- PCSK9 INHIBITORS AND METHODS OF USE THEREOF
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The invention relates to a novel inhibitor pharmacophore of PCSK9 and heteroaryl compounds that bind the PCSK9 protein.
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Page/Page column 146-147
(2020/07/31)
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- PCSK9 INHIBITORS AND METHODS OF USE THEREOF
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The invention relates to novel heteroaryl compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cardiovascular diseases, and methods treating sepsis or septic shock, using the novel heterocyclic compounds disclosed herein.
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Page/Page column 145-146
(2020/07/31)
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- Novel spirocyclic systems via multicomponent aza-Diels-Alder reaction
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Here we present a two-step diastereoselective methodology building on a multicomponent aza-Diels-Alder reaction. Using previously unexplored cyclic ketones, heterocyclic amines and cyclopentadiene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between drug-like molecules and natural products.
- Llona-Minguez, Sabin,Throup, Adam,Steiner, Emilie,Lightowler, Molly,Van Der Haegen, Sandra,Homan, Evert,Eriksson, Lars,Stenmark, P?l,Jenmalm-Jensen, Annika,Helleday, Thomas
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supporting information
p. 7758 - 7764
(2017/10/06)
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- The preparation of several 1,2,3,4,5-functionalized cyclopentane derivatives
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With the goal of eventually synthesizing [5]radialene (3), the still missing member of the parent radialene hydrocarbons, we have prepared the pentaacetates 21 and 31, the pentabromide 29 and the hexabromide 32. In principle these should be convertible by elimination reactions to the desired target molecule.
- Kelch, Andre S.,Jones, Peter G.,Dix, Ina,Hopf, Henning
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p. 1705 - 1712
(2013/10/22)
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- N-O bond as a glycosidic-bond surrogate: Synthetic studies toward polyhydroxylated N-alkoxypiperidines
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A series of novel polyhydroxylated N-alkoxypiperidines has been synthesized by ring-closing double reductive amination (DRA) of highly functionalized 1,5-dialdehydes with various hydroxylamines. The required saccharide-based dialdehydes were prepared efficiently from sodium cyclopentadienylide in seven steps. A two-step protocol has been developed for the DRA; it led, after deprotection, to isofagomine, 3-deoxyisofagomine, and numerous other N-alkoxy analogues. The barrier to inversion in these polyhydroxylated N-alkoxypiperidine derivatives was found by variable-temperature NMR methods to be approximately 15 kcal mol-1. With the exception of N-hydroxyisofagomine itself, none of the compounds prepared showed significant inhibitory activity against sweet almond β-glucosidase. Copyright
- Malik, Ga?lle,Ferry, Angélique,Guinchard, Xavier,Cresteil, Thierry,Crich, David
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supporting information
p. 2168 - 2179
(2013/03/29)
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- Cis,cis,cis,cis-1,2,3,4,5-Pentakis(hydroxymethyl)cyclopentane
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All-cis pentamethanolcyclopentane has been obtained in six steps by Diels-Alder condensation of maleic anhydride with (benzyloxymethyl)cyclopenta-2, 4-diene, reduction of the anhydride to a diol that was protected as the acetonide. Then, ozonolysis of the double bond, followed by reduction led to a cis-diol. Then successive deprotections of the three other methanol groups gave the cis,cis,cis,cis-1,2,3,4,5-pentakis(hydroxymethyl)cyclopentane.
- Pujol, Adeline R.,Ratel-Ramond, Nicolas,Gourdon, André
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p. 9139 - 9144
(2013/09/24)
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- Asymmetric synthesis of polyhydroxylated N -alkoxypiperidines by ring-closing double reductive amination: Facile preparation of isofagomine and analogues
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A de novo synthesis of novel polyhydroxylated N-alkoxypiperidines based on the ring-closing double reductive amination of 1,5-dialdehydes, obtained by oxidative cleavage of cyclopentene derivatives, with O-substituted hydroxylamines is reported. Isofagomine was accessed by cleavage of the N-O bond of an N-alkoxypiperidine.
- Malik, Gaelle,Guinchard, Xavier,Crich, David
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supporting information; experimental part
p. 596 - 599
(2012/02/16)
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- Synthesis of 2′,3′-modified carbocyclic L -nucleoside analogues
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New divergent approaches to 2′,3′-modified carbocyclic L-nucleoside analogues starting from enantiomerically pure (1R,2S)- or (1S,2R)-2-(benzyloxymethyl)cyclopent-3-enol are described. In the key step, stereochemically pure cyclopentanols were condensed with N3-protected thymine through a modified Mitsunobu protocol. Moreover, several routes to different cyclopentanol derivatives, to prepare carbocyclic L-2′,3′-didehydro- 2′,3′-dideoxynucleosides (L-d4N), L-2′,3′- dideoxynucleosides (L-ddN), and L-ribonucleosides are reported. Copyright
- Jessel, Soenke,Meier, Chris
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experimental part
p. 1702 - 1713
(2011/05/04)
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- Synthesis of [13C4]Baraclude (entecavir)
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Entecavir, labeled as 1H-[13C4]purin-6(9H)-one, was prepared from commercially available [13C]guanidine HCl, 1 and diethyl [1,2,3-13C3]malonate, 2. The reagents were condensed together to give 2-amino-4,6-dichloro[2,4,5,6-13C 4]pyrimidine 3, which in turn was coupled to an optically active amino cyclopentanol derivative, 9. A further sequence of eight reaction steps completed the constructions of the purine ring system and the exocyclic olefin attachment on the cyclic pentyl portion, 18. The removal of the methoxide and benzyl protecting groups gave [13C4]entecavir, 20 in an overall yield of 6.8%. The chemical purity of the title compound was determined by HPLC to be 99.23%. The percent isotopic [13C4] abundance was found by mass spectral analysis to be 96.7%. No detectable level of the unlabeled entecavir was found by LC-MS analysis. Copyright
- Tran, Scott B.,Ekhato, Ihoezo V.,Rinehart, J. Kent
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scheme or table
p. 485 - 489
(2010/07/04)
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- Cyclopentane-nucleobase coupling in the synthesis of carbocyclic L-nucleosides: Is a SN2-reaction an alternative to the mitsunobu-reaction?
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Several carbocyclic L-nucleosides have been synthesized by coupling a cyclopentane-system with heterocycles according to a modified Mitsunobu-protocol. This reaction gave two regioisomers, the N1-alkylated product and an unwanted O2-product. A simple SN2-reaction has been investigated as an alternative for such couplings. Copyright Taylor & Francis Group, LLC.
- Jessel,Hense,Meier
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p. 1181 - 1184
(2008/09/17)
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- Chemo-enzymatic synthesis of tetra-N-acetyl-chitotetraosyl allosamizoline
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A new compound 7, possessing a tetra-N-acetyl-chitotetraosyl moiety as a constituent, was synthesized by bacterial fermentation which used allosamizoline 6 as the initial acceptor.
- Huang, Gang-Liang,Mei, Xin-Ya,Zhang, Hou-Cheng,Wang, Peng-George
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p. 2860 - 2861
(2008/09/20)
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- New convergent synthesis of carbocyclic nucleoside analogues
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Two convergent approaches towards the synthesis of carbocyclic nucleoside analogs will be described. Both approaches start from the stereochemically pure cyclopentenol 8 that has been prepared enantioselectively from an alkylated cyclopentadiene. Using these approaches, carbocyclic analogues of dT, FdU and BVdU have been prepared. Moreover, the conversion into the cycloSalpronucleotide and the corresponding nucleotide will be presented for one example.
- Ludek, Olaf R.,Meier, Chris
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p. 2101 - 2109
(2007/10/03)
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- CARBOCYCLIC NUCLEOSIDE DERIVATIVES AS INHIBITORS OF RNA-DEPENDENT RNA VIRAL POLYMERASE
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The present invention provides carbocyclic nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such carbocyclic nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the carbocyclic nucleoside compounds of the present invention
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- Removal of pinanol via continuous steam distillation
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A practical procedure for the efficient removal of pinanol from the reaction mixture has been developed. The process was based on the observation that pinanol can be easily removed by steam distillation in the laboratory. On-scale, a continuous countercurrent column stripper was implemented to remove pinanol.
- Kotnis, Atul S.,Vanyo, Dale,Srivastava, Sushil,Singh, Ambarish K.,Bush, Joseph,Prasad, J. Siva,Kientzler, Donald C.,Delaney, Edward J.,Kiang, San
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p. 301 - 303
(2013/09/06)
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- Enantioselective approaches to aminocyclopentitols: A total synthesis of (+)-6-epitrehazolin and a formal total synthesis of (+)-trehazolin
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Potent inhibitors of trehalase, such as trehazolin and its congeners, represent an attractive approach to the design of effective new insect control agents. In this report, enantioselective total syntheses of (-)-6- epitrehazolin and (+)-trehazolin were achieved using the asymmetric heterocycloaddition between [(benzyloxy)methyl]cyclopentadiene and the acylnitroso compound arising from in situ oxidation of (S)-mandelohydroxamic acid with tetrabutylammonium periodate. Further functionalization of the resulting 3,4,5-trisubstituted cyclopentene, either involving osmylation or epoxidation of the double bond, efficiently created pentasubstituted cyclopentanes. Introduction of the quaternary carbon in both synthesis targets was achieved via stereoselective osmylation of an intermediate 2,3,4,5-substituted 1-methylenecyclopentane.
- Li, Jun,Lang, Fengrui,Ganem, Bruce
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p. 3403 - 3410
(2007/10/03)
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- Synthesis and anti-HIV activity of 9-[e-4,t-5-bis(hydroxymethyl)cyclopent- 2-en-r-1-yl]-9H-adenine
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The synthesis and in vitro anti-HIV activity of two new racemic nucleoside analogues are described; namely, 9-[c-4,t-5-bis(hydroxymethyl)cyclopent-2-en- r-1-yl]-9H-adenine (12) and its guanine analogue 18. While the latter (18) showed no activity, the therapeutic index of the former (12) was 200 and comparable to that (400) of carbovir. One enantiomer of 12 may be viewed as an analogue of carbocyclic oxetanocin and the other as an analogue of carbovir. Hence, these results indicate that one or both of the individual enantiomers of 12 could serve as candidates or lead compounds for the development of anti-AIDS agents.
- Katagiri,Nomura,Sato,Kaneko,Yusa,Tsuruo
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p. 1882 - 1886
(2007/10/02)
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- Use of Diethylaminosulphur Trifluoride (DAST) in the Preparation of Synthons of Carbocyclic Nucleosides
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Diethylaminosulphur trifluoride (DAST) converted the protected amino triol (4) into the fluorine-containing compounds (8) and (10).The same reagent converted the alcohol (9) into compounds (10), (5), and (11) and transformed the azido alcohol (15) into the fluoroazides (16) and (19).The fluorinated compounds (5), (8), and (16) are useful synthons for fluorocarbocyclic nucleosides.The effect of neighbouring groups on the course of some DAST reactions is discussed.
- Biggadike, Keith,Borthwick, Alan D.,Evans, Derek,Exall, Anne M.,Kirk, Barrie E.,et al.
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p. 549 - 554
(2007/10/02)
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- A Novel and Stereospecific Synthesis of (+/-)- and (-)-Aristeromycin
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A new, efficient synthetic route to (+/-)- and (-)-aristeromycin (1) has been developed which has as its key feature the cycloaddition of singlet oxygen to 5--1,3-cyclopentadiene (8) followed by in situ reduction to give ene diol 10.This reaction has been optimized and scaled-up to give 197 g (60percent) of partially purified 10.The key intermediate azide 15 was prepared from the partially purified 10 in 56percent yield by a three-step sequence of epoxidation to give 13, reaction with NaN3, and acetonation.Azide 15 was converted by standard chemistry via adenine intermediate 22 to (+/-)-aristeromycin (1) in 31percent overall yield.Intermediate 22 was also prepared in 25percent yield by a novel and shorter sequence which involved the reaction of epoxide 13 with the sodium salt of adenine and then acetonation.Alternatively, azide 15 was resolved by conversion to its naproxen ester 26, and the (-)-isomer of 15 was converted to the known amino triol 31, thus constituting a formal synthesis of (-)-aristeromycin.
- Madhavan, G. V. Bindu,Martin, John C.
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p. 1287 - 1293
(2007/10/02)
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