- Preparation method of key intermediate of elagolix
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The invention relates to the field of pharmacy, and concretely relates to a preparation method of a key intermediate of elagolix. The method adopts simple and easily available Boc-D-phenylglycinol asa starting material, and comprises the following steps:
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Paragraph 0016; 0022; 0028; 0034; 0040; 0046
(2019/07/16)
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- Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity
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In the preceding manuscript [Moreau et al. 2018, 10.1021/acs.jmedchem.7b01691] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.
- Skepper, Colin K.,Moreau, Robert J.,Appleton, Brent A.,Benton, Bret M.,Drumm, Joseph E.,Feng, Brian Y.,Geng, Mei,Hu, Cheng,Li, Cindy,Lingel, Andreas,Lu, Yipin,Mamo, Mulugeta,Mergo, Wosenu,Mostafavi, Mina,Rath, Christopher M.,Steffek, Micah,Takeoka, Kenneth T.,Uehara, Kyoko,Wang, Lisha,Wei, Jun-Rong,Xie, Lili,Xu, Wenjian,Zhang, Qiong,De Vicente, Javier
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supporting information
p. 3325 - 3349
(2018/05/01)
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- SYNTHESIS OF ARYL CYCLOHEXANE CARBOXAMIDE DERIVATIVES USEFUL AS SENSATES IN CONSUMER PRODUCTS
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Synthesis methods to produce a series of carboxamides built off of an (S)-2-amino acid backbone or an (R)-2-amino acid backbone, depending upon the desired diastereomer of the end product.
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Paragraph 0067; 0068
(2017/03/21)
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- SONIC HEDGEHOG MODULATORS
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Sonic Hedgehog modulators and methods of use thereof are provided for.
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- Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: Potent inhibitors of R5 HIV-1 replication
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The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
- Skerlj, Renato,Bridger, Gary,Zhou, Yuanxi,Bourque, Elyse,McEachern, Ernest,Metz, Markus,Harwig, Curtis,Li, Tong-Shuang,Yang, Wen,Bogucki, David,Zhu, Yongbao,Langille, Jonathan,Veale, Duane,Ba, Tuya,Bey, Michael,Baird, Ian,Kaller, Alan,Krumpak, Maria,Leitch, David,Satori, Michael,Vocadlo, Krystyna,Guay, Danielle,Nan, Susan,Yee, Helen,Crawford, Jason,Chen, Gang,Wilson, Trevor,Carpenter, Bryon,Gauthier, David,MacFarland, Ron,Mosi, Renee,Bodart, Veronique,Wong, Rebecca,Fricker, Simon,Schols, Dominique
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p. 8049 - 8065
(2013/11/06)
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- Asymmetric neutral amination of nitroolefins catalyzed by chiral bifunctional ammonium salts in water-rich biphasic solvent
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It′s just a phase: Environmentally benign title reaction was achieved under neutral phase-transfer conditions in the presence of 0.05 mol% of a chiral bifunctional ammonium bromide. The importance of bifunctional design of the chiral phase-transfer catalysts (PTC) was clearly shown in the transition-state model of the reaction based on the single-crystal X-ray structure. Bn=benzyl, Boc=tert-butoxycarbonyl.
- Wang, Lijia,Shirakawa, Seiji,Maruoka, Keiji
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p. 5327 - 5330
(2011/06/28)
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- N-urethane-protected amino alkyl isothiocyanates: Synthesis, isolation, characterization, and application to the synthesis of thioureidopeptides
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(Chemical Equation Presented) Synthetically useful N-Fmoc amino-alkyl isothiocyanates have been described, starting from protected amino acids. These compounds have been synthesized in excellent yields by thiocarbonylation of the monoprotected 1,2-diamines with CS2/TEA/p-TsCl, isolated as stable solids, and completely characterized. The procedure has been extended to the synthesis of amino alkyl isothiocyanates from Boc- and Z-protected amino acids as well. The utility of these isothiocyanates for peptidomimetics synthesis has been demonstrated by employing them in the preparation of a series of dithioureidopeptide esters. Boc-Gly-OH and Boc-Phe-OH derived isothiocyanates 9a and 9c have been obtained as single crystals and their structures solved through X-ray diffraction. They belong to the orthorhombic crystal system, and have a single molecule in the asymmetric unit (Z′ = 1). 9a crystallizes in the centrosymmetric space group Pbca, while 9c crystallizes in the noncentrosymmetric space group P212121.
- Sureshbabu, Vommina V.,Naik, Shankar A.,Hemantha,Narendra,Das, Ushati,Guru Row, Tayur N.
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supporting information; experimental part
p. 5260 - 5266
(2009/12/06)
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- Asymmetric hydrogenation of aromatic ketones catalyzed by the TolBINAP/DMAPEN-ruthenium(II) complex: A significant effect of N-substituents of chiral 1,2-diamine ligands on enantioselectivity
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(Chemical Equation Presented) Asymmetric hydrogenation of acetophenone in the presence of Ru(II) catalysts coordinated by TolBINAP and a series of chiral 1,2-diamines was studied. The sense and degree of enantioselectivity were highly dependent on the N-substituents of the diamine ligands. The N-substituent effect was discussed in detail. Among these catalysts, the (S)-TolBINAP/(R)- DMAPEN-Ru(II) complex showed the highest enantioselectivity. The mode of enantioface selection was interpreted by using transition state models based on the X-ray structure of the catalyst precursor. The chiral catalyst effected the hydrogenation of alkyl aryl ketones and arylglyoxal dialkyl acetals to afford the chiral alcohol in >99% ee in the best cases. Hydrogenation of racemic benzoin methyl ether with the chiral catalyst through dynamic kinetic resolution gave the anti-alcohol (syn:anti = 3:97) in 98% ee, while the reaction of α-amidopropiophenones resulted in the syn-alcohols (symanti = 96:4 to >99:1) in >98% ee.
- Ooka, Hirohito,Arai, Noriyoshi,Azuma, Keita,Kurono, Nobuhito,Ohkuma, Takeshi
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supporting information; experimental part
p. 9084 - 9093
(2009/04/11)
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- CHEMOKINE RECEPTOR BINDING COMPOUNDS
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The present invention relates to chemokine receptor binding compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to modulators of chemokine receptor activity, preferably modulators of CCR4 or CCR5. In one aspect, these compounds demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
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Page/Page column 28-29
(2010/11/26)
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- Enantioselective aza-Henry reactions assisted by ZnII and N-methylephedrine
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(Chemical Equation Presented) Hooray aza-Henry! A combination of zinc triflate, an amine base, and (-)-N-methylephedrine (NME), which can be easily recovered and reused, leads to high enantioselectivities in the aza-Henry reaction of N-Boc-protected aldimines and nitromethane (see scheme; Boc = tert-butyloxycarbonyl).
- Palomo, Claudio,Oiarbide, Mikel,Halder, Rajkumar,Laso, Antonio,Lopez, Rosa
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p. 117 - 120
(2007/10/03)
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- Synthesis of new pyrrolidine derivatives as inhibitors of α-mannosidase and of the growth of human glioblastoma cells
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New 2-benzylamino-3,4-dihydroxypyrrolidines bearing aromatic and aliphatic amido side chains have been prepared. The influence of the amido substituents on the inhibitory activity of these diamines toward 24 commercially available glycosidases was determi
- Favre, Sylvain,Fiaux, Hele,Schuetz, Catherine,Vogel, Pierre,Juillerat-Jeanneret, Lucienne,Gerber-Lemaire, Sandrine
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p. 179 - 192
(2008/02/10)
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- Bifunctional-thiourea-catalyzed diastereo- And enantioselective Aza-Henry reaction
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Bifunctional thiourea 1a catalyzes aza-Henry reaction of nitroalkanes with N-Boc-imines to give syn-β-nitroamines with good to high diastereo- and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N-protecting groups of the imines have a determining effect on the chirality of the prod ucts, that is, the reaction of N-Bocimines gives R adducts as major products, whereas the same reaction of N-phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP-99,994.
- Xu, Xuenong,Furukawa, Tomihiro,Okino, Tomotaka,Miyabe, Hideto,Takemoto, Yoshiji
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p. 466 - 476
(2008/09/20)
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- Asymmetric allylic substitution catalyzed by C1-symmetrical complexes of molybdenum: Structural requirements of the ligand and the stereochemical course of the reaction
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Application of new chiral ligands (R)-(-)-12a and (S)-(+)-12c (VALDY), derived from amino acids, to the title reaction, involving cinnamyl (linear) and isocinnamyl (branched) type substrates (4 and 5 → 6), led to excellent regio- and enantioselectivities (>30:1, ≤98% ee), showing that ligands with a single chiral center are capable of high asymmetric induction. The structural requirements of the ligand and the mechanism are discussed. The application of single enantiomers of deuterium-labeled substrates (both linear 38c and branched 37c) and analysis of the products (41-43) by 2{ 1H) NMR spectroscopy in a chiral liquid crystal matrix allowed the stereochemical pathways of the reaction to be distinguished. With ligand (S)-(+)-12c, the matched enantiomer of branched substrate was found to be (S)-5, which was converted into (R)-6 with very high regio- and stereoselectivity via a process that involves net retention of stereochemistry. The mismatched enantiomer of the branched substrate was found to be (R)-5, which was also converted into (R)-6, that is, with apparent net inversion, but at a lower rate and with lower overall enantioselectivity. This latter feature, which may be termed a "memory effect", reduced the global enantioselectivity in the reaction of the racemic substrate (±)-5. The stereochemical pathway of the mismatched manifold has been shown also to be one of net retention, the apparent inversion occurring through equilibration via an Mo-allyl intermediate prior to nucleophilic attack. Incomplete equilibration leads to the memory effect and thus to lower enantioselectivity. Analysis of the mismatched manifold over the course of the reaction revealed that the memory effect is progressively attenuated with the nascent global selectivity increasing substantially as the reaction proceeds. The origin of this effect is suggested to be the depletion of CO sources in the reaction mixture, which attenuates turnover rate and thus facilitates greater equilibrium. The linear substrate was also converted into the branched product with net syn stereochemistry, as shown by isotopic labeling. An analogous process operates in the generation of small quantities of linear product from branched substrate.
- Malkov, Andrei V.,Gouriou, Laure,Lloyd-Jones, Guy C.,Stary, Ivo,Langer, Vratislav,Spoor, Paul,Vinader, Victoria,Kocovsky, Pavel
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p. 6910 - 6929
(2007/10/03)
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- Structure-activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists
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SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM.
- Guo, Zhiqiang,Wu, Dongpei,Zhu, Yun-Fei,Tucci, Fabio C.,Regan, Collin F.,Rowbottom, Martin W.,Struthers, R. Scott,Xie, Qiu,Reijmers, Shelby,Sullivan, Susan K.,Sai, Yang,Chen, Chen
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p. 3685 - 3690
(2007/10/03)
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- Functionalized pyrrolidines inhibit α-mannosidase activity and growth of human glioblastoma and melanoma cells
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New substituted pyrrolidine-3,4-diol derivatives were prepared from D-(-)- and L-(+)-phenyl glycinol. The influence of the configuration and the substitution of the lateral side chain of these derivatives on the inhibition of 25 commercial glycosidases we
- Fiaux, Hélène,Popowycz, Florence,Favre, Sylvain,Schütz, Catherine,Vogel, Pierre,Gerber-Lemaire, Sandrine,Juillerat-Jeanneret, Lucienne
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p. 4237 - 4246
(2007/10/03)
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- Chiral Proton Catalysis: A Catalytic Enantioselective Direct Aza-Henry Reaction
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Despite Nature's longstanding ability to use a proton, the most prevalent Lewis acid, to both activate and orient a substrate during an enantioselective reaction, this work represents the first example of this phenomenon outside of a protein. A chiral, no
- Nugent, Benjamin M.,Yoder, Ryan A.,Johnston, Jeffrey N.
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p. 3418 - 3419
(2007/10/03)
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- 1-(3,4-Dihydro-4-oxoquinazolin-3-yl)aziridines (Q-substituted aziridines): Ring-opening reactions with C-N bond cleavage and preparation of Q-free chirons
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The presence of the Q group in ring-opening reactions of N-(Q)-aziridines 3, 4, 5 and 6 has been found to be advantageous in the following ways, (i) nucleophilic ring-opening by cuprate or by azide with inversion of configuration is assisted by the electron-withdrawing character of the Q group, (ii) ring-opening of aziridines 5 or 6 to the corresponding alcohols 36 and 23 with retention of configuration can be accomplished by participation of the Q group: the Q carbonyl oxygen becomes the hydroxy oxygen in the alcohol product, (iii) the combined effects of the electron-withdrawing Q group and ring strain allow preparation of individual aziridine N-invertomers 3 and 4 whose ring-opening with hydrogen chloride in dichloromethane proceeds with complementary stereochemistry. The Q group is also believed to be involved in ring-opening of aziridines 5 and 6 mediated by samarium(III) nitrate hexahydrate with predominant retention of configuration. Reductive removal of the Q group from these ring-opened products gave chirons 12, 19 and 21. The Royal Society of Chemistry 2000.
- Atkinson, Robert S.,Ayscough, Andrew P.,Gattrell, William T.,Raynham, Tony M.
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p. 3096 - 3106
(2007/10/03)
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- Ring-opening of chiral N-(3,4-dihydro-4-oxoquinazolin-3-yl)-substituted aziridines (Q*-substituted aziridines): Access to Q*-free chirons
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The presence of the quinazolin-4(3H)-one ring (Q*) in N-(Q*)-aziridines facilitates ring-opening by nucleophiles: removal of the Q* group from enantiopure ring-opened products gives useful chirons.
- Atkinson, Robert S.,Ayscough, Andrew P.,Gattrell, William T.,Raynham, Tony M.
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p. 497 - 500
(2007/10/03)
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- Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 8. Incorporation of amide or amine functionalities into a series of disubstituted ureas and carbamates. Effects of ACAT inhibition in vitro and efficacy in vivo
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A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O- acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was β to the urea moiety and not α, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (- 47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.
- O'Brien,Sliskovic,Blankley,Roth,Wilson,Hamelehle,Krause,Stanfield
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p. 1810 - 1822
(2007/10/02)
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