- Triazolone derivatives, use thereof, and intermediates therefor
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Triazolone derivatives represented by the formula wherein R1represents optionally substituted C1-10alkyl, A1—L1—, A1—ON═CA2, etc.; R2represents hydrogen, C1-6alkyl, etc.; R3represents C1-6alkoxy, etc.; one of T, U, and V represents CR4, another represents CH or nitrogen, and the remaining one represents CR5or nitrogen; and W represents CR6or nitrogen.
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- Inhibitors of acyl-CoA:cholesterol O-acetyltransferase (ACAT). Part 1: Identification and structure-activity relationships of a novel series of substituted N-alkyl-N-biphenylmethyl-N'-arylureas
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A series of N-alkyl-N-biphenylylmethyl-N'-arylurea and related derivatives represented by 1 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Linking of two phenyl groups via oxygen and introduction of fluorine at appropriate positions on the biphenyl moiety improved in vitro and in vivo activity. From this series of analogs, compound 40 (FR179254), which had potent in vitro potency (rabbit intestinal microsomes IC50 = 25 nM), showed excellent plasma cholesterol-lowering activity when administered via the diet (ED50 = 0.045 mg/kg). However, the hypocholesterolemic effect of this compound was moderate when dosed by oral gavage in PEG400 as a vehicle (ED50 = 5.3 mg/kg). Modification of the N'-aryl moiety led to the identification of compound 50 (FR182980) which was efficacious in both dosing models (ED50 = 0.034 mg/kg and 0.11 mg/kg, respectively).
- Tanaka, Akira,Terasawa, Takeshi,Hagihara, Hiroyuki,Sakuma, Yuri,Ishibe, Noriko,Sawada, Masae,Takasugi, Hisashi,Tanaka, Hirokazu
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- Synthesis of aryl(difluoromethylenephosphonates) via electrophilic fluorination of α-carbanions of benzylic phosphonates with N- fluorobenzenesulfonimide.
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The electrophilic fluorination of a wide variety of benzylic phosphonates with N-fluorobenzenesulfonimide has been examined. The fluorination reaction proceeds well in the presence of an array of functional groups such as nitro, bromo, ketone, ester, phenyl and ether groups. Phenyl and biphenyl derivatives containing two α,α-difluoromethylenephosphonate groups can also be prepared. This procedure is compatible with methyl or ethyl phosphonate esters but not with t-butyl esters or with benzylic phosphonates containing an additional benzylic moiety at the para-position.
- Taylor, Scott D.,Kotoris, Christopher C.,Dinaut, A. Nicole,Chen, Mei-Jin
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p. 1691 - 1714
(2007/10/03)
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- Endothelin receptor antagonists
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The present invention provides novel compounds represented by the general formula I: STR1 wherein R 1 is a straight or branched lower alkyl, a cycloalkyl-lower alkyl, an aryl-lower alkyl, a cycloalkyl, an aryl an aryl-cycloalkyl, lower alkoxy, an aryloxy, or a heteroaryl;R 2 is hydrogen, a straight or branched lower alkyl, a cycloalkyl, or a cycloalkyl-lower alkyl;R 3 and R 3 '' are each the same or different and each is hydrogen atom, a straight or branched lower alkyl, a cycloalkyl, an aryl-lower alkyl, an aryl, or a heteroaryl; orR 3 and R 3 '' together form a ring structure;R 3 "" is hydrogen, lower alkyl or an aryl; orR 2 and R 3 "" together form a lower alkylene group --(CH 2) n -- wherein n is an integer of 1, 2 or 3; orR 2 and R 3 "" together form a group represented by the formula: --(CH 2) p --Ar-- or --Ar--(CH 2) p --, respectively, wherein p is zero or an integer of 1 or 2, and Ar is an arylene or heteroarylene;C( X) is C( O), C( S), C( NH), C( N-lower alkyl); C NH--OH, or CH 2 ;Y is a direct bond, --NH--, a lower alkyl-N, an oxygen atom, or methylene; orC( X) is CHOH and Y is a direct bond or methylene;R 4 is --(CH 2) s --Ar'' wherein s is zero or an integer of 1, 2 or 3; and Ar'' is an aryl, or a heteroaryl; andR 5 is carboxy, substituted or unsubstituted carboxamide, PO(OH) 2, tetrazole, CH 2 OH, CN, or hydrogen;and salts thereof.
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- Insecticidal 5-substituted-2,4-diaminopyrimidine derivatives
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An insecticidal composition comprising, in admixture with an agriculturally acceptable carrier, an insecticidally effective amount of a compound of the formula: STR1 wherein R, R1, R2, R3, R7, R8, m, n, and p are as defined herein, and agriculturally acceptable salts thereof, and methods of using the same.
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- Potent, Orally Active, Competitive N-Methyl-D-aspartate (NMDA) Receptor Antagonists Are Substrates for a Neutral Amino Acid Uptake System in Chinese Hamster Ovary Cells
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A series of enantiomerically pure (phosphonomethyl)-substituted phenylalanine derivatives related to SDZ EAB 515 (1) were prepared as competitive N-methyl-D-aspartate (NMDA) receptor antagonists.Unlike most known competitive NMDA antagonists, analogs in this series with the S-configuration are potent NMDA antagonists whereas analogs with the unnatural R-configuration are weak NMDA antagonists, as determined by receptor binding experiments and their anticonvulsant action in mice.Examination in a previously reported competitive NMDA pharmacophore model revealed that receptor affinity can be explained partially by a cavity that accommodates the biphenyl ring of 1, while the biphenyl ring of the R-enantiomer 2 extends into a disallowed steric region.We proposed that analogs with the natural S-configuration and a large hydrophobic moiety would have an advantage in vivo over analogs with an R-configuration by being able to use a neutral amino acid uptake system to enhance both peripheral adsorption and transport into the brain.Examination in a system L neutral amino acid transport carrier assay shows that 1 competes with L-Phe for transport in an apparent competitive and stereospecific manner (estimated Ki=50 μM).The 1- and 2-naphthyl derivatives 3a,3b were found to be among the most potent, competitive NMDA antagonists yet discovered, being ca. 15-fold more potent than 1 in vitro and in vivo, with a long duration of action.The title compound 3a had potent oral activity in MES (ED50=5.0 mg/kg). 3a also retains its ability to compete, albeit more weakly than 1 (estimated Ki=200 μM), for L-Phe uptake to CHO cells.In this series, analogs with the R-configuration are not substrates for the system L neutral amino acid transport carrier.These results provide evidence that central nervous system active agents can be designed as substrates of a neutral amino acid transporter as a means to enhance penetration of the blood-brain barrier.
- Li, Jia-He,Bigge, Christopher F.,Williamson, Rufus M.,Borosky, Susan A.,Vartanian, Mark G.,Ortwine, Daniel F.
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p. 1955 - 1965
(2007/10/02)
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- New Methods of Formation of Meta-Substituted Aromatic Compounds
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The addition of organolithium reagents to the oxa tricyclic ketone 1 occurs stereospecifically to produce the corresponding tertiary carbinols 2a-d.When the alcohols 2a-d are treated with TiCl4, ring fragmentation and dehydration occur to produce good yields of 5,6-dihydrobenzaldehydes 3a-d.Oxidation of aldehydes 3a-d then leads to the corresponding meta-substituted benzaldehydes 4a-d.Alternatively, use of the Lewis acid Me2BBr did not stop at the dihydrobenzaldehyde stage.Tautomerization of the diene aldehydes 3a-d produced meta-substituted benzyl alcohols 7a-d or benzyl bromides 8a-d under prolonged reaction times.The addition of silica gel to the reactions accelerated the formation of the benzyl bromides.
- Adams, Julian,Belley, Michel
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p. 3878 - 3881
(2007/10/02)
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