- Indium-catalyzed synthesis of keto esters from cyclic 1,3-diketones and alcohols and application to the synthesis of seratrodast
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Esterification reactions from cyclic 1,3-diketones and alcohols are carried out in the presence of several Lewis acids. In particular, indium(III) triflate, In(OTf)3, iron(III) triflate, Fe-(OTf)3, copper(II) triflate, Cu(OTf)2, and silver(I) triflate, AgOTf, show high catalytic activities. These reactions proceed through the carbon-carbon bond cleavage by a retro-aldol reaction and were found to be highly regioselective even in the presence of other functional groups. This type of reaction can also be applied to the preparation of the keto esters during the synthesis of seratrodast, which is an antiasthmatic and eicosanoid antagonist.
- Kuninobu, Yoichiro,Kawata, Atsushi,Noborio, Taihei,Yamamoto, Syun-Ichi,Matsuki, Takashi,Takata, Kazumi,Takai, Kazuhiko
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scheme or table
p. 941 - 945
(2010/07/07)
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- TRICYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE
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A series of substituted oxazole compounds having an alpha keto side chain at the 2 position and an aromatic, heteroaromatic or heterocycle substituent at the 5 position are disclosed. These compounds exhibit inhibition of fatty acid amid hydrolase and are useful for treatment of malconditions involving that enzyme.
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Page/Page column 102
(2009/01/24)
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- Structure-activity relationships of α-ketooxazole inhibitors of fatty acid amide hydrolase
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A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, K, - 2.6 nM), with 5hh (aryl -3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
- Hardouin, Christophe,Kelso, Michael J.,Romero, F. Anthony,Rayl, Thomas J.,Leung, Donmienne,Hwang, Inkyu,Cravatt, Benjamin F.,Boger, Dale L.
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p. 3359 - 3368
(2008/02/13)
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- Takai-Utimoto reactions of oxoalkylhalides catalytic in chromium and cobalt
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The scope of chromium(II)/cobalt(I)-catalyzed Takai-Utimoto reactions was extended to substrates with unprotected reactive functional groups. In the presence of a higher chlorosilane and manganese the first chromium(II)/cobalt(I)-catalyzed version for the
- Wessjohann, Ludger A.,Schrekker, Henri S.
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p. 4323 - 4325
(2008/02/04)
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- Preparation of Alkylchromium Reagents by Reduction of Alkyl Halides with Chromium(II) Chloride under Cobalt Catalysis
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Alkyl halides and tosylates are reduced with CrCl2 in the presence of a catalytic amount of vitamin B12 or cobalt phthalocyanine to give alkylchromium reagents, which add to aldehydes without affecting the coexisting ketone or ester groups.
- Takai, Kazuhiko,Nitta, Kenji,Fujimura, Osamu,Utimoto, Kiitiro
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p. 4732 - 4734
(2007/10/02)
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- Quinones. 4. Novel eicosanoid antagonists: Synthesis and pharmacological evaluation
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A new series of ω-phenyl-ω-quinonylalkanoic acids and related compounds was synthesized. The compounds were tested for their inhibitory effects on U-44069-induced contraction of the rabbit aorta. (±)-7-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (4d) (AA-2414) with pA2 value of 8.28 was one of the most potent compounds. Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA2 = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC50 = 3.5 x 10-7 M). Compound 4d displaced the binding of [3H]U-46619 to guinea pig platelets (IC50 = 7.4 x 10-9 M). Compound 4d also showed very potent inhibitory effects with an MED of 0.3 mg/kg (po) on U-46619-, LTD4-, PAF-, or IgG1-induced bronchoconstriction in guinea pigs. The enantiomers of 4d were prepared. The R-(+) isomer 8a was active in both in vitro and in vivo tests, but the S-(-) isomer 8b was much less active. We concluded that the antiasthmatic effects of 4d were based mainly on the TXA2 receptor antagonistic action. In addition, compound 4d showed potent inhibitory effects on PGD2-, PGF(2α)-, and 11-epi-PGF(2α)-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity.
- Shiraishi,Kato,Terao,Ashida,Terashita,Kito
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p. 2214 - 2221
(2007/10/02)
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