- COMPOUNDS FOR TREATING FAMILIAL DYSAUTONOMIA
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The present description relates to compounds useful for improving pre-mRNA splicing in a cell. In particular, another aspect of the present description relates to substituted thieno [3,2-d]pyrimidine compounds, forms, and pharmaceutical compositions there
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- Cobalt-Catalyzed Desymmetric Isomerization of Exocyclic Olefins
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Chiral cyclic olefins, 1-methylcyclohexenes, are versatile building blocks for the synthesis of pharmaceuticals and natural products. Despite the prevalence of these structural motifs, the development of efficient synthetic methods remains an unmet challenge. Herein we report a novel desymmetric isomerization of exocyclic olefins using a series of newly designed chiral cobalt catalysts, which enables a straightforward construction of chiral 1-methylcyclohexenes with diversified functionalities. The synthetic utility of this methodology is highlighted by a concise and enantioselective synthesis of a natural product, β-bisabolene. The versatility of the reaction products is further demonstrated by multifarious derivatizations.
- Lan, Yu,Liu, Qiang,Liu, Shihan,Liu, Xufang,Rong, Xianle
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p. 20633 - 20639
(2021/12/17)
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- Synthesis method for tert-butyl 1,2,3-oxathiazolidine-3-carboxylic ester 2,2-dioxide compound
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The invention relates to a synthesis method for a tert-butyl 1,2,3-oxathiazolidine-3-carboxylic ester 2,2-dioxide compound. The tert-butyl 1,2,3-oxathiazolidine-3-carboxylic ester 2,2-dioxide compoundhas a structural formula as shown in a formula I which is described in the specification. The synthesis method comprises the step of allowing a compound as shown in a formula II which is described inthe specification with sulfonyl chloride in the presence of an organic solvent to generate the compound as shown in the formula I. The structural formula of the compound as shown in the formula I andthe structural formula of the compound as shown in the formula II are described in the specification. The synthesis method disclosed by the invention is simple to operate; compared with a conventional published two-step method, the synthesis method provided by the invention only needs one step; and the synthesis method is more convenient, reduces byproducts, is high in yield, does not need to usea catalyst and a highly-toxic substance in the reaction, and is safe and low in cost.
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Paragraph 0041-0047; 0083-0089
(2020/07/13)
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- COMPOUNDS AND METHOD OF USE
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This present disclosure relates to compounds with ferroptosis inducing activity, a method of treating a subject with cancer with the compounds, and combination treatments with a second therapeutic agent.
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- Discovery of N-Substituted 3-Amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic Acids as Highly Potent Third-Generation Inhibitors of Human Arginase i and II
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Recent efforts to identify new highly potent arginase inhibitors have resulted in the discovery of a novel family of (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid analogues with up to a 1000-fold increase in potency relative to the current standards, 2-amino-6-boronohexanoic acid (ABH) and N-hydroxy-nor-l-arginine (nor-NOHA). The lead candidate, with an N-2-amino-3-phenylpropyl substituent (NED-3238), example 43, inhibits arginase I and II with IC50 values of 1.3 and 8.1 nM, respectively. Herein, we report the design, synthesis, and structure-activity relationships for this novel series of inhibitors, along with X-ray crystallographic data for selected examples bound to human arginase II.
- Van Zandt, Michael C.,Jagdmann, G. Erik,Whitehouse, Darren L.,Ji, Minkoo,Savoy, Jennifer,Potapova, Olga,Cousido-Siah, Alexandra,Mitschler, Andre,Howard, Eduardo I.,Pyle, Anna Marie,Podjarny, Alberto D.
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p. 8164 - 8177
(2019/10/02)
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- Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)
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The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
- Ward, Richard A.,Anderton, Mark J.,Bethel, Paul,Breed, Jason,Cook, Calum,Davies, Emma J.,Dobson, Andrew,Dong, Zhiqiang,Fairley, Gary,Farrington, Paul,Feron, Lyman,Flemington, Vikki,Gibbons, Francis D.,Graham, Mark A.,Greenwood, Ryan,Hanson, Lyndsey,Hopcroft, Philip,Howells, Rachel,Hudson, Julian,James, Michael,Jones, Clifford D.,Jones, Christopher R.,Li, Yongchao,Lamont, Scott,Lewis, Richard,Lindsay, Nicola,McCabe, James,McGuire, Thomas,Rawlins, Philip,Roberts, Karen,Sandin, Linda,Simpson, Iain,Swallow, Steve,Tang, Jia,Tomkinson, Gary,Tonge, Michael,Wang, Zhenhua,Zhai, Baochang
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p. 11004 - 11018
(2019/12/02)
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- Nucleophilic Trifluoromethylthiolation of Cyclic Sulfamidates: Access to Chiral β- And γ-SCF3 Amines and α-Amino Esters
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The regio- and stereoselective ring opening of 1,2- and 1,3-sulfamidates with trifluoromethanethiolate anion is reported. This direct introduction of the whole SCF3 motif is a straightforward synthetic route toward β- and γ-SCF3 amines and α-amino acid derivatives. The utility of this reaction was further illustrated by incorporation of Cys(S-CF3) into di- and tripeptides.
- Zeng, Jun-Liang,Chachignon, Hélène,Ma, Jun-An,Cahard, Dominique
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p. 1974 - 1977
(2017/04/27)
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- DIHYDROPYRROLOPYRAZINONE DERIVATIVES USEFUL IN THE TREATMENT OF CANCER
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The invention concerns compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R1 has any of the meanings hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and t
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- DIHYDROIMIDAZOPYRAZINONE DERIVATIVES USEFUL IN THE TREATMENT OF CANCER
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The present disclosure concerns compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R1, R2 and R3 have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cancer.
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- Total Synthesis and Stereochemical Revision of the Anti-Tuberculosis Peptaibol Trichoderin A
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The first total synthesis of the postulated structure of the aminolipopeptide trichoderin A and its epimer are reported. A late-stage solution phase C-terminal coupling was employed to introduce the C-terminal aminoalcohol moiety. This methodology provides a foundation to prepare analogues of trichoderin A to establish a structure-activity relationship. NMR spectroscopic analysis established that the C-6 position of the 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue in trichoderin A possesses an (R)-configuration as opposed to the originally proposed (S)-configuration.
- Kavianinia, Iman,Kunalingam, Lavanya,Harris, Paul W. R.,Cook, Gregory M.,Brimble, Margaret A.
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p. 3878 - 3881
(2016/08/16)
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- SUBSTITUTED 3,4-DIHYDROPYRROLO[1,2-A]PYRAZIN-1 (2H)-ONE DERIVATIVES AS KINASE INHIBITORS
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Compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R1, R2, R3, R4, R5 and R6 have any of the meanings defined hereinbefore in the description, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cancer are disclosed.
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- Copper-catalysed cross-coupling affected by the Smiles rearrangement: A new chapter on diversifying the synthesis of chiral fluorinated 1,4-benzoxazine derivatives
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Synthesis of different chiral fluorinated Boc-[1,4]benzoxazins from their open chain precursors were investigated. The NMR spectra and crystallographic data showed the presence of the Smiles Rearrangement (SR) followed by copper catalysed coupling. The in
- Alapour, Saba,Ramjugernath, Deresh,Koorbanally, Neil A.
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p. 83576 - 83580
(2015/10/28)
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- Ionic liquid crystals derived from amino acids
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Novel chiral amino acid derived ionic liquid crystals with amine and amide moieties as spacers between the imidazolium head group and the alkyl chain were synthesised. The key step in the synthesis utilised the relatively uncommon SO3 leaving group in a microwave-assisted reaction. The mesomorphic properties of the mesogens were determined by differential scanning calorimetry (DSC), polarising optical microscopy (POM) and X-ray diffraction. All liquid crystalline salts exhibit a smecticA mesophase geometry with strongly interdigitated bilayer structures. An increase of the steric bulk of the stereogenic centre hindered the formation of mesophases. In case of phenylalanine-derived derivatives a mesomorphic behaviour was observed for shorter alkyl chains as compared to other amino acid derivatives indicating an additional stabilising effect by the phenyl moiety. Ionic liquid crystals from amino acids: Novel chiral amino acid derived imidazolium salts with amine or amide units were prepared through the sulfamidate. Depending on the steric bulk of the R group, the chain lengths and the type of anion X, stable SmA phases were detected (see scheme; Bn=benzyl). Copyright
- Mansueto, Markus,Frey, Wolfgang,Laschat, Sabine
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supporting information
p. 16058 - 16065
(2014/04/03)
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- Catalytic asymmetric alkylation reactions for the construction of protected ethylene-amino and propylene-amino motifs attached to quaternary stereocentres
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An efficient catalytic and stereoselective method for the direct construction of protected ethylene-amino and propylene-amino scaffolds attached to quaternary stereocentres is reported. Preliminary investigations revealed a mild base catalysed nucleophilic ring opening of N-sulfonyl aziridines using the commercially available phosphazene base 2-tert-butylimino-2-diethylamino-1,3- dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) was possible and resulted in highly efficient alkylation reactions with a range of methine carbon acids. This reaction could be rendered highly asymmetric (up to 97 % ee) by employing phase-transfer catalysis to control stereoinduction. Incorporation of alkyl substituents onto the aziridine electrophile, resulted in a highly diastereoselective (up to 30:1 d.r.) variant of this methodology. A further extension using N-protected cyclic sulfamidates as the electrophilic component was successful with a range of pro-nucleophiles (up to 96 % ee and 45:1 d.r.) and allowed a range of nitrogen protecting groups (carbamate, sulfonyl, phosphonyl, benzyl) to be incorporated into the alkylation adducts. Finally, the utility of the products have been demonstrated in the synthesis of useful heterocycles and compounds bearing structural components of natural products. Open sesame: The enantio- and diastereoselective nucleophilic ring opening of protected aziridines and cyclic sulfamidates using asymmetric phase-transfer catalysis (PTC) is reported. The ring-opening alkylation reactions create quaternary chiral centres containing ethylene- and propylene-amino motifs in good yields with good to excellent enantioselectivities (see scheme). These reactions are broad in scope and a wide range of pro-nucleophiles are tolerated. Copyright
- Moss, Thomas A.,Barber, David M.,Kyle, Andrew F.,Dixon, Darren J.
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supporting information
p. 3071 - 3081
(2013/03/28)
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- The first synthesis of β-amino phosphonates using cyclic sulfamidates
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Cyclic sulfamidates (prepared from α-amino acids and β-amino alcohols) have been used for the first time for the synthesis of novel β-amino phosphonates (chiral and achiral) by treatment with dialkyl phosphites using sodium hydride. 2-Substituted and 1,2-disubtituted β-amino phosphonates have efficiently been prepared following this method. The products are formed in high yield (79-84%) within 8-12 h.
- Das, Biswanath,Reddy, Cheruku Ravindra,Nagendra, Siddavatam,Lingaiah, Maram
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p. 3496 - 3498
(2011/07/08)
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- Ring opening of cyclic sulfamidates with bromophenyl metal reagents: Complementarity of sulfamidates and aziridines
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Bromophenyl magnesium reagents generated via a Knochel type magnesium-halogen exchange of aryl iodides undergo regioselective ring opening of cyclic primary and secondary N-Boc sulfamidates in good to excellent yields. With secondary sulfamidates the reaction proceeds with clean inversion of the stereochemistry. This protocol complements the ring opening of aziridines with bromophenyl metal reagents and extends its scope to secondary substrates.
- Hebeisen, Paul,Weiss, Urs,Alker, André,Staempfli, Andreas
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p. 5229 - 5233
(2011/10/31)
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- Catalytic enantio- and diastereoselective alkylations with cyclic sulfamidates
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(Figure Presented) Open for business: The enantio- and diastereoselective nucleophilic ring opening of five-membered and six-membered cyclic sulfamidates under asymmetric phase-transfer catalysis is presented. A range of pro-nucleophiles have been successfully alkylated in good yields and in good to excellent enantioselectivites.
- Moss, Thomas A.,Alonso, Beatriz,Fenwick, David R.,Dixon, Darren J.
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supporting information; experimental part
p. 568 - 571
(2010/04/05)
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- NOVEL MICROBIOCIDES
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Compounds of the formula (I), in which the substituents are as defined in claim 1 are suitable for use as microbiocides.
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Page/Page column 41
(2009/03/07)
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- Combinatorial synthesis of functionalized chiral and doubly chiral ionic liquids and their applications as asymmetric covalent/non-covalent bifunctional organocatalysts
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A facile combinatorial strategy was developed for the construction of libraries of functionalized chiral ionic liquids (FCILs) including doubly chiral ionic liquids and bis-functional chiral ionic liquids. These FCIL libraries have the potential to be use
- Zhang, Long,Luo, Sanzhong,Mi, Xueling,Liu, Song,Qiao, Yupu,Xu, Hui,Cheng, Jin-Pei
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supporting information; experimental part
p. 567 - 576
(2008/10/09)
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- Enantiopure 1,4-benzoxazines via 1,2-cyclic sulfamidates. Synthesis of levofloxacin
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1,2-Cyclic sulfamidates undergo efficient and regiospecific nucleophilic cleavage with 2-bromophenols (and related anilines and thiophenols), followed by Pd(0)mediated amination to provide an entry to substituted and enantiomerically pure 1,4-benzoxazines (and quinoxalines and 1,4-benzothiazines). This chemistry provides a short and efficient entry to (3S)-3-methyl-1,4-benzoxazine 19, a late stage intermediate in the synthesis of levofloxacin.
- Bower, John F.,Szeto, Peter,Gallagher, Timothy
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p. 3283 - 3286
(2008/02/12)
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- DIPEPTIDYL PEPTIDASE-IV INHIBITORS
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The present invention relates generally to pyrrolidine and thiazolidine DPP-IV inhibitor compounds. The present invention also provides synthetic methods for preparation of such compounds, methods of inhibiting DPP-IV using such compounds and pharmaceutical formulations containing them for treatment of DPP-IV mediated diseases, in particular, Type-2 diabetes.
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Page/Page column 69-70
(2008/06/13)
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- 5-HT2C receptor agonists for the treatment of obesity. Biological and chemical adventures
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Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. There is increasing evidence suggesting an important role for the 5-HT 2C receptor in appetite control. Collaboration between F. Hoffmann-La Roche Ltd and Vernalis Research Ltd has allowed rapid construction of a solid structure-activity relationship around a pyrroloindole core. A one-pot Sonogashira reaction followed by nucleophilic double cyclisation allows an elegant and expedient route to this central motif. Introduction of a (2S)-aminopropyl group in place of the aminoethyl endogenous ligand side-chain enhanced the affinity at the 5-HT2C receptor and reduced affinity towards monoamine oxidase enzymes (MAO). Sulfamidate reagents were found to be very effective for the introduction of the 2-aminopropyl moiety in a stereoselective manner. The substitution at position 5 (indole numbering) was found to be crucial for both affinity and selectivity. Pyrroloindoles bearing an alkoxyether in this position exhibit promising pharmacokinetic parameters in rodent and significant reduction of food intake, after per os application.
- Adams, David,Benardeau, Agnes,Bickerdike, Mike J.,Bentley, Jon M.,Bissantz, Caterina,Bourson, Anne,Cliffe, Ian A.,Hebeisen, Paul,Kennett, Guy A.,Knight, Antony R.,Malcolm, Craig S.,Mizrahi, Jacques,Plancher, Jean-Marc,Richter, Hans,Roever, Stephan,Taylor, Sven,Vickers, Steven P.
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p. 613 - 620
(2007/10/03)
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- New routes to N-alkylated cyclic sulfamidates
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BOC- and dibenzosuberyl-protected chiral and hindered cyclic sulfamidates ([1,2,3]-oxathiazolidine-2,2-dioxides) were synthesized and subsequently deprotected using trifluoroacetic acid. The resulting crystalline sulfamidates were then used in several alk
- Posakony, Jeffrey J.,Grierson, John R.,Tewson, Timothy J.
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p. 5164 - 5169
(2007/10/03)
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- Aza- indolyl derivatives for treating obesity
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Novel compounds of formula (I): wherein X1, X2, X3 and X4, n, R1, R2 and R3 are defined in the specification, and pharmaceutically acceptable salts and prodrugs of the compounds of formula (I) have therapeutic uses. These compounds are useful for the treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus, and sleep apnea. They are particularly useful for the treatment of obesity.
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