- Practical Synthesis of a 6-Triazolylazabicyclo[3.1.0]hexane
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We describe a practical, scalable synthesis of an advanced heterocyclic intermediate, (1R,5S,6s)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane. A robust synthetic sequence based on a Kulinkovich-de Meijere pyrroline cyclopropanation followed by tran
- Sirois, Lauren E.,Xu, Jie,Angelaud, Remy,Lao, David,Gosselin, Francis
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p. 728 - 735
(2018/06/26)
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- Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex- 3-yl)- N -hydroxypyrimidine-5-carboxamide (CHR-3996), a class i selective orally active histone deacetylase inhibitor
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A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.
- Moffat, David,Patel, Sanjay,Day, Francesca,Belfield, Andrew,Donald, Alastair,Rowlands, Martin,Wibawa, Judata,Brotherton, Deborah,Stimson, Lindsay,Clark, Vanessa,Owen, Jo,Bawden, Lindsay,Box, Gary,Bone, Elisabeth,Mortenson, Paul,Hardcastle, Anthea,Van Meurs, Sandra,Eccles, Suzanne,Raynaud, Florence,Aherne, Wynne
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p. 8663 - 8678
(2011/03/19)
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- 2-AMINO PYRIDINE COMPOUNDS
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The present invention is directed to 2-aminopyrimidine compounds and pharmaceutically acceptable salts thereof, their synthesis and their use as HSP-90 inhibitors.
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Page/Page column 77-79
(2008/12/05)
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- HISTONE DEACETYLASE INHIBITORS
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Compounds of formula: (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: (I) wherein Q, V and W independently represent -N= or -C=;
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Page/Page column 18; 29
(2010/11/25)
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- Mono- and disubstituted N,N-dialkylcyclopropylamines from dialkylformamides via ligand-exchanged titanium - Alkene complexes
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Dibenzylformamide was treated with cyclohexylmagnesium bromide in the presence of either titanium tetraisopropoxide or methyltitanium triisopropoxide and a variety of cyclic and acyclic alkenes and alkadienes to give new mono- and disubstituted as well as bicyclic dialkylcyclopropylamines (Tables 1-3) in yields ranging from 18 to 90% (in most cases around 55%). 3-Benzyl-6-(N,N-dibenzylamino)-3-azabicyclo[3.1.0]hexane (10a) and the orthogonally bisprotected 3-tert-butoxycarbonyl-6-(N,N-dibenzyl)- 3-azabicyclo[3.1.0]hexane (10d) as well as the analogous 6-(N,N-dibenzylamino)bicyclo[3.1.0]hexane (12) were obtained as pure exo diastereomers in particularly high yields (87, 90, and 88%, respectively) from N-benzylpyrroline (15a), N-Boc-pyrroline (15d; Boc = tert-butyloxycarbonyl) and cyclopentene (19). 1,3-Butadiene (52) and substituted 1,3-butadienes were also aminocyclopropanated quite well to give 2-ethenylcyclopropylamines in good yields (51-64%). Except for alkenyl and aryl-substituted compounds, N,N-dibenzylcyclopropylamines can be debenzylated by catalytic hydrogenation to the primary cyclopropylamines as demonstrated for 10a and 10d to yield the fully deprotected 10e (93%) and mono-Boc-protected 10f (98%), respectively. The latter are interesting templates for combinatorial syntheses of libraries of small molecules with a well defined distance of 4.3 A between two nitrogen atoms.
- De Meijere, Armin,Williams, Craig M.,Kourdioukov, Alexandre,Sviridov, Sergei V.,Chaplinski, Vladimir,Kordes, Markus,Savchenko, Andrei I.,Stratmann, Christian,Noltemeyer, Mathias
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p. 3789 - 3801
(2007/10/03)
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