- Efficient synthesis of 5-(hydroxymethyl)piperazin-2-ones using automatically prepared chiral bromocarboxylic acid and Garner's aldehyde as versatile building blocks
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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
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supporting information
(2021/05/04)
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- Direct synthesis of α-thio aromatic acids from aromatic amino acids
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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.
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supporting information
p. 1140 - 1142
(2018/02/23)
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- Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
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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
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supporting information
p. 542 - 559
(2018/05/24)
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- 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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p. 3883 - 3890
(2017/07/27)
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- MIXED INHIBITORS OF AMINOPEPTIDASE N AND NEPRILYSIN
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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.
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Paragraph 0194-0198
(2015/11/18)
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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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- Triazolium Carbene Catalysts and Stereoselective Bond Forming Reactions Thereof
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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.
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Page/Page column 8
(2011/10/04)
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- PROCESS FOR PREPARING (R)-2-BROMO-3-PHENYL-PROPIONIC ACID
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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
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- Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], processes for its preparation and its use
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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.
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Page/Page column 5
(2008/06/13)
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- DERIVATIVES OF SUCCINIC AND GLUTARIC ACIDS AND ANALOGS THEREOF USEFUL AS INHIBITORS OF PHEX
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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.
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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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- Crystallization-induced chiral inversion as the key step for synthesis of (S)-2-acetylthio-3-phenylpropanoic acid from L-phenylalanine
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(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.
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p. 3233 - 3235
(2007/10/03)
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- Method for the preparation of (s) -2-acetylthio-3-phenylpropionic acid
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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-
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- Process for the preparation of(R)-2-bromo-3-phenyl -propionic acid
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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
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- Synthesis and Biological Activity of Hydroxamic Acid-Derived Vasopeptidase Inhibitor Analogues
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(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.
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p. 2047 - 2050
(2007/10/03)
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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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p. 2037 - 2039
(2007/10/03)
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- Process for preparing (R)-2-bromo-3-phenyl-propionic acid
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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
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- Synthesis and activity of HIV protease inhibitors
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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
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p. 423 - 436
(2007/10/03)
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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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- N-[MERCAPTOACYL(AMINO ACID OR PEPTIDE)] COMPOUNDS AND S-LIPOPHILIC ALIPHATIC CARBONYL DERIVATIVES THEREOF AS ANTIHYPERTENSIVES
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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.
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- Inhibition of carboxypeptidase A by (S)-2-mercapto-3-phenylpropanoic acid
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(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.
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p. 2309 - 2310
(2007/10/03)
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- MERCAPTOACETYLAMIDE BICYCLIC LACTAM DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACE
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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
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- Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors
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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
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p. 1210 - 1219
(2007/10/03)
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- Synthesis of C2-symmetric HIV-protease inhibitors with sulfur-containing central units
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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
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p. 1457 - 1460
(2007/10/02)
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- Acylmercaptoalkanoyldipeptides, methods of preparation and their therapeutic use
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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.
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- Mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
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The present invention relates to novel mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase.
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- Cyclic RGD Peptide Analogues as Antiplatelet Antithrombotics
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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.
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p. 2040 - 2048
(2007/10/02)
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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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p. 2562 - 2566
(2007/10/02)
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