- Synthesis of C-substituted cyclic amines using azacycloalkyl organozinc reagents
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Azetidine and piperidine derived organozinc species have been prepared from the corresponding azacycloalkyl iodides by direct Zn insertion. They have been shown to readily undergo Pd(0) mediated cross-coupling reactions and to transmetallate with CuCN.2LiCl.
- Billotte
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- One-pot synthesis of novel tert-butyl-4-substituted phenyl-1H-1,2,3-triazolo piperazine/piperidine carboxylates, potential GPR119 agonists
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We have synthesized a new series of 1,2,3-triazolo piperazine and piperidine carboxylate derivatives using a simple and one-pot click chemistry with significantly reduced reaction times (~5 min) and enhanced reaction yields (~95–98%). The fourteen novel compounds thus synthesized were tested for ability to target GPR119, a G-protein coupled target receptor that plays critical role in regulation of type-2 diabetes mellitus. Four analogs (3e, 3g, 5e and 5g) demonstrated similar or better EC50 values over previously reported AR231453 activity towards GPR119.
- Bashetti, Nagaraju,Shanmukha Kumar,Seelam, Naresh Varma,Prasanna,Mintz, Akiva,Damuka, Naresh,Devanathan, Sriram,Solingapuram Sai, Kiran Kumar
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- Design, synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging
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Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [125I]8 and [125I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [125I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [125I]11. Incubation of [125I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [125I]8. In biodistribution experiments using tumor-bearing mice, [125I]8 accumulation in the tumor 1 h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [125I]IIQP, used in our previous research. These results indicate that [125I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands.
- Effendi, Nurmaya,Mishiro, Kenji,Takarada, Takeshi,Yamada, Daisuke,Nishii, Ryuichi,Shiba, Kazuhiro,Kinuya, Seigo,Odani, Akira,Ogawa, Kazuma
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- Regioselective samarium diiodide induced couplings of carbonyl compounds with 1,3-diphenylallene and alkoxyallenes: A new route to 4-hydroxy-1-enol ethers
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Since its introduction into synthetic organic chemistry, samarium diiodide has found broad application in a variety of synthetically important transformations. Herein, we describe the first successful intermolecular additions of samarium ketyls to typical allenes such as 1,3-diphenylallene (7), methoxyallene (12) and benzyloxyallene (25). Reaction of different samarium ketyls with 1,3-diphenylallene (7) occurred exclusively at the central carbon atom of the allene to afford products 9 in moderate to good yields. In contrast, reductive coupling of cyclic ketones to methoxyallene (12) regioselectively provided 4-hydroxy-1-enol ethers 13, which derive from addition to the terminal allene carbon atom of 12, in moderate to good yields. Whereas the E/Z selectivity with respect to the enol ether double bond is low, excellent diastereoselectivity has been observed in certain cases with regard to the ring configuration (e.g. compound 13 b). Studies with deuterated tetrahydrofuran and alcohol were performed to gain information about the reaction mechanism of this coupling process, which involves alkenyl radicals. The couplings of samarium ketyls derived from acyclic ketones and aldehydes gave lower yields, and in several cases cyclopentanols 20 are formed as byproducts. Branched acyclic ketones and conformationally more flexible cyclic ketones such as cycloheptanone led to a relatively high amount of cyclopentanol derivatives 20, whose formation involves an intramolecular hydrogen atom transfer through a geometrically favoured six-membered transition state followed by a cyclization step. The samarium diiodide mediated addition of 8b to benzyloxyallene (25) afforded the expected enol ethers 26, albeit in only low yield. Additionally, spirocyclic compounds 27 and 28 were obtained, which are formed by a cascade reaction involving an addition/cyclization sequence. In the novel coupling process described here methoxyallene (12) serves as an equivalent of acrolein. The 1,4-dioxygenated products obtained contain a masked aldehyde functionality and are therefore valuable building blocks in organic synthesis.
- Hoelemann, Alexandra,Reissig, Hans-Ulrich
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- Hierarchically assembled helicates as reaction platform – from stoichiometric Diels–Alder reactions to enamine catalysis
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The stereoselectivity of a Diels–Alder reaction within the periphery of hierarchically assembled titanium(IV) helicates formed from mixtures of achiral, reactive and chiral, unreactive ligands was investigated in detail. Following the pathway of the chiral induction, the chiral ligands, solvents as well as substituents at the dienophile were carefully varied. Based on the results of the stoichiometric reaction, a secondary amine-catalyzed nitro-Michael reaction is performed as well which afforded reasonable diastereoselectivities.
- Albrecht, Markus,Begall, Jenny,Craen, David Van,Gro?kurth, Johannes,Himmel, Leonard,Isaak, Elisabeth,Linnenberg, Oliver
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- A novel amalgamation of 1,2,3-triazoles, piperidines and thieno pyridine rings and evaluation of their antifungal activity
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It is the first report of the novel amalgamation of 1,2,3-triazoles, piperidines, thieno pyridine rings and evaluation of their antifungal activity. The synthesized compounds showed interesting moderate to good antifungal activity, wherein they were able to discriminate between the two species Aspergillus flavus and Aspergillus niger of the same genus. In addition, the main highlight of this series is the sensitivity of the fungal strain Cryptococcus neoformans to the compounds having p-chlorobenzoyl (9h), methane sulfonyl (9i) and p-methylbenzene sulfonyl (9j) attached to the piperazine nitrogen.
- Darandale, Sunil N.,Mulla, Nayeem A.,Pansare, Dattatraya N.,Sangshetti, Jaiprakash N.,Shinde, Devanand B.
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- Selective reduction of ketones using water as a hydrogen source under high hydrostatic pressure
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A selective reduction of a broad variety of ketones is described. The method is based on the combination of a Ni-Al alloy and high hydrostatic pressure (HHP, 2.8 kbar) in an aqueous medium. The reaction of the Ni-Al alloy with water provides in situ hydrogen generation and the high pressure ensures that the H2 formed remains in the solution, thus the CO reduction readily occurs. The application of the HHP resulted in selective formation of the desired products and the common problem of non-selective overhydrogenation could be avoided. In most cases the reductions resulted in high yields and excellent selectivities without the use of any base.
- Tomin, Anna,Lazarev, Alexander,Bere, Matthew P.,Redjeb, Hana,T?r?k, Béla
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- An Efficient approach to the securinega alkaloids empowered by cooperative n-heterocyclic carbene/lewis acid catalysis
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Folding it all together: Most of the syntheses developed for the securinega alkaloid class require lengthy sequences to create their bridging butenolide domains. A novel approach uses N-heterocyclic carbenes (NHCs) and Lewis acids to forge the entire domain in a single step from appropriate precursors, showing that ynal-derived homoenolates can participate as nucleophiles in intramolecular settings (see scheme). Copyright
- Elsohly, Adel M.,Wespe, Daniel A.,Poore, Tyler J.,Snyder, Scott A.
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- Water-soluble pleuromutilin derivative with excellent in vitro and in vivo antibacterial activity against Gram-positive pathogens
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Although earlier pleuromutilin analogues showed potent in vitro antibacterial activity against some Gram-positive pathogens, their in vivo efficacy was low because of insufficient pharmacokinetic properties. We designed novel thioether pleuromutilin derivatives having a purine ring as a polar and water solubilizing group and identified a promising pleuromutilin analogue 6 with good solubility in water (~50 mg/mL). Compound 6 exhibited excellent in vitro and in vivo antibacterial activity against some Gram-positive strains, including drug-resistant pathogens.
- Hirokawa, Yoshimi,Kinoshita, Hironori,Tanaka, Tomoyuki,Nakata, Katsuhisa,Kitadai, Noriyuki,Fujimoto, Koichi,Kashimoto, Shigeki,Kojima, Tsuyoshi,Kato, Shiro
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- An air and moisture tolerant iminotrihydroquinoline-ruthenium(ii) catalyst for the transfer hydrogenation of ketones
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Reaction of 8-amino-5,6,7,8-tetrahydroquinoline with RuCl2(PPh3)3 at room temperature affords the ruthenium(ii) chelate (8-NH2-C9H10N)RuCl2(PPh3)2 (E), in which the two triphenylphosphine ligands are disposed mutually cis. By contrast, when the reaction is performed at reflux ligand oxidation/dehydrogenation occurs along with cis-trans reorganization of the triphenylphosphines to form the 8-imino-5,6,7-trihydroquinoline-ruthenium(ii) complex, (8-NH-C9H9N)RuCl2(PPh3)2 (F). Complex F can also be obtained in higher yield by heating a solution of E alone to reflux. Comparison of their molecular structures highlights the superior binding properties of the bidentate imine ligand in F over its amine-containing counterpart in E. Both complexes are highly effective in the transfer hydrogenation of a wide range of alkyl-, aryl- and cycloalkyl-containing ketones affording their corresponding secondary alcohols with loadings of as low as 0.1 mol%. Significantly, F can deliver excellent conversions even in bench quality 2-propanol in reaction vessels open to the air, whereas the catalytic efficiency of E is diminished by the presence of air but only operates efficiently under inert conditions.
- Li, Jiaoyan,Ma, Yingmiao,Wang, Zheng,Liu, Qingbin,Solan, Gregory A.,Ma, Yanping,Sun, Wen-Hua
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- The first radiosynthesis of [11C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling
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The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2-5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2-4% overall chemical yield. The target tracer [11C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[11C]methylacetamide} ([11C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [11C]CH3OTf under basic condition (NaH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [11C]CO2and decay corrected to end of bombardment (EOB) with 370-1110 GBq/μmol specific activity at EOB.
- Wang, Min,Gao, Mingzhang,Zheng, Qi-Huang
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- N-[18F]fluoroethyl-4-piperidyl acetate ([18F]FEtP4A): A PET tracer for imaging brain acetylcholinesterase in vivo.
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N-[(18)F]Fluoroethyl-4-piperidyl acetate ([(18)F]FEtP4A) was synthesized and evaluated as a PET tracer for imaging brain acetylcholinesterase (AchE) in vivo. [(18)F]FEtP4A was previously prepared by reacting 4-piperidyl acetate (P4A) with 2-[(18)F]fluoroethyl bromide ([(18)F]FEtBr) at 130 degrees C for 30 min in 37% radiochemical yield using an automated synthetic system. In this work, [(18)F]FEtP4A was synthesized by reacting P4A with 2-[(18)F]fluoroethyl iodide ([(18)F]FEtI) or 2-[(18)F]fluoroethyl triflate ([(18)F]FEtOTf in improved radiochemical yields, compared with [(18)F]FEtBr under the corresponding condition. Ex vivo autoradiogram of rat brain and PET summation image of monkey brain after iv injection of [(18)F]FEtP4A displayed a high radioactivity in the striatum, a region with the highest AchE activity in the brain. Moreover, the distribution pattern of (18)F radioactivity was consistent with that of AchE in the brain: striatum>frontal cortex>cerebellum. In the rat and monkey plasma, two radioactive metabolites were detected. However, their presence might not preclude the imaging studies for AchE in the brain, because they were too hydrophilic to pass the blood-brain barrier and to enter the brain. In the rat brain, only [(18)F]fluoroethyl-4-piperidinol ([(18)F]FEtP4OH) was detected at 30 min postinjection. The hydrolytic [(18)F]FEtP4OH displayed a slow washout and a long retention in the monkey brain until the PET experiment (120 min). Although [(18)F]FEtP4A is a potential PET tracer for imaging AchE in vivo, its lower hydrolytic rate and lower specificity for AchE than those of [(11)C]MP4A may limit its usefulness for the quantitative measurement for AchE in the primate brain.
- Zhang, Ming-Rong,Furutsuka, Kenji,Maeda, Jun,Kikuchi, Tatsuya,Kida, Takayo,Okauchi, Takashi,Irie, Toshiaki,Suzuki, Kazutoshi
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- Design, synthesis and biological evaluation of 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles as inhibitors of ebola virus infection
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Novel 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles were designed and synthesized as Ebola virus inhibitors. The proposed structures of the new prepared benzimidazole-piperidine hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-Ebola activity. Among tested molecules, compounds 26a (EC50=0.93 μM, SI = 10) and 25a (EC50=0.64 μM, SI = 20) were as potent as and more selective than Toremifene reference drug (EC50 = 0.38 μM, SI = 7) against cell line. Data suggests that the mechanism by which 25a and 26a block EBOV infection is through the inhibition of viral entry at the level of NPC1. Furthermore, a docking study revealed that several of the NPC1 amino acids that participate in binding to GP are involved in the binding of the most active compounds 25a and 26a. Finally, in silico ADME prediction indicates that 26a is an idealy drug-like candidate. Our results could enable the development of small molecule drug capable of inhibiting Ebola virus, especially at the viral entry step.
- Bessières, Maxime,Plebanek, El?bieta,Chatterjee, Payel,Shrivastava-Ranjan, Punya,Flint, Mike,Spiropoulou, Christina F.,Warszycki, Dawid,Bojarski, Andrzej J.,Roy, Vincent,Agrofoglio, Luigi A.
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- Design of a "two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites
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Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.
- Bauer, Nicolas,Berger, Benedict-Tilman,Berger, Lena M.,Beyett, Tyler S.,Corona, Cesear R.,Eck, Michael J.,Heppner, David E.,Knapp, Stefan,Laufer, Stefan A.,Rana, Jaimin K.,Robers, Matthew B.,Schmoker, Anna M.,Shin, Bo Hee,To, Ciric,Vasta, James D.,Wittlinger, Florian,Günther, Marcel,J?nne, Pasi A.
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supporting information
(2021/11/13)
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- Sustainable Route Toward N-Boc Amines: AuCl3/CuI-Catalyzed N-tert-butyloxycarbonylation of Amines at Room Temperature
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N-tert-butoxycarbonyl (N-Boc) amines are useful intermediates in synthetic/medicinal chemistry. Traditionally, they are prepared via an indirect phosgene route with poor atom economy. Herein, a step- and atom-economic synthesis of N-Boc amines from amines, t-butanol, and CO was reported at room temperature. Notably, this N-tert-butyloxycarbonylation procedure utilized ready-made substrates, commercially available AuCl3/CuI as catalysts, and O2 from air as the sole oxidant. This catalytic system provided unique selectivity for N-Boc amines in good yields. More significantly, gram-scale preparation of medicinally important N-Boc amine intermediates was successfully implement, which demonstrated a potential application prospect in industrial syntheses. Furthermore, this approach also showed good compatibility with tertiary and other useful alcohols. Investigations of the mechanisms revealed that gold catalyzed the reaction and copper acted as electron transfer mediator in the catalytic cycle.
- Cao, Yanwei,He, Lin,Huang, Yang
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- Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities
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Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.
- Cioffi, Christopher L.,Muthuraman, Parthasarathy,Raja, Arun,Varadi, Andras,Racz, Boglarka,Petrukhin, Konstantin
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p. 11054 - 11084
(2020/11/09)
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- NOVEL ARYLOXYPIPERIDINE PYRAZOLE COMPOUNDS AS INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS
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Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.
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Page/Page column 103
(2020/03/15)
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- COMPOUNDS AS NEURONAL HISTAMINE RECEPTOR-3 ANTAGONISTS AND USES THEREOF
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The present invention relates compounds of Formula (A) as H3R antagonists, as well as their preparation and uses, and further relates pharmaceutical compositions comprising these compounds and their uses as modulators of Histamine 3 Receptor (H3R) functions. The present invention also relates to the uses of the compounds or pharmaceutical compositions in treating or preventing certain disorders and diseases which relate to H3R functions in humans.
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Paragraph 0358; 0359
(2020/04/24)
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- GSK-3beta/ChE double inhibitor as well as preparation method and application thereof
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The invention discloses a GSK-3beta/ChE double inhibitor with the structural formula shown as formula (I), or pharmaceutically acceptable salts and solvates of formula (I). The chemical small molecules involved in the invention can effectively inhibit the enzyme activity of GSK-3 beta, AChE and BChE, have the effects of improving cognition, reducing tau protein phosphorylation and reducing neuroinflammation, and have important application value in the preparation of drugs for preventing or treating Alzheimer's disease.
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Paragraph 0188; 0189
(2020/04/22)
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- Hydrochloride of [1, 2, 4] triazine and [6,1-a] isoindole compound and application thereof
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The invention belongs to the field of chemical medicines, and relates to a [1,2,4]triazine[6,1-a]isoindole compound with ALK/C-MET kinase duplex restraining activity, a pharmaceutical composition containing the compound and application of the compound or the composition in medicine preparation, in particular to hydrochloride and application of the [1,2,4]triazine[6,1-a]isoindole compound. The compound has good dissolubility and stability, and a better option is provided for dosage form research.
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Paragraph 0049; 0051-0054
(2020/03/13)
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- Copper-Catalyzed Cross-Coupling between Alkyl (Pseudo)halides and Bicyclopentyl Grignard Reagents
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The development of a copper-catalyzed cross-coupling between primary and secondary (pseudo)halides and bicyclopentyl Grignard reagents is reported. Highly strained bicyclopentanes can be cross-coupled with a large panel of primary alkyl mesylates and secondary alkyl iodides. The catalytic system is simple and cheap, and the reaction is general and chemoselective.
- Andersen, Claire,Bernardelli, Patrick,Cossy, Janine,Daumas, Marc,Ferey, Vincent,Guérinot, Amandine
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supporting information
(2020/08/05)
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- Catalytic Transfer Hydrogenation of Arenes and Heteroarenes
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Transfer hydrogenation reactions are of great interest to reduce diverse molecules under mild reaction conditions. To date, this type of reaction has only been successfully applied to alkenes, alkynes and polarized unsaturated compounds such as ketones, imines, pyridines, etc. The reduction of benzene derivatives by transfer hydrogenation has never been described, which is likely due to the high energy barrier required to dearomatize these compounds. In this context, we have developed a catalytic transfer hydrogenation reaction for the reduction of benzene derivatives and heteroarenes to form complex 3-dimensional scaffolds bearing various functional groups at room temperature without needing compressed hydrogen gas.
- Gelis, Coralie,Heusler, Arne,Nairoukh, Zackaria,Glorius, Frank
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supporting information
p. 14090 - 14094
(2020/10/19)
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- Amine-Responsive Disassembly of AuI–CuI Double Salts for Oxidative Carbonylation
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A sensitive amine-responsive disassembly of self-assembled AuI-CuI double salts was observed and its utilization for the synergistic catalysis was enlightened. Investigation of the disassembly of [Au(NHC)2][CuI2] revealed the contribution of Cu-assisted ligand exchange of N-heterocyclic carbene (NHC) by amine in [Au(NHC)2]+ and the capacity of [CuI2]? on the oxidative step. By integrating the implicative information coded in the responsive behavior and inherent catalytic functions of d10 metal complexes, a catalyst for the oxidative carbonylation of amines was developed. The advantages of this method were clearly reflected on mild reaction conditions and the significantly expanded scope (51 examples); both primary and steric secondary amines can be employed as substrates. The cooperative reactivity from Au and Cu centers, as an indispensable prerequisite for the excellent catalytic performance, was validated in the synthesis of (un)symmetric ureas and carbamates.
- Cao, Yanwei,Yang, Jian-Gong,Deng, Yi,Wang, Shengchun,Liu, Qi,Shen, Chaoren,Lu, Wei,Che, Chi-Ming,Chen, Yong,He, Lin
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supporting information
p. 2080 - 2084
(2019/12/24)
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- BENZIMIDAZOL DERIVATIVES FOR TREATING FILOVIRUS INFECTION
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The present invention relates to compounds comprising a benzimidazole scaffold, and the use of such compounds for the treatment of viral diseases. The invention also relates to pharmaceutical compositions comprising said compounds as an active ingredient. In particular the compounds of the invention comprising a benzimidazole scaffold are used for the treatment of filoviruses or retroviruses, and preferably for the treatment of Ebola virus or HIV virus.
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Page/Page column 72
(2018/04/13)
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- “Inverse” Frustrated Lewis Pairs: An Inverse FLP Approach to the Catalytic Metal Free Hydrogenation of Ketones
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For the first time have boron-containing weak Lewis acids been demonstrated to be active components of Frustrated Lewis Pair (FLP) catalysts in the hydrogenation of ketones to alcohols. Combining the organosuperbase (pyrr)3P=NtBu with the Lewis acid 9-(4-CF3-C6H4)-BBN generated an “inverse” FLP catalyst capable of hydrogenating a range of aliphatic and aromatic ketones including N-, O- and S-functionalized substrates and bio-mass derived ethyl levulinate. Initial computational and experimental studies indicate the mechanism of catalytic hydrogenation with “inverse” FLPs to be different from conventional FLP catalysts that contain strong Lewis acids such as B(C6F5)3.
- Mummadi, Suresh,Brar, Amandeep,Wang, Guoqiang,Kenefake, Dustin,Diaz, Rony,Unruh, Daniel K.,Li, Shuhua,Krempner, Clemens
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supporting information
p. 16526 - 16531
(2018/10/20)
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- SMALL MOLECULE ACTIVATORS OF NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) AND USES THEREOF
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Provided herein are small molecule activators of Nicotinamide Phosphoribosyltransferase (NAMPT), compositions comprising the compounds, and methods of using the compounds and compositions.
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Paragraph 01009
(2018/08/03)
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- Synthesis method of N-Boc-4-hydroxypiperidine
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The invention discloses a synthesis method of N-Boc-4-hydroxypiperidine and belongs to the technical field of organic chemistry. The synthesis method comprises the following steps of: adopting 4-piperidone hydrate hydrochloride and di-tert-butyl dicarbonate ester as raw materials, adding alkali for reaction to generate N-Boc-4-piperidone, then adding into an organic solvent, under the existence ofaluminium isopropoxide and isopropanol, and after rising the temperature for reaction, thus obtaining the N-Boc-4-hydroxypiperidine. The synthesis method disclosed by the invention has the characteristics of easy raw material obtaining, high reaction yield, low cost, environmental-friendly effect and good product quality, and is suitable for industrial production.
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Paragraph 0019; 0021; 0022; 0024; 0025; 0027; 0028; 0030
(2018/03/01)
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- Radical Deuteration with D2O: Catalysis and Mechanistic Insights
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Selective incorporation of deuterium atoms into molecules is of high interest for labeling purposes and for optimizing properties of drug candidates. A mild and environmentally benign method for the deuteration of alkyl iodides via radical pathway using D2O as source of deuterium has been developed. The reaction is initiated and mediated by triethylborane in the presence of dodecanethiol as a catalyst. This method is compatible with a wide range of functional groups and provides the monodeuterated products in good yields and with a high level of deuterium incorporation. It opens promising opportunities for the development of enantioselective radical reactions. Moreover, a revision of the mechanism of the deoxygenation reaction of xanthates using R3B and water (Wood deoxygenation) is presented.
- Soulard, Valentin,Villa, Giorgio,Vollmar, Denis Patrick,Renaud, Philippe
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supporting information
p. 155 - 158
(2018/01/17)
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- Reversed isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis
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Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy. The potency of some compounds against various strains of M. tuberculosis (4a–c, 7 and 8; H37Rv-MIC99 ≤1.25 μM, R5401-MIC99 ≤2.5 μM, X_61-MIC99 ≤5 μM) demonstrated the potential of the reversed anti-TB agent strategy towards the development of novel anti-mycobacterial agents to address the rapidly growing issue of resistance. Further, macrophage activity with >90% inhibition by 1a–c and 3b (MIC90 ≤13.42 μM) and inhibition of EB efflux demonstrated by these compounds are encouraging.
- Kumar, Malkeet,Singh, Kawaljit,Ngwane, Andile H.,Hamzabegovic, Fahreta,Abate, Getahun,Baker, Bienyameen,Wiid, Ian,Hoft, Daniel F.,Ruminski, Peter,Chibale, Kelly
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supporting information
p. 833 - 844
(2018/01/22)
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- Preparation method of nitrogen-containing heterocyclic derivative
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The invention discloses a preparation method of a nitrogen-containing heterocyclic derivative (4-(4-bromobenyl) piperazine-1-yl) piperidine-1-tert butyl formate. The preparation method comprises the following steps: taking 4-hydroxypyrazole as a starting raw material; and carrying out Boc feeding, condensation, nucleophilic substitution and amidation to obtain an objective product. The compound isan important medical intermediate.
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Paragraph 0020; 0021-0022
(2018/03/24)
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- C-3 NOVEL TRITERPENONE WITH C-17 REVERSE AMIDE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to C-3 novel triterpenone with C-17 reverse amide compounds of Formula (I); and pharmaceutically acceptable salts thereof, wherein ring Formula (II), R1, R2, R3, R4, R5, R6, R7, 'n' and 'm' are as defined in Formula (I). The invention also relates to C-3 novel triterpenone with C-17 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 41
(2018/03/06)
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- JANUS KINASE 1 SELECTIVE INHIBITOR AND PHARMACEUTICAL USE THEREOF
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Janus kinase 1 selective inhibitors and pharmaceutical use thereof are provided.
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Paragraph 0317-0326
(2018/06/07)
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- Preparation method of piperazine derivative
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The invention discloses a preparation method of a piperazine derivative, namely (4-(4-trifluoromethyl benzoyl)piperazine-1-yl)piperidine-1-tert-butyl formate. 4-hydroxy piperazine is taken as a starting material and is subjected to Boc treatment, condensation, nucleophilic substitution and amidation to obtain a target product. The compound is an important medical intermediate.
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Paragraph 0020-0022
(2018/10/19)
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- Substituted heteroaryl compound and composition thereof, and uses of substituted heteroaryl compound and composition thereof
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The present invention provides a substituted heteroaryl compound and a composition thereof, and uses of the substituted heteroaryl compound and the composition, wherein the compound is a compound represented by a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound represented by the formula (I). The present invention further provides a pharmaceutical composition containing the compound, wherein the pharmaceutical composition can regulate activity of protein kinases, particularly Aurora kinases and JAK kinases, and can be used for prevention, treatment, therapy and alleviation of protein kinases, particularly Aurora kinases and JAK kinase activity mediated diseases or disorders.
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Paragraph 0997; 0998; 0999; 1000
(2017/04/29)
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- Substituted heteroaryl compounds and composition thereof, and applicaitons of compounds and composition
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The invention provides substituted heteroaryl compounds and a composition thereof, and applicaitons of the compounds and the composition. The compounds are compounds represented by the formula (I) or the formula (II) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds represented by the formula (I) or the formula (II). The invention also provides the pharmaceutical composition comprising the compounds; the compounds and the pharmaceutical composition can adjust the activity of protein kinase, and are used for prevention, processing, treatment and remission of diseases or disorders mediated by the protein kinase.
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Paragraph 0666; 0667; 0668; 0669
(2017/07/31)
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- Tankyrase inhibitor
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The invention belongs to the technical field of medicines and particularly relates to a tankyrase inhibitor represented by a general formula (I) shown in the description and pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof, wherein R1, R2, R3, m, n, Z, L, Q, A, X1, X2 and Y are as defined in the description. The invention further relates to a preparation method for the compounds, pharmaceutical preparations and pharmaceutical compositions containing the compounds and application of the compound and the pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof in preparation of drugs for treating and/or preventing tankyrase mediated cancers and related diseases.
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Paragraph 0260-0262
(2017/10/13)
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- BENZENESULFONAMIDE COMPOUNDS AND THEIR USE AS THERAPEUTIC AGENTS
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This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.
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Page/Page column 282
(2017/12/18)
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- Preparation method of 1-t-butyloxycarboryl-4-piperidinol
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The invention relates to a preparation method of 1-t-butyloxycarboryl-4-piperidinol. The preparation method comprises a following step: in an organic solvent and carbon dioxide, 1-t-butyloxycarboryl-4-piperidone is subjected to reduction with NaBH4 at 5 to 10 DEG C so as to obtain 1-t-butyloxycarboryl-4-piperidinol, wherein the molar ratio of NaBH4 to 1-t-butyloxycarboryl-4-piperidone is controlled to be 0.71-0.75:1. The preparation method possesses following advantages: high purity 1-t-butyloxycarboryl-4-piperidone containing C=O bonds is taken as the raw material, selective reduction of the C=O bonds on piperidine rings with NaBH4 is realized, product purity is ensured, the organic solvent and carbon dioxide are mixed for reaction, product yield is increased greatly to be 80% or higher, and the preparation method is simple, and is suitable for industrialized large-scale production.
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Paragraph 0013; 0014; 0015; 0016; 0017
(2017/08/29)
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- NOVEL BETULINIC SUBSTITUTED AMIDE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to novel betulinic substituted amide compounds of formula (I); and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and are Formula (II) as defined herein. The invention novel betulinic substituted amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 38
(2017/02/24)
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- COMPOUNDS FOR BINDING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
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The present disclosure relates to novel compounds, methods, and compositions capable of binding to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity. The compounds of the disclosure include compounds Formula (I).
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Paragraph 0230
(2017/09/15)
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- Selection of microbial biocatalysts for the reduction of cyclic and heterocyclic ketones
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The reduction of carbonyl compounds plays an important role in the synthesis of complex chiral molecules. In particular, enantiopure substituted cyclic and heterocyclic compounds are useful intermediates for the synthesis of several antiviral, antitumor, and antibiotic agents, and recently, they have also been used as organocatalysts for C-C addition. Alcohol dehydrogenases (ADH) are enzymes involved in the transformation of prochiral ketones to chiral hydroxyl compounds. While significant scientific effort has been paid to the use of aliphatic and exocyclic ketones as ADH substrates, reports on (hetero)cyclic carbonyl compounds as substrates of these enzymes are scarce. In the present study, 109 bacteria and 36 fungi were screened, resulting in 10 organisms belonging to both kingdoms capable of transforming cyclic and heterocyclic ketones into the corresponding alcohols. Among them, Erwinia chrysanthemi could quantitatively reduce cyclododecanone and Geotrichum candidum could stereoselectively reduce N-Boc-3-piperidone and N-Boc-3-pyrrolidinone to their corresponding (S)-alcohols; however, the anti-Prelog isomer was obtained when acetophenone was the substrate.
- Bianchi, Paola,Varela, Romina Fernández,Bianchi, Dario A.,Kemppainen, Minna,Iribarren, Adolfo M.,Lewkowicz, Elizabeth
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p. 137 - 144
(2017/06/21)
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- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
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Paragraph 0407
(2017/03/28)
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- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
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Paragraph 0454
(2017/04/14)
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- Synthesis of 11C-labelled ureas by palladium(II)-mediated oxidative carbonylation
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Positron emission tomography is an imaging technique with applications in clinical settings as well as in basic research for the study of biological processes. A PET tracer, a biologically active molecule where a positron-emitting radioisotope such as carbon-11 has been incorporated, is used for the studies. Development of robust methods for incorporation of the radioisotope is therefore of the utmost importance. The urea functional group is present in many biologically active compounds and is thus an attractive target for incorporation of carbon-11 in the form of [11C]carbon monoxide. Starting with amines and [11C]carbon monoxide, both symmetrical and unsymmetrical 11C-labelled ureas were synthesised via a palladium(II)-mediated oxidative carbonylation and obtained in decay-corrected radiochemical yields up to 65%. The added advantage of using [11C]carbon monoxide was shown by the molar activity obtained for an inhibitor of soluble epoxide hydrolase (247 GBq/μmol-319 GBq/μ mol). DFT calculations were found to support a reaction mechanism proceeding through an 11C-labelled isocyanate intermediate.
- Roslin, Sara,Brandt, Peter,Nordeman, Patrik,Larhed, Mats,Odell, Luke R.,Erikssoni, Jonas
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-
- Preparation method for piperazine derivative
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The invention discloses a preparation method for a piperazine derivative (4-(4-methyl benzoyl) piperazine-1-yl) piperidine-1-tert-butyl formate. 4-hydroxy piperazine is taken as an initial raw material and then is subjected to Boc, condensation, nucleophilic substitution and amidation so as to acquire a target product. The compound is an important medical intermediate.
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Paragraph 0020-0022
(2018/04/01)
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- Preparation method of crizotinib intermediate
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The invention discloses a synthetic method of anti-tumor molecular targeted drug crizotinib, belongs to the field of pharmaceuticals, and relates to a synthetic method of a crizotinib intermediate. The method comprises two reduction processes: a bromination reaction process comprises the following reaction steps: a reduction process I: carrying out reduction reaction on a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound and sodium dithionate under a mechanical chemical condition to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; a reduction process II: dissolving the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound into an organic solvent, carrying out catalytic hydrogenation and reduction treatment to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; the bromination reaction process comprises a step of carrying out reaction between the compound and potassium hydrogen persulfate as well as bromate to obtain the crizotinib intermediate. The process is low in cost, the raw materials are easy to purchase, the operation is simple, convenient and safe, and the yield is high; moreover, the process is suitable for large-scale production.
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Paragraph 0021
(2017/12/29)
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- Electrochemical Deprotection of para-Methoxybenzyl Ethers in a Flow Electrolysis Cell
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Electrochemical deprotection of p-methoxybenzyl (PMB) ethers was performed in an undivided electrochemical flow reactor in MeOH solution, leading to the unmasked alcohol and p-methoxybenzaldehyde dimethyl acetal as a byproduct. The electrochemical method removes the need for chemical oxidants, and added electrolyte (BF4NEt4) can be recovered and reused. The method was applied to 17 substrates with high conversions in a single pass, yields up to 92%, and up to 7.5 g h-1 productivity. The PMB protecting group was also selectively removed in the presence of some other common alcohol protecting groups.
- Green, Robert A.,Jolley, Katherine E.,Al-Hadedi, Azzam A. M.,Pletcher, Derek,Harrowven, David C.,De Frutos, Oscar,Mateos, Carlos,Klauber, David J.,Rincón, Juan A.,Brown, Richard C. D.
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supporting information
p. 2050 - 2053
(2017/04/27)
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- FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
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The disclosure provides novel chemical compounds represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. The compounds can be used as an inhibitor of Trk and are useful in the treatment of pain, cancer, inflammation, neurodegenerative disease and certain infectious diseases. In some compounds of Formula I, Q is —CH═CR3C(O)NR4R5, —C≡CC(O)NR4R5, or
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Paragraph 0474; 0475
(2016/07/05)
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- HETEROAROMATIC DERIVATIVES AND PHARMACEUTICAL APPLICATIONS THEREOF
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Disclosed are heteroaryl derivatives, pharmaceutical composition and uses in the manufacture of a medicine for treating respiratory diseases, especially for chronic obstructive pulmonary disease (COPD).
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Paragraph 00573
(2016/05/02)
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- Aromatic heterocyclic derivatives and applications of aromatic heterocyclic derivatives in medicines
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The present invention discloses aromatic heterocyclic derivatives and applications of the aromatic heterocyclic derivatives in medicines, and specifically provides a class of aromatic heterocyclic compounds or stereoisomers, geometric isomers, tautomers, racemic bodies, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions containing the compounds. The present invention further discloses uses of the compounds or pharmaceutical compositions in drug preparation, wherein the drug is used for treatment of respiratory diseases, particularly chronic obstructive pulmonary disease (COPD).
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Paragraph 1255-1257
(2016/10/09)
-
- Novel anti-tumor compound
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The invention provides a pyrazolopyridine derivative anti-tumor compound with excellent anti-tumor activity. The anti-tumor compound is shown as a formula I, wherein X represents -NH2, -NHOH, -NHX, amino acid residue and the like (shown as the accompanying diagram); Y represents hydrogen atoms, alkyl groups, naphthenic bases, benzyl groups, aryl groups, heteroaryl, alkyl amino groups, -COX2 or -CONHX3, wherein the aryl group, the heteroaryl and the alkyl group are respectively, independently and randomly substituted by one or a plurality of materials from halogen, trifluoromethyl, amino groups, alkyl amino groups, hydroxyl, hydroxyalkyl, alkoxy, cyanogroup, nitryl, aryl groups and heteroaryl; the definitions of R1, R2, X1 and X2 are identical to the definitions in the specifications. The invention also provides a preparation method of an anti-tumor agent and application of the anti-tumor agent to lung cancer, colon cancer and ovarian cancer anti-tumor medicine.
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Paragraph 0103; 0104; 0105
(2016/10/09)
-
- Novel pyrazolopyridine antineoplastic compound
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The invention provides a novel pyrazolopyridine antineoplastic compound with excellent antineoplastic activity. The antineoplastic compound is shown as the formula I, wherein M groups are freely selected from hydrogen atoms, alkyl groups and naphthenic groups, Y represents N atom site substituted or non-substituted nitrogen atom containing 5-8 membered rings, and the substituent group is a -X1 group or -CO2X2 or -COX3 or -CONHX4. The definitions of X1, X2, X3 and X4 are the same as definitions in the description. The invention further provides a preparation method of the antineoplastic compound and an application of the antineoplastic compound in antineoplastic drugs for lung cancer, colon cancer and ovarian cancer. The compound has good antineoplastic activity. The formula is shown in the description.
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Paragraph 0088; 0089
(2016/10/09)
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- Pyrimidine derivative, preparation method therefor and application thereof in medicine
-
The invention relates to a pyrimidine derivative, a preparation method therefor and an application thereof in medicine. Particularly, the invention relates to a compound as shown in general formula (M) or a stereisomer, an aquo-complex, a metabolic product, a solvate, a pharmaceutically acceptable salt, a co-crystallization or a prodrug thereof; the preparation method thereof; and the application of the medicine composition thereof and the compound medicine compound in the medicine, particularly the application as an EGFR target spot inhibitor, wherein the definition of each substituent group in the general formula (M) is the same as that of the specification.
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Paragraph 0162; 0163; 0164; 0165; 0166
(2016/10/07)
-
- Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease
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Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing (Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016, in press, doi: 10.1038/npp.2016.163).
- Rabal, Obdulia,Sánchez-Arias, Juan A.,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,García-Barroso, Carolina,Ugarte, Ana,Estella-Hermoso De Mendoza, Ander,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Haizhong, Tan,Wei, Wu,Musheng, Xu,Garcia-Osta, Ana,Oyarzabal, Julen
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supporting information
p. 8967 - 9004
(2016/10/22)
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- With anti-platelet aggregation activity of the piperidinyl substituted 5- hydroxy color acid derivatives
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The invention relates to the field of pharmaceutical chemistry, particularly piperidyl substituted 5-hydroxytryptophane derivatives (I) with anti-platelet aggregation activity, and a preparation method and pharmaceutical application thereof, wherein R1, R2 and n are defined in the specification. The pharmacodynamical test proves that the piperidyl substituted 5-hydroxytryptophane derivatives have favorable anti-platelet aggregation activity.
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Paragraph 0055; 0056
(2017/02/09)
-
- Pyridone protein kinase inhibitor
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The invention discloses a compound capable of regulating protein kinase activity and used for treating or preventing diseases related to protein kinase, particularly relates to a pyridone protein kinase inhibitor, belongs to compounds for regulating anaplastic lymphoma kinase (ALK) activity, and provides a preparation method of the compounds and pharmaceutical application of the compounds to the treatment or prevention of the diseases related to ALK.
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Paragraph 0088; 0090; 0091
(2017/04/19)
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- ALKYNE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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Provided are compounds of formula (Ia) and pharmaceutically acceptable salts thereof, wherein A, B, R 1, R 2, m and n are as defined herein, which are active as inhibitors of S-Nitrosoglutathione reductase (GSNOR). These compounds prevent, inhibit, or suppress the action of GSNOR and are therefore useful in the treatment of GSNOR mediated diseases, disorders, syndromes or conditions such as, e.g., pulmonary hypertension, acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis, interstitial lung diseases, cystic fibrosis and chronic obstructive pulmonary disease (COPD).
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Page/Page column 116
(2016/05/02)
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- Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C-H Functionalization of Trialkylamine N-CH3 Groups
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We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+?, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C-H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure-activity relationships.
- Barham, Joshua P.,John, Matthew P.,Murphy, John A.
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supporting information
p. 15482 - 15487
(2016/12/09)
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