- An efficient, practical approach to the synthesis of 2,4-disubstituted thiazoles and oxazoles: Application to the synthesis of GW475151
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GlaxoWellcome Research and Development, Chemical Development Division, Medicines Research Centre,. A new method for the synthesis of 2,4-disubstituted oxazoles and thiazoles and 2,4,5-trisubstituted oxazoles from readily available starting materials is described. The methodology has been applied on multigram scale and involves transfer of oxidation state through a molecular framework. In particular the oxazole-containing amino acid fragment of the 5,5-transfused lactam GW475151, 1, has been prepared in excellent yield and purity.
- Hermitage, Stephen A.,Cardwell, Kevin S.,Chapman, Tim,Cooke, Jason W. B.,Newton, Rebecca
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- A new method for the formation of 2,4-disubstituted oxazoles: Internal transfer of oxidation state through a molecular framework
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A new method for the synthesis of 2,4-disubstituted oxazoles is described from readily available starting materials. The synthesis avoids the necessity for the oxidation of an oxazoline to an oxazole by utilising an internal transfer of oxidation state across a molecular framework and has been performed on multigram scale. (C) 2000 Elsevier Science Ltd.
- Cardwell, Kevin S.,Hermitage, Stephen A.,Sjolin, Asa
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- Facile synthesis of autophagonizer and evaluation of its activity to induce autophagic cell death in apoptosis-defective cell line
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Some cancer cells are resistant to apoptosis, rendering them irresponsive towards apoptosis-inducing chemotherapy drugs. Another mode of action to kill these apoptosis-defective cells is essential and autophagy, a dynamic process that degrades cytoplasmic contents for cellular maintenance, has been considered as one of the alternate routes. A small molecule inducer of autophagy, autophagonizer was reported to induce cell death through a novel process that is independent of extrinsic apoptosis and the normal signaling pathways of autophagy. Here, we describe an efficient synthetic procedure for the autophagonizer. The newly synthesized autophagonizer (DK-1-49) resulted in an accumulation of autophagy-associated LC3-II and enhanced levels of autophagosomes and acidic vacuoles. Furthermore, cell viability was inhibited by autophagic cell death in not only human cancer cells but also Bax/Bak double-knockout cells. These findings highlight that intrinsic apoptosis is not also involved in the induction of cellular death by the autophagonizer suggesting the autophagonizer is a promising candidate for anticancer therapeutics for cancer cells that are resistant to apoptosis-inducing chemotherapy.
- Nguyen, Jennifer,Chen, Luxi,Kumar, Dhiraj,Lee, Jiyong
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Read Online
- MACROCYCLIC FUSED PYRRAZOLES AS MCL-1 INHIBITORS
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Provided are compounds represented by Formula IA: (IA), and the pharmaceutically acceptable salts and solvates thereof, wherein R, R 1a, R 1b, L 1, L 2, L 3, X, A, B and C are as defined as set forth
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Paragraph 0956
(2020/08/13)
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- HETEROCYCLIC MITOCHONDRIAL ACTIVITY INHIBITORS AND USES THEREOF
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Heterocyclic compounds of Formula (I) and pharmaceutically acceptable salt thereof are disclosed. The use of such heterocyclic compounds and pharmaceutically acceptable salt thereof for the treatment of cancers, and more particularly cancers sensitive to mitochondrial activity inhibition and increased reactive oxygen species (ROS) levels, is also disclosed. Such cancers include acute myeloid leukemia (AML), preferably AML characterized by certain features, such as high level of expression of one or more Homeobox (HOX)-network genes, high and/or low expression of specific genes, the presence of one or more cytogenetic or molecular risk factors such as intermediate cytogenetic risk, Normal Karyotype (A/K), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8) and/or abnormal chromosome (5/7), and/or a high leukemic stem cell (LSC) frequency.
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Page/Page column 148
(2019/05/22)
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- N-[2-(3-AMINO-2,5-DIMETHYL-1,1-DIOXIDO-5,6-DIHYDRO-2H-1,2,4-THIADIAZIN-5-YL)-1,3-THIAZOL-4-YL] AMIDES USEFUL AS BACE INHIBITORS
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The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, wherein the variables R1, R2 and R3/su
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Page/Page column 62; 63
(2017/04/11)
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- N-[2-(2-AMINO-6,6-DISUBSTITUTED-4, 4A, 5, 6-TETRAHYDROPYRANO [3,4-D][1,3] THIAZIN-8A (8H)-YL) -1, 3-THIAZOL-4-YL] AMIDES
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The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variables R1, R2 and R3
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Page/Page column 104; 105
(2017/04/11)
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- Development of a practical and scalable route for the preparation of the deacetoxytubuvaline (dTuv) fragment of pretubulysin and analogs
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We present herein a novel and convenient route for the scaling-up of the dTuv fragment of pretubulysin. The newly conceived chemical path involves a practical and efficient one-step procedure for the preparation of a key thiazole intermediate, followed by high-yielding Wittig olefination/reduction steps. The optimized route, starting from the inexpensive and non-toxic l-cysteine, encompasses five synthetic steps and only two chromatographic purifications, thus displaying a dramatically increased overall yield. The versatility of the proposed approach also provides new hints for the exploration of pretubulysin derivatives bearing diverse heterocyclic portions.
- Brindisi, Margherita,Maramai, Samuele,Grillo, Alessandro,Brogi, Simone,Butini, Stefania,Novellino, Ettore,Campiani, Giuseppe,Gemma, Sandra
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supporting information
p. 920 - 923
(2016/02/05)
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- 2-AMINO-6-METHYL-4,4a,5,6-TETRAHYDROPYRANO[3,4-d][1,3]THIAZIN-8a(8H)-YL-1,3-THIAZOL-4-YL AMIDES
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The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variable R1 is as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
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Page/Page column 75; 76
(2015/11/17)
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- Incorporation of heterocycles into the backbone of peptoids to generate diverse peptoid-inspired one bead one compound libraries
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Combinatorial libraries of peptoids (oligo-N-substituted glycines) have proven to be useful sources of protein ligands. Each unit of the peptoid oligomer is derived from 2-haloacetic acid and a primary amine. To increase the chemical diversity available in peptoid libraries, we demonstrate here that heterocyclic halomethyl carboxylic acids can be employed as backbone building blocks in the synthesis of peptoid-based oligomers. Optimized conditions are reported that allow the creation of large, high quality combinatorial libraries containing these units.
- Aditya, Animesh,Kodadek, Thomas
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scheme or table
p. 164 - 169
(2012/05/19)
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- Total synthesis of (-)-virginiamycin m2: Application of crotylsilanes accessed by enantioselective Rh(II) or Cu(I) promoted carbenoid Si-H insertion
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A stereoselective synthesis of the antibiotic (-)-virginiamycin M 2 is detailed. A convergent strategy was utilized that proceeded in 10 steps (longest linear sequence) from enantioenriched silane (S)-15. This reagent, which was prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si-H insertion, was used to introduce the desired olefin geometry and stereocenters of the C1-C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-mediated alkyne-alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,-E)-diene. An underutilized late-stage SmI2-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural product (Figure presented).
- Wu, Jie,Panek, James S.
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scheme or table
p. 9900 - 9918
(2012/03/08)
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- FARNESOID X RECEPTOR AGONISTS
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The present invention relates to famesoid X receptors (FXR, NR1H4) FXR is a member of the nuclear receptor class of ligand-activate transcription factors More particularly, the present invention relates to compounds useful as agonists for FXR, pharmaceutical formulations comprising such compounds, and therapeutic use of the same Novel isoxazole compounds are disclosed as part of pharmaceutical compositions for the treatment of a condition mediated by decreased FXR activity, such as obesity, diabetes, cholestatic liver disease, liver fibrosis, and metabolic syndrome
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Page/Page column 225-226
(2009/03/07)
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- Chemical Compounds
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This invention relates to non-steroidal compounds that are modulators of androgen, glucocorticoid, mineralocorticoid, and progesterone receptors, and also to the methods for the making and use of such compounds.
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Page/Page column 48
(2009/07/17)
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- DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS
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The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
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Page/Page column 169
(2009/10/09)
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- Samarium Barbier reactions of α-iodomethyloxazoles and thiazoles with aliphatic aldehydes
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(Chemical Equation Presented) The reductive coupling of substituted α-iodomethyloxazoles and thiazoles with aliphatic aldehydes under Barbier conditions provides an effective method for the direct incorporation of intact heterocyclic systems.
- Williams, David R.,Berliner, Martin A.,Stroup, Bryan W.,Nag, Partha P.,Clark, Michael P.
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p. 4099 - 4102
(2007/10/03)
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- Total synthesis of pristinamycin II(B)
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An intramolecular Takai reaction of the iodoaldehyde 4a proceeded with a moderate efficiency to give the macrocyclic hydroxy compound 1b, identified to an authentic sample.
- Breuilles,Uguen
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p. 3149 - 3152
(2007/10/03)
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