- Substituted α-mercaptoketones, new types of specific neprilysin inhibitors
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New neprilysin inhibitors containing an α-mercaptoketone HSC(R1R2)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S1, S
- Poras, Hervé,Patouret, Rémi,Leiris, Simon,Ouimet, Tanja,Fournié-Zaluski, Marie-Claude,Roques, Bernard P.
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- Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1
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Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50=77nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration. (C) 2000 Elsevier Science Ltd.
- Fink, Cynthia A.,Moskal, Michael,Firooznia, Fariborz,Hoyer, Denton,Symonsbergen, David,Wei, Dongchu,Qiao, Ying,Savage, Paula,Beil, Michael E.,Trapani, Angelo J.,Jeng, Arco Y.
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- Diethyl zinc catalyzed diastereoselective addition of ketenes to (S)-(+)-3-hydroxytetrahydrofuran
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The reaction of (S)-(+)-3-hydroxytetrahydrofuran with phenyl methyl ketene in presence of n-BuLi and Et2Zn results in the formation of the diastereomeric esters (SS+SR) with a high degree of diastereoselectivity (98:2).
- Tandon, Vishnu K.
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- Nucleophilic Substitution Reactions of Alkyl Halides By Using New Polymer-Supported Reagents Containing Hemin
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A new polymer reagent consisting of hemin, divinylbenzene, and 2-methyl-5-vinylpyridine was synthesized by suspension copolymerization.Substitution reactions of primary, secondary, and tertiary alkyl halides with the hemin copolymer combined with cyanide, azide, and thiocyanate ions were given satisfactory yields.This reaction mechanism was revealed to be a SNi type on the basis of stereochemical study.The hemin copolymer was not only a polymer-supported reagent with functional capabilities, but also served to separate the product from the reaction mixture.
- Saito, Kiyoshi,Harada, Kaoru
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- Synthesis and screening of stereochemically diverse combinatorial libraries of peptide tertiary amides
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Large combinatorial libraries of N-substituted peptides would be an attractive source of protein ligands, because these compounds are known to be conformationally constrained, whereas standard peptides or peptoids are conformationally mobile. Here, we report an efficient submonomer solid-phase synthetic route to these compounds and demonstrate that it can be used to create high quality libraries. A model screening experiment and analysis of the hits indicates that the rigidity afforded by the stereocenters is critical for high affinity binding.
- Gao, Yu,Kodadek, Thomas
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- TRICYCLIC COMPOUNDS HAVING SULFINYL AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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It is intended to provide a compound that exhibits a wide antibacterial spectrum against various bacteria including gram-negative bacteria, and a pharmaceutical composition having an antibacterial activity against carbapenem-resistant bacteria.
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Paragraph 0069
(2020/01/02)
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- PHARMACEUTICAL COMPOSITION CONTAINING TRICYCLIC COMPOUND HAVING SULFINYL OR SULFONYL
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PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that has antibacterial activity against carbapenem-resistant bacteria. SOLUTION: A pharmaceutical composition contains a compound represented by formula (I), its ester body or their pharmaceutically acceptable salts, or their hydrates (W is S(=O) or S(=O)2; T is CR4AR4B or CR5AR5B-CR6AR6B; R4A, R4B, R5A, R5B, R6A and R6B independently represent halogen, hydroxy, carbonyl, alkyl, cycloalkyl, aryl or the like; R1 is a carbocycle or heterocycle; R2A and R2B independently represent H, amino, hydroxy and the like, or R2A and R2B together form methylidene, hydroxyimino and the like; R3 is H, methoxy or the like). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0299
(2018/08/02)
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- Synthesis of tertiary and quaternary amine derivatives from wood resin as chiral NMR solvating agents
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Chiral tertiary and quaternary amine solvating agents for NMR spectroscopy were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution of enantiomers of model compounds [Mosher's acid (3) and its n-Bu4N salt (4)] (guests) by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts (hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts in enantiomeric excess (ee) determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is described, allowing the enhancement of enantiomeric discrimination when the resolution of multiplets is insufficient.
- Laaksonen, Tiina,Heikkinen, Sami,W?h?l?, Kristiina
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supporting information
p. 20873 - 20886
(2015/12/23)
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- Enantioselective protonation of α-hetero carboxylic acid-derived ketene disilyl acetals under chiral ionic Bronsted acid catalysis
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Highly enantioselective protonation of α-halo and alkoxy carboxylic acid-derived ketene disilyl acetals is achieved by using P-spiro chiral diaminodioxaphosphonium barfate as a Bronsted acid catalyst, where the enantiofacial discrimination by the catalyst mainly stems from the recognition of the electronic difference between two substituents on the ketene disilyl acetal.
- Uraguchi, Daisuke,Kizu, Tomohito,Ohira, Yuki,Ooi, Takashi
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supporting information
p. 13489 - 13491
(2015/01/09)
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- PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE 2-HALOGENO- CARBOXYLIC ACIDS
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The invention provides processes for producing efficiently optically active 2-halogenocarboxylic acids useful in the preparation of drugs or the like and salts thereof with amines. Specifically, an optically active 2-halogenocarboxylic acid is produced by halogenating an optically active amino acid in water in the presence of a hydrophobic organic solvent and nitrous acid with the configuration retained and with the racemization inhibited through the removal of 2-hydroxy- bromocarboxylic acid formed as a by-product; the obtained optically active 2-halogenocarboxylic acid is transferred to an aqueous phase by converting it into a salt thereof with a base, followed by the removal of the organic phase; and the optically active 2-halogenocarboxylic acid is transferred again to an organic solvent phase, followed by the removal of the aqueous phase, whereby an optically active 2-halogenocarboxylic acid is obtained through the removal of a halogen component. Further, a high-quality salt of an optically active 2-halogenocarboxylic acid with an amine can be obtained by a crystallization method wherein the amine is added over the period of 1/2 hour or longer either continuously or in portions and/or wherein the crystallization solvent consists of a hydrophobic organic solvent and a hydrophilic organic solvent.
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE 2-SUBSTITUTED CARBOXYLIC ACID
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The present invention relates to a process for efficiently producing an optically active 2-bromocarboxylic acid and an optically active 2-sulfonyloxycarboxylic acid, which are important in the production of medicinal compounds and so forth. An optically active 2-sulfonyloxycarboxylic acid ester is subjected to deprotection under acid conditions to obtain an optically active 2-sulfonyloxycarboxylic acid. A metal bromide is caused to act on the acid to brominate it with configuration inversion at position 2 to thereby produce an optically active 2-bromocarboxylic acid. The resultant optically active 2-bromocarboxylic acid is isolated/purified by subjecting it to a step in which the acid is crystallized and separated as a salt with a base. Thus, an optically active 2-bromocarboxylic acid having a high chemical purity and high optical purity can be produced.
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- (R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries for the asymmetric synthesis of α-hydroxy acids
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Rac-α-bromo acids, rac-4, have been converted into(R)- or(S)-α-hydroxy acids, (R)- or (S)-9 by DCC-induced esterification with the chiral auxiliaries (R)or (S)-1, followed by reaction with sodium p-methoxyphenoxide in the presence of tetra-n-hexylammonium iodide, conditions of dynamic kinetic resolution, to give quite diastereoselectively the (αR,3S)- or (αS,3R)-α-(p-methoxyphenoxy) esters, 7, which were then oxidized with eerie ammonium nitrate and hydrolyzed under controlled acid conditions.
- Camps, Pelayo,Perez, Francesc,Soldevilla, Nuria
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p. 1877 - 1894
(2007/10/03)
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- COMPOUNDS CONTAINING A FUSED BICYCLE RING AND PROCESSES THEREFOR
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Compounds of the formula STR1 wherein X is O or S--(O) t ; n is one or two; m is zero or one; Y is CH 2, O, or S--(O) t provided that Y is O or S--(O) t only when m is one; and A is STR2 are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective ACE inhibitors. Also disclosed are methods of preparation and intermediates.
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- MERCAPTOSULFIDE METALLOPROTEINASE INHIBITORS
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Novel mercaptosulfide matrix metalloproteinase inhibitors of the Formula I, STR1 wherein: n is 0 or 1;R 1 is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); and R 2 is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH (lower alkyl); orR 1 and R. sup.2 together are--CH 2--CH 2--CH 2--; R 3 is selected from the group consisting of hydrogen, lower alkyl, aralkyl and heteroaralkyl; andR 4 is selected from the group consisting of hydrogen, lower alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, aralkyl and 2-indolylmethyl; andR 5 is selected from the group consisting of lower alkyl, aralkyl and--CH(R 6)--C(O)NH 2,wherein R. sup.6 is selected from the group consisting of hydrogen, lower-alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, hydroxymethyl, 1-hydroxyethyl, mercapto lower-alkyl, and methylthio lower-alkyl; ora pharmaceutically acceptable ester, ether or salt thereof, useful for treating diseases and disease conditions associated with matrix metalloproteinase modulation.
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- Asymmetric Synthesis of 2-Chloro- and 2-Bromo-alkanoic acids by Halogenation of α-D-Glucofuranose-Derived Silyl Ketene Acetals.
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Optically active (S)-2-bromo- and 2-chloro-alkanoic acids 6 and 7 have been obtained via the diastereoselective halogenation of chiral silyl ketene acetals 3a-f, and subsequent saponification of the resulting crude esters.Examples characterized by e.e. values up to 95percent are reported.The diastereoface selectivity is independent of the silyl ketene acetal E/Z configuration.
- Angibaud, P.,Chaumette, J. L.,Desmurs, J. R.,Duhamel, L.,Ple, G.,et al.
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p. 1919 - 1932
(2007/10/03)
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- Biosynthesis of the indolizidine alkaloid cyclizidine: incorporation of singly and doubly labelled precursors
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Incorporation of CH313C18O2Na and CD3CH213CO2Na into the indolizidine alkaloid cyclizidine 1, produced by Streptomyces species NCIB 11649, shows that the oxygen attached to C-2 is derived intact from acetate and that the cyclopropyl ring is derived from a single intact propionate unit.However, the level and stereochemistry of the incorporation of deuteriated sodium propionate indicates that it undergoes unexpected modification during incorporation into the cyclopropyl ring.
- Leeper, Finian J.,Shaw, Susan E.,Satish, Padma
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p. 131 - 141
(2007/10/02)
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- Syntheses of (2S,3R)- and (2S,3R)2H>- 3-Methylaspartic acid: Slow Substrates for a syn-Elimination Reaction catalysed by Methylaspartase.
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Methylaspartase catalyses the slow syn-elimination of ammonia from the (2S,3R)--diastereomer of the natural substrate, (2S,3S)-3-methylaspartic acid, to give mesaconic acid.To provide material of sufficient stereochemical purity to probe the mechanism of the reaction, two synthetic routes to (2S,3R)- and (2S,3R)2H>- 3-methylaspartic acid were devised.The use of these (2S,3R)-3-methylaspartic acids revealed that the enzymic reaction does not involve C-3 epimerisation followed by normal anti-elimination, ruling-out the possibility of a carbanion intermediate.Conversely, the substrate displayed very large primary deuterium isotope effects indicating rate-limiting C-H bond cleavage.
- Archer, Catherine H.,Thomas, Neil R.,Gani, David
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p. 1141 - 1152
(2007/10/02)
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- BIOSYNTHESIS OF THE POLYETHER ANTIBIOTIC MONENSIN-A. RESULTS FROM THE INCORPORATIONS OF LABELLED ACETATE AND PROPIONATE AS A PROBE OF THE CARBON CHAIN ASSEMBLY PROCESSES
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The incorporation of sodium - and (S)--propionate into the polyether antibiotic monensin-A in cultures of Streptomyces cinnamonensis occurs with retention of label only at C-4 and C-6, whereas during the incorporation of sodium (R)-propionate the deuterium label is lost to the medium.These results are consistent with the formation of (S)-methylmalonyl-CoA from the labelled propionate by carboxylation of propionyl-CoA with loss of the 2-pro-R hydrogen.The (S)-methylmalonyl-CoA is subsequently incorporated into the antibiotic by a decarboxylative condensation occuring with overall inversion.The incorporations of sodium -and -acetates into monensin-A provide evidence for a pathway of metabolism leading to methylmalonyl-CoA that does not proceed via succinyl-CoA.Instead, acetyl-CoA may be processed via butyryl-CoA and isobutyryl-CoA, to afford (S)-methylmalonyl-CoA.
- Sood, Gulshan R.,Ashworth, Doreen M.,Ajaz, Abid A.,Robinson, John A.
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p. 3183 - 3194
(2007/10/02)
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- The Determination of Small Amounts of Enantiomeric Impurities in α-Halo Carboxylic Acids
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The accurate determination of the enantiomeric composition of α-halo carboxylic acids is reported.Such data are of importance in the synthesis of chiral compounds and in mechanistic studies involving the title compounds.
- Watabe, K.,Chang, S.-C.,Gil-Av, E.,Koppenhoefer, B.
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p. 225 - 228
(2007/10/02)
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- Enantiospecific Synthesis of the trans-9-carbazoles
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The compounds in the title, (R,R)- and (S,S)-2, are isomers of the cis-dimethyl compound 1, which is in human trials as an antipsychotic.They were made starting with chiral alanine esters (6) and the 2-bromopropionic esters made from the alanines of opposite chirality (5) and proceeding by cyclization of the ethoxycarbonyl-protected iminodipropionic acids 9, via anhydride 10, with 3-(9-carbazolyl)propylamine and subsequent BH3 reduction of the imides 12 followed by hydrolytic removal of the COOEt.Selection of the reagents necessary to minimize racemization D 20 values at each condensation stage and the 1H and 13C NMR absorption data required for structure proof of 2 are given; a ring inversion rate of 5200 s-1 is calculated based on low and ambient temperature 13C NMR data.
- Harfenist, Morton,Hoerr, David C.,Crouch, Ronald
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p. 1356 - 1359
(2007/10/02)
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