- A Facile, Six-Step Process for the Synthesis of (3 S,5 S)-3-Isopropyl-5-((2 S,4 S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-carboxylic Acid tert -Butyl Ester, the Key Synthetic Intermediate of Aliskiren
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A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxotetrahydro- furan-2-yl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester from (S)-4-benzyloxazolidin-2-one 2 in an overall 50% yield is reported. The key transformations include: a highly efficient diastereoselective epoxidation, Lewis acid-catalyzed ring-opening with bromide, an SN2 reaction using NaN3, and a tandem reduction-cyclization reaction.
- Pan, Xianhua,Xu, Siyao,Huang, Rui,Yu, Wansheng,Liu, Feng
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Read Online
- Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors
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Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC50 values without having a cation-pi interaction with the Arg258 sidechain.
- Bessho, Yuki,Akaki, Tatsuo,Hara, Yoshinori,Yamakawa, Maki,Obika, Shingo,Mori, Genki,Ubukata, Minoru,Yasue, Katsutaka,Nakane, Yoshitomi,Terasako, Yasuo,Orita, Takuya,Doi, Satoki,Iwanaga, Tomoko,Fujishima, Ayumi,Adachi, Tsuyoshi,Ueno, Hiroshi,Motomura, Takahisa
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- JAK INHIBITORS
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Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.
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Paragraph 00166
(2021/04/02)
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- JAK INHIBITORS
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Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.
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Paragraph 00165
(2021/02/12)
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- JAK INHIBITORS
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Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.
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Paragraph 00223
(2020/11/22)
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- A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose
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Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.
- Durham, Timothy B.,Marimuthu, Jothirajah,Toth, James L.,Liu, Chin,Adams, Lisa,Mudra, Daniel R.,Swearingen, Craig,Lin, Chaohua,Chambers, Mark G.,Thirunavukkarasu, Kannan,Wiley, Michael R.
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p. 5933 - 5939
(2017/07/22)
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- Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5-C6 Disconnection and CO2H-NH2 Equivalence
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A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale.
- Cini, Elena,Banfi, Luca,Barreca, Giuseppe,Carcone, Luca,Malpezzi, Luciana,Manetti, Fabrizio,Marras, Giovanni,Rasparini, Marcello,Riva, Renata,Roseblade, Stephen,Russo, Adele,Taddei, Maurizio,Vitale, Romina,Zanotti-Gerosa, Antonio
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p. 270 - 283
(2016/03/04)
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- Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands
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A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2′ pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P2′ substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resolution crystallography, microcalorimetry, and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors.
- Krimmer, Stefan G.,Cramer, Jonathan,Betz, Michael,Fridh, Veronica,Karlsson, Robert,Heine, Andreas,Klebe, Gerhard
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p. 10530 - 10548
(2016/12/16)
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- A preparation N-substituted oxazole alkone chiral method of ligand
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The invention relates to the technical field of a method for preparing an N-substituted oxazolone chiral ligand. The method for preparing the N-substituted oxazolone chiral ligand provided by the invention comprises the following steps of: reacting a compound A shown as the following formula (described in the specification) with R1-COC1 under the action of alkaline reagent potassium tert-butoxide, sodium methyoxide or NaNH2 to obtain a target product (I), wherein R1 is an alkyl with the number of carbon atoms of being less than or equal to 7, and R2 is phenyl, benzyl or isopropyl. In the invention, potassium tert-butoxide is used for substituting butyl lithium and lithium bis(trimethylsilyl)amide which are frequently used in the prior art, reaction can be carried out at normal temperature, reaction time is shortened, reaction is completed after batch charging is completed, then aftertreatment operation can be carried out, and dynamic cost is saved; less gas is released in the aftertreatment process, and safety is high; and yield of the obtained target compound is high, and purity is high, thus the method provided by the invention is applicable to industrial production.
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Paragraph 0030; 0031
(2017/02/09)
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- Process for Producing Aliskiren
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A new route of synthesis of the compound Aliskiren of formula (I), used in the treatment of hypertension, is described.
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Paragraph 0124-0127
(2013/03/28)
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- A total synthesis of aliskiren
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A total synthesis of aliskiren (20) was accomplished. A key in our synthesis was to use the symmetric trans-cisoid-trans-bis-lactone 1 as a precursor. It was expediently prepared by three different routes (Scheme 2). Appending the end groups and functional group transformations completed the synthesis (Scheme 3). Copyright
- Nam, Gyeok,Ko, Soo Y.
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p. 1937 - 1945,9
(2012/12/12)
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- β N-O turns and helices induced by β2-aminoxy peptides: Synthesis and conformational studies
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Herein, we report an efficient route for the asymmetric synthesis of β2-aminoxy acids as well as experimental and theoretical studies of conformations of peptides composed of β2-aminoxy acids. The nine-membered-ring intramolecular hydrogen bonds, namely, β N-O turns, are generated between adjacent residues in those peptides, in accordance with our computational results. The presence of two consecutive homochiral β N-O turns leads to the formation of β N-O helical structures in solution, although both helical (composed of two β N-O turns of the same handedness) and reverse-turn (composed of two β N-O turns with opposite handedness) structures are of similar stability, as suggested by theoretical studies. Nevertheless, two slightly different conformations, with the same handedness, of β2-aminoxy monomers have been observed in the solid state and in solution according to our X-ray and 2D NOESY studies.
- Jiao, Zhi-Gang,Chang, Xiao-Wei,Ding, Wei,Liu, Guo-Jun,Song, Ke-Sheng,Zhu, Nian-Yong,Zhang, Dan-Wei,Yang, Dan
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supporting information; experimental part
p. 1791 - 1799
(2012/02/02)
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- PROCESS FOR PRODUCING ALISKIREN
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A new route of synthesis of the compound Aliskiren of formula (I), used in the treatment of hypertension, is described.
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Page/Page column 24
(2011/12/14)
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- Total synthesis of "Aliskiren": The first renin inhibitor in clinical practice for hypertension
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We report a "macrocycle route" toward aliskiren, a drug presently marketed for the treatment of hypertension, using a highly stereocontrolled approach starting from a common "isopropyl chiron". Highlights of the synthesis include a challenging RCM reaction to produce a nine-membered unsaturated lactone, a highly stereoselective catalytic Du Bois aziridination, and a regio- and diastereoselective aziridine ring-opening to a vicinal amino alcohol.
- Hanessian, Stephen,Guesne, Sebastien,Chenard, Etienne
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supporting information; scheme or table
p. 1816 - 1819
(2010/09/16)
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- Process and intermediates for the preparation of aliskiren
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The present invention relates to a process and intermediates for the manufacture of aliskiren or pharmaceutically acceptable salts thereof.
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Page/Page column 22; 23
(2010/06/15)
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- Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues
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Subtle exchange: Replacement of an amide function with alkene or fluoroalkene groups provides a new class of epoxidation catalysts (see scheme). The structure-dependent catalytic behavior of these isosteric peptides provides mechanistic insights in their mode of action. (Chemical Equation Presented).
- Jakobsche, Charles E.,Peris, Gorka,Miller, Scott J.
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supporting information; experimental part
p. 6707 - 6711
(2009/03/12)
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- P3 cap modified Phe*-Ala series BACE inhibitors
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With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3 NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC50 50 ～1 μM).
- Chen, Shu-Hui,Lamar, Jason,Guo, Deqi,Kohn, Todd,Yang, Hsiu-Chiung,McGee, James,Timm, David,Erickson, Jon,Yip, Yvonne,May, Patrick,McCarthy, James
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p. 245 - 250
(2007/10/03)
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- Stereoselective Conjugate Addition of Organoaluminum Chlorides to α,β-Unsaturated Carboxylic Acid Derivatives
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Organoaluminum chlorides react smoothly with α,β-unsaturated N-acyloxazolidinones providing chiral β-branched carboxylic acid derivatives.An unexpected contrast between the mode of reaction of dimethylaluminum chloride and that of the higher homologues is observed.While diethylaluminum chloride and its higher homologues react with the acceptors at low temperature via a polar pathway, dimethylaluminum chloride requires activation by UV-light or radical initiation under otherwise identical conditions.With bicyclic oxazolidinones derived from galactosamine a high stereoselection is accomplished in the formation of the branched carboxylic acid derivative.
- Rueck, Karola,Kunz, Horst
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p. 1018 - 1028
(2007/10/02)
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- The Asymmetric Synthesis of α-Amino and α-Hydrazino Acid Derivatives via The Stereoselective Amination of Chiral Enolates with Azodicarboxylate Esters.
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The utility of azodicarboxylate esters as (+)NH2 and (+)NH-NH2 synthons in highly diastereoselective reactions with chiral carboximide-derived enolates has been demonstrated.The lithium enolates derived from 4-substituted N-acyl 2-oxazolidinones were found to react with di-tert-butyl azodicarboxylate (DBAD) to afford the derived 2-hydrazido carboxylic acid derivetives in yields in excess of 90 percent.The diastereoselectivities of these reactions ranged from 97percent to greater than 99percent.The subsequent transformation of these adducts to both α-hydrazino and α-amino acids in enantiomeric purities in excess of 99percent is described.
- Evans, David A.,Britton, Thomas C.,Dorow, Roberta L.,Dellaria, Joseph F.
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p. 5525 - 5540
(2007/10/02)
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- ASYMMETRIC HALOGENATION OF CHIRAL IMIDE ENOLATES. A GENERAL APPROACH TO THE SYNTHESIS OF ENANTIOMERICALLY PURE α-AMINO ACIDS.
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The chiral N-acyl oxazolidones 2, as the derived dibutyl boron enolates, have been demonstrated to undergo diastereoselective bromination and subsequent azide displacement to give the α-azido carboximides 4a (5 cases).These adducts may be hydrolyzed under mild conditions to the enantiomerically pure α-azido carboxylic acids 5a.
- Evans, David A.,Ellman, Jon A.,Dorow, Roberta L.
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p. 1123 - 1126
(2007/10/02)
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