- Direct synthesis of α-thio aromatic acids from aromatic amino acids
-
Modified amino acids are useful synthetic components in both chemistry and biology. Here we describe a simple, scalable two-step procedure to generate α-thio aromatic acids from aromatic amino acids with yields of up to 96%. Diazotization and α-lactone me
- Samuels, Eric R.,Sevrioukova, Irina F.
-
-
Read Online
- Crystallization-induced chiral inversion as the key step for synthesis of (S)-2-acetylthio-3-phenylpropanoic acid from L-phenylalanine
-
(Chemical Equation Presented) A novel crystallization-induced chiral inversion of (S)-2-bromo-3-phenylpropanoic acid to its (R)-enantiomer with excellent enantiomeric excess (96-99%) is achieved. Optically pure (S)-2-acetylthio-3-phenylpropanoic acid can
- Chen, Jason G.,Zhu, Jingyang,Skonezny, Paul M.,Rosso, Victor,Venit, John J.
-
-
Read Online
- Catalytic Asymmetric Conjugate Addition and Sulfenylation of Diarylthiazolidin-2,4-diones
-
This work reports the first application of diarylthiazolidin-2,4-diones as nucleophiles in asymmetric catalysis. By utilizing chiral amino acid-based (thio)urea-tertiary amines as the catalysts, we successively established asymmetric conjugate addition to nitroolefins and sulfenylation to N-(sulfanyl)-succinimides of diarylthiazolidin-2,4-diones. Two series of biologically important 5-aryl-5-substituted thiazolidin-2,4-diones were obtained with high enantio- and diastereoselectivities (up to >99% ee and >19:1 dr). The enantioenriched adducts were found to show satisfactory anticancer activities against three different cancer cell lines using the MTT assay. All of these successes depended on the development of a general and expedient synthetic strategy to provide diverse 5H-thiazolidin-2,4-diones.
- Jiao, Lihui,Bu, Liwei,Ye, Xinyi,Zhao, Xiaowei,Jiang, Zhiyong
-
-
Read Online
- Efficient synthesis of 5-(hydroxymethyl)piperazin-2-ones using automatically prepared chiral bromocarboxylic acid and Garner's aldehyde as versatile building blocks
-
An efficient method for the synthesis of substituted 5-(hydroxymethyl)piperazin-2-ones was established by using an automated synthesis process. Thirteen piperazinones were synthesized from chiral α-bromocarboxylic acids and Garner's aldehyde which were prepared by using our originally developed automated synthesizer, ChemKonzert. The automated method of synthesizing chiral α-bromocarboxylic acids was efficient and safe because the rate of the dropwise addition of the reagent can be controlled using the automated synthesizer. This method is expected to contribute to the synthesis of pharmaceuticals.
- Masui, Hisashi,Naito, Kohei,Minoshima, Mai,Kusayanagi, Akira,Yosugi, Sae,Shoji, Mitsuru,Takahashi, Takashi
-
supporting information
(2021/05/04)
-
- ANTIVIRAL COMPOUNDS
-
The present invention relates to novel compounds of general formula (I) wherein R1 to R4 and n have the meanings given in the description and claims, process for preparing these compounds and their use as for treating, preventing or ameliorating viral infections and their use for treating, preventing or ameliorating diseases which are associated with PLA2G16.
- -
-
Paragraph 085; 086; 087
(2019/04/27)
-
- NiH-Catalyzed Remote Asymmetric Hydroalkylation of Alkenes with Racemic α-Bromo Amides
-
Reported here is a terminal-selective, remote asymmetric hydroalkylation of olefins with racemic α-bromo amides. The reaction proceeds by NiH-catalyzed alkene isomerization and subsequent alkylation reaction, and can enantioconvergently introduce an unsymmetrical secondary alkyl group from a racemic α-bromo amide onto a terminal C(sp3)?H position along the hydrocarbon chain of the alkene. This mild process affords a range of structurally diverse chiral α-alkylalkanoic amides in excellent yields, and high regio- and enantioselectivities. In addition, the synthetic utility of this protocol is further highlighted by the regioconvergent conversion of industrial raw materials of isomeric olefin mixtures into enantioriched α-alkylalkanoic amides on large scale.
- Zhou, Fang,Zhang, Yao,Xu, Xianfeng,Zhu, Shaolin
-
supporting information
p. 1754 - 1758
(2019/01/19)
-
- Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
-
The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
- Xue, Xiaoqian,Zhang, Yan,Wang, Chao,Zhang, Maofeng,Xiang, Qiuping,Wang, Junjian,Wang, Anhui,Li, Chenchang,Zhang, Cheng,Zou, Lingjiao,Wang, Rui,Wu, Shuang,Lu, Yongzhi,Chen, Hongwu,Ding, Ke,Li, Guohui,Xu, Yong
-
supporting information
p. 542 - 559
(2018/05/24)
-
- Cobalt-Catalyzed Enantioselective Negishi Cross-Coupling of Racemic α-Bromo Esters with Arylzincs
-
The first cobalt-catalyzed enantioselective Negishi cross-coupling reaction, and the first arylation of α-halo esters with arylzinc halides, are disclosed. Employing a cobalt-bisoxazoline catalyst, various α-arylalkanoic esters were synthesized in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield). A diverse range of functional groups, including ether, halide, thioether, silyl, amine, ester, acetal, amide, olefin and heteroaromatics is tolerated by this method. This method was suitable for gram-scale reactions, enabling the synthesis of (R)-xanthorrhizol with high enantiopurity. Radical clock experiments support the intermediacy of radicals.
- Liu, Feipeng,Zhong, Jiangchun,Zhou, Yun,Gao, Zidong,Walsh, Patrick J.,Wang, Xueyang,Ma, Sijie,Hou, Shicong,Liu, Shangzhong,Wang, Minan,Wang, Min,Bian, Qinghua
-
supporting information
p. 2059 - 2064
(2018/02/14)
-
- Substituted α-mercaptoketones, new types of specific neprilysin inhibitors
-
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.
-
p. 3883 - 3890
(2017/07/27)
-
- Synthesis and anti-parasitic activity of C-benzylated (N-arylcarbamoyl)alkylphosphonate esters
-
Unexpected substituent-dependent regioselectivty challenges in the synthesis of C-benzylated (N-arylcarbamoyl)phosphonate esters have been resolved. The C-benzylated N-furfurylcarbamoyl derivative showed low micromolar PfLDH inhibition, while one of the C-benzylated N-arylcarbamoyl analogues was active against Nagana Trypanosoma brucei parasites which are responsible for African trypanosomiasis in cattle.
- Adeyemi, Christiana M.,Isaacs, Michelle,Mnkandhla, Dumisani,Klein, Rosalyn,Hoppe, Heinrich C.,Krause, Rui W.M.,Lobb, Kevin A.,Kaye, Perry T.
-
p. 1661 - 1667
(2017/03/08)
-
- MIXED INHIBITORS OF AMINOPEPTIDASE N AND NEPRILYSIN
-
Mixed inhibitors of aminopeptidase N and neprilysin are disclosed. Pharmaceutical compositions containing at least one of these compounds, used alone or in combination with morphine and derivatives thereof, endocannabinoids and inhibitors of endocannabinoid metabolism, GABA derivatives such as gabapentin or pregabalin, duloxetine or methadone, can be used as an analgesic, anxiolytic, antidepressant or anti-inflammatory.
- -
-
Paragraph 0194-0198
(2015/11/18)
-
- Synthesis of Polysubstituted γ-Butenolides via a Radical Pathway: Cyclization of α-Bromo Aluminium Acetals and Comparison with the Cyclization of α-Bromoesters at High Temperature
-
Polysubstituted butenolides were obtained in good to high yields from α-bromoesters derived from propargyl alcohols by a one-pot reaction involving the radical cyclization of α-bromo aluminium acetals, followed by the oxidation of the resulting cyclic aluminium acetals in an Oppenauer-type process and migration of the exocyclic C-C bond into the α,β-position. Comparison with the direct cyclization of α-bromoesters at high temperature and under high dilution conditions is described. Deuterium-labelling experiments allowed us to uncover "invisible" 1,5-hydrogen atom transfers (1,5-HATs) that occur during these cyclization processes, together with the consequences of the latter in the epimerization of stereogenic centres. Compared to the classical approach, the cyclization of aluminium acetals proved to be highly chemoselective and its efficiency was illustrated by the short total syntheses of optically enriched γ-butenolides isolated from Plagiomnium undulatum and from Kyrtuhrix maculans.
- Bénéteau, Romain,Despiau, Carole F.,Rouaud, Jean-Christophe,Boussonnière, Anne,Silvestre, Virginie,Lebreton, Jacques,Dénès, Fabrice
-
supporting information
p. 11378 - 11386
(2015/08/03)
-
- Enantioselective protonation of α-hetero carboxylic acid-derived ketene disilyl acetals under chiral ionic Bronsted acid catalysis
-
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
-
supporting information
p. 13489 - 13491
(2015/01/09)
-
- Enantioselective construction of tetrasubstituted stereogenic carbons through bronsted base catalyzed michael reactions: α′-hydroxy enones as key enoate equivalent
-
Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C-C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Bronsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.
- Badiola, Eider,Fiser, Bla,Gmez-Bengoa, Enrique,Mielgo, Antonia,Olaizola, Iurre,Urruzuno, Iaki,Garca, Jess M.,Odriozola, Jos M.,Razkin, Jess,Oiarbide, Mikel,Palomo, Claudio
-
supporting information
p. 17869 - 17881
(2015/02/19)
-
- Cobalt-bisoxazoline-catalyzed asymmetric kumada cross-coupling of racemic α-bromo esters with aryl grignard reagents
-
The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt-bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.
- Mao, Jianyou,Liu, Feipeng,Wang, Min,Wu, Lin,Zheng, Bing,Liu, Shangzhong,Zhong, Jiangchun,Bian, Qinghua,Walsh, Patrick J.
-
supporting information
p. 17662 - 17668
(2015/02/02)
-
- Synthesis of enantiomerically enriched-bromonitriles from amino acids
-
Two methods were investigated for the preparation of six chiral-bromonitriles with different optic purities. The nitrous deamination of amino acids gives-bromoacids, which react with chlorosulfonyl isocyanate followed by triethylamine to afford-bromonitriles with moderate enantiomeric excess. However, the dehydration of corresponding-bromoamids using thionyl chloride gives-bromonitriles with good enantiomeric excess up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than 30% racemization as determined by high-performance liquid chromatograpic analysis.
- Tka, Najeh,Kraem, Jamil,Hassine, Bechir Ben
-
p. 735 - 743
(2013/01/15)
-
- Reactions of α-mercaptocarboxylic acid hydrazides with triethyl orthoesters: Synthesis of 1,3,4-thiadiazin-5(6H)-ones and 1,3,4-oxadiazoles
-
Reactions of α-mercapto-β-phenylpropionic and α-mercaptophenylacetic acid hydrazides with triethyl orthoesters were conducted under N2 in glacial acetic acid and resulted in the formation of two groups of products, derivatives of 1,3,4-thiadiazin-5(6H)-ones and 2-(1-mercaptomethyl)-1,3,4-oxadiazoles. When conducting the same transformations on α-mercaptophenylacetic acid hydrazide in the presence of air, two different products from the 1,3,4-oxadiazole family, the appropriate bis(1,3,4-oxadiazol-2-yl-phenylmethyl) disulfides and 2-benzyl-1,3,4- oxadiazoles, were formed with the liberation of free sulfur. The oxygenated bis(1,3,4-oxadiazol-2-yl-phenylmethyl) disulfides were reduced to the corresponding 2-(1-mercaptomethyl)-1,3,4-oxadiazoles with the use of zinc powder under mild conditions.
- Kudelko, Agnieszka
-
experimental part
p. 3616 - 3625
(2012/06/18)
-
- Regioselective multicomponent sequential synthesis of hydantoins
-
The development of new practical and green methods for the synthesis of small heterocycles is an attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the drug discovery process. Herein we report a one-pot, three-component sequential procedure for the synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions, using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which are particularly interesting bioactive compounds in medicinal chemistry. The Royal Society of Chemistry 2012.
- Olimpieri, Francesca,Bellucci, Maria Cristina,Marcelli, Tommaso,Volonterio, Alessandro
-
p. 9538 - 9555
(2013/01/16)
-
- Highly enantioselective access to α-dibenzylamino ketones from chiral nonracemic α-bromo α′-sulfinyl ketones by dynamic kinetic resolution: Synthesis of (2R,1′S)-2-[1-(dibenzylamino)alkyl]oxiranes
-
A novel and efficient synthesis of enantiomerically pure α-dibenzylamino α′-sulfinyl ketones starting from a mixture of both epimers of α-bromo α′-(R)-sulfinyl ketone has been realized through combined in situ substitution-epimerization in a so-called Dynamic Kinetic Resolution (DKR). The scope of the reaction has been examined, and four differently substituted α-(S)-dibenzylamino α′-(R)- sulfinyl ketones were obtained in good yields with excellent diastereoselectivities. The utility of these derivatives was further illustrated with a highly stereoselective synthesis of syn-(2R,1′S)-2-(1- dibenzylaminoalkyl)oxiranes.
- Geant, Pierre-Yves,Martinez, Jean,Salom-Roig, Xavier J.
-
experimental part
p. 1300 - 1309
(2011/04/17)
-
- Triazolium Carbene Catalysts and Stereoselective Bond Forming Reactions Thereof
-
Provided herein are triazolium carbine catalysts useful for asymmetric hydration, fluorination, and deuteration, and processes for their preparation. Also provided are synthetic reactions in which these catalysts are used, in particular, in stereoselective formation of carbon-chlorine, carbon-hydrogen, carbon-fluorine, and carbon-deuterium bonds.
- -
-
Page/Page column 8
(2011/10/04)
-
- SUBSTITUTED BENZIMIDAZOLONE DERIVATIVES, MEDICAMENTS COMPRISING THEM AND THEIR USE
-
The present invention relates to novel benzimidazolone derivatives of the general formula (I) in which the substituents R1, R2, R3, A1, A2, and B are as defined in claim 1, medicaments comprising these, and the use thereof for the prophylaxis and/or treatment of vasopressin-dependent diseases.
- -
-
Page/Page column 63
(2008/06/13)
-
- Investigation of the synthetic and mechanistic aspects of the highly stereoselective transformation of α-thioamides to α-thio-β- chloroacrylamides
-
Treatment of a series of α-thioamides with N-chlorosuccinimide results in efficient transformation to the analogous α-thio-β- chloroacrylamides. The mechanistic pathway has been established through isolation and characterisation of intermediate compounds. The scope of the transformation has been explored - aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and Z-stereoisomers is formed. The Royal Society of Chemistry.
- Murphy, Maureen,Lynch, Denis,Schaeffer, Marcel,Kissane, Marie,Chopra, Jay,O'Brien, Elisabeth,Ford, Alan,Ferguson, George,Maguire, Anita R.
-
p. 1228 - 1241
(2008/02/03)
-
- Carboxylic Acid Compounds and Use Thereof
-
Provision of a superior URAT1 activity inhibitor effective for the treatment and the like of a pathology involving uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary lithiasis, renal dysfunction, coronary heart disease, ischemic cardiac diseases and the like. A URAT1 activity inhibitor containing a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: [image] wherein each symbol is as defined in the specification.
- -
-
Page/Page column 84
(2010/11/28)
-
- Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], processes for its preparation and its use
-
The present invention relates to ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate], the preparation of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] from (2R)-2-bromo-3-phenylpropionic acid and ethylenediamine in 2-propanol, and the use of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] for the preparation of ACE/NEP inhibitors.
- -
-
Page/Page column 5
(2008/06/13)
-
- DERIVATIVES OF SUCCINIC AND GLUTARIC ACIDS AND ANALOGS THEREOF USEFUL AS INHIBITORS OF PHEX
-
The present invention relates to derivatives of succinic and glutaric acids and analogues thereof, having the following general formula (I), useful as inhibitors of PHEX. These derivatives are useful for promoting generation of bone mass and treating or preventing diseases or conditions associated with a phosphate metabolism defect. Methods for preparation and intermediates are also disclosed.
- -
-
-
- PROCESS FOR PRODUCING OPTICALLY ACTIVE 2-SUBSTITUTED CARBOXYLIC ACID
-
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.
- -
-
-
- PROCESS FOR PREPARING (R)-2-BROMO-3-PHENYL-PROPIONIC ACID
-
It is described a process for preparing (R)-2-bromo-3-phenyl-propionic acid starting from (D)-phenyl-alanine, sodium nitrite and concentrated hydrobromic acid in a mixture of an aqueous solvent and a solvent selected from the group consisting of halogenat
- -
-
-
- Process for the preparation of(R)-2-bromo-3-phenyl -propionic acid
-
Process for the preparation of (R)-2-bromo-3-phenylpropionic acid starting from D-phenylalanine, sodium nitrite and HBr in an aqueous solution, the reaction being carried out in the presence of a bromide salt, at a temperature between ?10 and 30° C. The t
- -
-
-
- Method for the preparation of (s) -2-acetylthio-3-phenylpropionic acid
-
Method for the preparation of (S)-2-acetylthio-3-phenylpropionic acid, wherein (R)-2-bromo-3-phenylpropionic acid is contacted with thioacetic acid and an organic base, for example triethylamine. Preferably the base is metered to a mixture of (R)-2-bromo-
- -
-
-
- Synthesis and Biological Activity of Hydroxamic Acid-Derived Vasopeptidase Inhibitor Analogues
-
(Equation Presented) Syntheses of novel hydroxamic acid-derived azepinones containing pendant mercaptoacyl groups or formyl hydroxamates are described. These new analogues of therapeutically important ACE and NEP inhibitors include unprecedented changes a
- Walz, Andrew J.,Miller, Marvin J.
-
p. 2047 - 2050
(2007/10/03)
-
- Process for preparing (R)-2-bromo-3-phenyl-propionic acid
-
It is described a process for preparing (R)-2-bromo-3-phenyl-propionic acid starting from (D)-phenyl-alanine, sodium nitrite and concentrated hydrobromic acid in a mixture of an aqueous solvent and a solvent selected from the group consisting of halogenat
- -
-
-
- Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1
-
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.
-
p. 2037 - 2039
(2007/10/03)
-
- Synthesis and activity of HIV protease inhibitors
-
We report here the synthesis and activity of HIV protease inhibitors. In the first stage hydrophobic compounds incorporating a 'carba' bond surrogate or a beta-homologated residue were synthesized. Secondly, we synthesized cyclic compounds in which we incorporated 2-quinoline carboxylic acid in the P3 position and the amino-hydroxyindane moiety in the P'3. The last part of this work was dedicated to a structure/activity study of a peptide substrate. These modifications allowed us to work up the synthesis of new pseudopeptide bonds: amino-amide and hydroxy-amide. Compounds with activity in the micromolar range were actually a starting point for the synthesis of new protease inhibitors.
- Garrouste, Patrick,Pawlowski, Macek,Tonnaire, Thierry,Sicsic, Sames,Dumy, Pascal,De Rosny, Eve,Reboud-Ravaux, Michele,Fulcrand, Pierre,Martinez, Jean
-
p. 423 - 436
(2007/10/03)
-
- Mercaptoacyl matrix metalloproteinase inhibitors: The effect of substitution at the mercaptoacyl moiety
-
The in vitro potency of orally-active mercaptoacyl matrix metalloproteinase inhibitors is increased by the introduction of appropriate substitutents on the mercaptoacyl moiety.
- Baxter, Andrew D.,Bhogal, Ranjev,Bird, John B.,Buckley, George M.,Gregory, David S.,Hedger, Paul C.,Manallack, David T.,Massil, Tracy,Minton, Kevin J.,Montana, John G.,Neidle, Stephen,Owen, David A.,Watson, Robert J.
-
p. 2765 - 2770
(2007/10/03)
-
- MERCAPTOACETYLAMIDE BICYCLIC LACTAM DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACE
-
The present invention relates to certain novel mercaptoacetylamide bicyclic lactam derivatives useful as inhibitors of enkephalinase and of ACE.These mercaptoacetylamide bicyclic lactam derivatives can be described by the following formula: STR1 whe
- -
-
-
- (R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries for the asymmetric synthesis of α-hydroxy acids
-
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
-
p. 1877 - 1894
(2007/10/03)
-
- N-[MERCAPTOACYL(AMINO ACID OR PEPTIDE)] COMPOUNDS AND S-LIPOPHILIC ALIPHATIC CARBONYL DERIVATIVES THEREOF AS ANTIHYPERTENSIVES
-
N-[Mercaptoacyl(amino acid or peptide)] compounds and S-lipophilic aliphatic carbonyl derivatives thereof, and pharmaceutical compositions comprising such compounds, as well as the use of these compounds as antihypertensives by the inhibition of neutral endopeptidase and/or peptidyldipeptidase A are disclosed. Methods for preparing the such compounds and derivatives are disclosed also.
- -
-
-
- Inhibition of carboxypeptidase A by (S)-2-mercapto-3-phenylpropanoic acid
-
(S)-2-Mercapto-3-phenylpropanoic acid is an effective competitive inhibitor of carboxypeptidase A, comparable in potency to (S)-3-mercapto-2-benzylpropanoic acid.
- Lanthier, Christopher M.,MacKinnon, Gregory R.,Dmitrienko, Gary I.
-
p. 2309 - 2310
(2007/10/03)
-
- Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors
-
An interesting approach for the treatment of congestive heart failure and chronic hypertension could be to avoid the formation of angiotensin II by inhibiting angiotensin converting enzyme (ACE) and to protect atrial natriuretic factor by blocking neutral endopeptidase 24.11 (NEP). This is supported by recent results obtained with potent dual inhibitors of the two zinc metallopeptidases, such as RB 105, HSCH2CH(CH3)PhCONHCH(CH3)COOH (Fournie-Zaluski et al. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4072-4076), which reduces blood pressure in experimental models of hypertension, independently of the salt and renin angiotensin system status. In order to develop new dual inhibitors with improved affinities, long duration of action, and/or better bioavailabilities, various series of mercaptoacyldipeptides corresponding to the general formula HSCH(R1)CONHCH(R1')CON(R)CH(R2')COOH have been synthesized. The introduction of well-selected β-branched chains in positions R1 and R1', associated with a tyrosine or a cyclic amino acid in the C-terminal position, led to potent dual inhibitors of NEP and ACE such as 21 [N-[(2S)-2-mercapto- 3-methylbutanoyl]-Ile-Tyr] and 22 [N-[(2S)-2-mercapte-3-phenylpropanoyl]Ala- Pro] which have IC50 values in the nanomolar range for NEP and subnanomolar range for ACE. These compounds could have different modes of binding to the two peptidases. In NEP, the dual inhibitors seem to interact only with the S1' and S2' subsites, whereas additional interactions with the S1 binding subsite of ACE probably account for their subnanomolar inhibitory potencies for this enzyme. The localization of the Pro residue of 22 outside the NEP active site is supported by biochemical data using (Arg102,Glu)NEP and molecular modeling studies with thermolysin used as model of NEP. One hour after oral administration in mice of a single dose (2.7 x 10-5 mol/kg), 21 inhibited 80% and 36% of kidney NEP and lung ACE, respectively, while 22 inhibited 40% of kidney NEP and 56% of lung ACE.
- Coric, Pascale,Turcaud, Serge,Meudal, Hervé,Roques, Bernard Pierre,Fournie-Zaluski, Marie-Claude
-
p. 1210 - 1219
(2007/10/03)
-
- Diastereoselective Synthesis of α-Bromo amides leading to Diastereomerically Enriched α-Amino-, α-Hydroxy- and α-Thiocarboxylic Acid Derivatives
-
α-Bromo amides derived from Oppolzer's camphorsultam can be prepared diastereoselectively starting from racemic α-bromo acids, and undergo epimerisation under appriopriate conditions leading to an enhanced d.e..By reacting the individual isomers or the mi
- Ward, Robert S.,Pelter, Andrew,Goubet, Dominique,Pritchard, Martyn C.
-
p. 469 - 498
(2007/10/02)
-
- Mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
-
The present invention relates to novel mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase.
- -
-
-
- Synthesis of C2-symmetric HIV-protease inhibitors with sulfur-containing central units
-
Sulfide-, sulfoxide-, and sulfone- containing C2-symmetric peptide analogs were obtained stereospecifically starting from phenylalanine. The compounds were evaluated as potential HIV-protease inhibitors and found to be inactive within the limit
- Spaltenstein,Leban,Furfine
-
p. 1457 - 1460
(2007/10/02)
-
- Acylmercaptoalkanoyldipeptides, methods of preparation and their therapeutic use
-
This invention is directed to a compound of the formula that inhibits simultaneously neutral endopeptidase and peptidyldipeptidase A and is useful in treating hypertension. The invention is also directed to the preparation of the compound, pharmaceutical compositions containing it, and methods for its pharmaceutical use.
- -
-
-
- Cyclic RGD Peptide Analogues as Antiplatelet Antithrombotics
-
Stimulation of platelets activates GPIIbIIIa, the heterodimeric integrin receptor, to bind fibrinogen (Fg), which results in platelet aggregation.GPIIbIIIa/Fg binding inhibitors are potentially suitable for acute use during and after thrombolytic therapy
- Barker, Peter L.,Bullens, Sherron,Bunting, Stuart,Burdick, Daniel J.,Chan, Kathryn S.,et al.
-
p. 2040 - 2048
(2007/10/02)
-
- Nucleophilic Substitution Reactions of Alkyl Halides By Using New Polymer-Supported Reagents Containing Hemin
-
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
-
p. 2562 - 2566
(2007/10/02)
-
- Process for producing an α-halogeno-β-phenylpropionic acid
-
A process for producing an α-halogeno-β-phenylpropionic acid represented by the general formula: STR1 where X is a halogen atom, which comprises hydrolyzing under heating a halogen-containing ethylbenzene derivative represented by the general formula: STR
- -
-
-
- Preparation of α-Bromo- and α-Chlorocarboxylic Acids from α-Amino Acids
-
Diazotization of α-amino acids in 48:52 (w/w) hydrogen fluoride/pyridine along with excess of potassium halide results in the corresponding α-halocarboxylic acids in good to excellent yields (Table 1 and 2).
- Olah, George A.,Shih, Joseph,Prakash, G. K. Surya
-
p. 1028 - 1030
(2007/10/02)
-
- Direct Conversion of Arylamines to the Halides by Deamination with Thionitrite or Related Compounds and Anhydrous Copper(II) Halides
-
Reactions of various arylamines with either t-butyl thionitrite, t-butyl thionitrate, or p-toluenesulfonyl nitrite in the presence of anhydrous copper(II) halides under mild conditions gave corresponding aryl halides in good yields.This reaction in the presence of such olefins as acrylonitrile, styrene, and acrylic acid gave the corresponding 2-aryl-1-haloethanes as the main products. t-Butyl thionitrite, t-butyl thionitrate, and p-toluenesulfonyl nitrite were found to be better deaminative reagents than alkyl nitrites or alkyl nitrates due to their weak sulfur-nitrogen bonds.
- Oae, Shigeru,Shinhama, Koichi,Kim, Yong Hae
-
p. 1065 - 1069
(2007/10/02)
-