disease such as an immune or an allergic disease [e.g., an atopic disease, an autoimmune disease (e.g., multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, Sjogren's syndrome and the like), systemic inflammatory response syndrome (SIRS), a rejection response to transplanted organ, tissue and/or cell or the like], a gastrointestinal disease [e.g., an inflammatory bowel disease or the like], or a respiratory disease [e.g., asthma, a chronic obstructive pulmonary disease or the like].
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Page/Page column 40
(2010/11/30)
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- NOVEL 4-(2FUROYL)AMINOPIPERIDINES, INTERMEDIATES IN SYNTHESIZING THE SAME,PROCESS FOR PRODUCING THE SAME AND MEDICINAL USE OF THE SAME
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There are provided novel 4-(2-furoyl)aminopiperidines represented by the general formula (I), their synthetic intermediates, processes for their preparation and medicaments containing them. In the above formula, X is CH or N, and Y is a group of the following general formula (II), formula (II-a) or formula (III): wherein a, b and c are each an integer of 0-6; Z is CH2 or NH; W is O or S; T is O or N-R15 wherein R15 is H, a C1-C6 alkyl group, a benzyl group or a phenethyl group; and R1 is H, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, or the like.The 4-(2-furoyl) aminopiperidine derivatives according to this invention possess opioid μ antagonistic activity and are useful for the treatment or prevention of side effects which are caused by μ receptors agonist and which are selected from constipation, nausea/emesis or itch, or for the treatment or prevention of idiopathic constipation, postoperative ileus, paralytic ileus, irritable bowel syndrome or chronic pruritus.
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- Reaction of Superoxide with Aci-Reductones
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Three reductones, 2,3-dihydroxy-4,4-diphenyl-2,5-cyclohexadien-1-one (11), 3,4-dihydroxycoumarin (35), and 3,4-dihydroxyspiroundecan-3-en-4-one (64), were prepared and subsequently reacted with superoxide anion radical (O2(.-), generated from KO2 and 18-crown-6-polyether.The reactions were carried out in aprotic media and quenched with methyl iodide which facilitates the trapping of the various oxyanions formed.While a plethora of products were formed in each case undeca-1,4-dien-3-one (66), 2-hydroxyspirodec-1-en-3-one (70), dimethyl 1,1-cyclohexanediacetate (73), and dimethyl α-keto-1-cyclohexane-1-propionate) (75) from 64> an overall analysis of the product distribution indicates that the basic elements of the reaction sequence are the same.The first step involves facile deprotonation and the concomitant generation of the reductone monoanion, a process which lends support to the suggestion of Afanas'ev and co-workers (Afanas'ev, I.B., Grabovietskii, V.V.; Kuprianova, N.S. J.Chem.Soc.Perkin Trans. 2 1987, 281-285).Oxidation of this monoanion yields the corresponding triketone.Of the various options available to this polyketone, superoxide attack at the most electrophilic central carbonyl followed by oxidative cleavage and/or benzylic acid rearrangement are clearly the most prominent.These are followed by a variety of base catalyzed autoxidative processes which are highly dependent on the nature of the substrate.
- Frimer, Aryeh A.,Marks, Vered,Gilinsky-Sharon, Pessia,Aljadeff, Gladis,Gottlieb, Hugo E.
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p. 4510 - 4520
(2007/10/02)
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- Superoxide Anion Radical (O2-anionradical) Mediated Base Catalyzed Autooxidation of α-Keto Enols
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Eight 4,4-disubstituted 2-hydroxycyclohexa-2,5-dien-1-ones were prepared by the base-catalysed autooxidation (BCA) of the corresponding 4,4- or 5,5-disubstituted cyclohex-2-en-1-ones.Upon reaction with superoxide anion radical (O2-anionradical, generated from KO2/18-crown-6) in inert nonpolar aprotic media at room temperature, α-keto enols 3a-g undergo initial deprotonation of the enol hydrogen followed by BCA at C3 of the resulting enolate.Aqueous acid workup of the reaction mixture yields lactols 4, while methyl iodide quenching generates methoxy lactones 5.Lactols 4 can be readily converted to their acetoxy analogues 8, opened to aldehydo methyl esters 6, or reduced to the related lactones 7.The latter suggests a convenient one-pot synthesis of 2,3-unsaturated δ-valerolactones from the corresponding cyclohex-2-en-1-ones. 4,4-Diphenyl enol 3h, by contrast, resists BCA (whether mediated by O2-anionradical or t-C4H9O-anion) to the corresponding lactol yielding instead a variety of oxidative cleavage products 13-18. 2-Hydroxyspirodec-1-en-3-one (21) also underwent O2-anionradical-mediated BCA, yielding diacids 22 and 26 as well as lactol 30.The synthetic applications of these results are also discussed.
- Frimer, Aryeh A.,Gilinsky-Sharon, Pessia,Aljadeff, Gladis,Marks, Vered,Rosental, Zilpa
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p. 4866 - 4872
(2007/10/02)
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