- Efficient Approaches for the Synthesis of Diverse α-Diazo Amides
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Metal-catalysed carbenoid chemistry can be exploited for the synthesis of diverse ranges of small molecules from α-diazo carbonyl compounds. In this paper, three synthetic approaches to α-diazo amides are described, and their scope and limitations are determined. On the basis of these synthetic studies, recommendations are provided to assist the selection of the most appropriate approach for specific classes of product. The availability of practical and efficient syntheses of diverse α-diazo acetamides is expected to facilitate the discovery of many different classes of bioactive small molecules.
- Arter, Christopher,Chow, Shiao,Green, Adam I.,Karageorgis, George,Leggott, Abbie,Liver, Samuel,Nelson, Adam,Trask, Luke,Warriner, Stuart
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- Design, Synthesis, and Biological Evaluation of Novel 3-Aminomethylindole Derivatives as Potential Multifunctional Anti-Inflammatory and Neurotrophic Agents
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The development of multifunctional molecules that are able to simultaneously interact with several pathological components has been considered as a solution to treat the complex pathologies of neurodegenerative diseases. Herein, a series of aminomethylindole derivatives were synthesized, and evaluation of their application for antineuroinflammation and promoting neurite outgrowth was disclosed. Our initial screening showed that most of the compounds potently inhibited lipopolysaccharide (LPS)-stimulated production of NO in microglial cells and potentiated the action of NGF to promote neurite outgrowth of PC12 cells. Interestingly, with outstanding NO/TNF-α production inhibition and neurite outgrowth-promoting activities, compounds 8c and 8g were capable of rescuing cells after injury by H2O2. Their antineuroinflammatory effects were associated with the downregulation of the LPS-induced expression of the inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Western blotting and immunofluorescence assay results indicated that the mechanism of their antineuroinflammatory actions involved suppression of the MAPK/NF-κB signal pathways. Further studies revealed that another important reason for the high comprehensive antineuroinflammatory activity was the anti-COX-2 capabilities of the compounds. All these results suggest that the potential biochemical multifunctional profiles of the aminomethylindole derivatives provide a new sight for the treatment of neurodegenerative diseases.
- Wang, Wei-Wei,Liu, Ting,Lv, Yu-Meng,Zhang, Wu-Yang,Liu, Zhi-Gang,Gao, Jin-Ming,Li, Ding
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p. 1593 - 1605
(2021/05/31)
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- Epoxide-Mediated Stevens Rearrangements of α-Amino-Acid-Derived Tertiary Allylic, Propargylic, and Benzylic Amines: Convenient Access to Polysubstituted Morpholin-2-ones
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A new strategy has been established for the synthesis of polysubstituted morpholin-2-ones through Stevens rearrangements of tertiary amines via in situ activation with epoxides. A range of α-amino acid-derived tertiary allylic, propargylic, and benzylic amines reacted with epoxides in the presence of zinc halide catalysts to afford structurally diverse allyl-, allenyl-, and benzyl-substituted morpholin-2-ones, respectively, in moderate-to-good yields with high regioselectivity. The process involves [2,3]- and [1,2]-Stevens rearrangements of quaternary ammonium ylide intermediates and constitutes a very convenient method to prepare polysubstituted morpholin-2-ones through tandem formation of C?N, C?O, and C?C bonds. Moreover, replacing epoxides with aziridines permitted the synthesis of polysubstituted piperazin-2-ones.
- Jin, You-Xiang,Yu, Bang-Kui,Qin, Si-Ping,Tian, Shi-Kai
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p. 5169 - 5172
(2019/03/28)
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- Selective synthesis of mono- and di-methylated amines using methanol and sodium azide as C1 and N1 sources
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A Ru(ii) complex mediated synthesis of various N,N-dimethyl and N-monomethyl amines from organic azides using methanol as a methylating agent is reported. This methodology was successfully applied for a one-pot reaction of bromide derivatives and sodium azide in methanol. Notably, by controlling the reaction time several N-monomethylated and N,N-dimethylated amines were synthesized selectively. The practical applicability of this tandem process was revealed by preparative scale reactions with different organic azides and synthesis of an anti-vertigo drug betahistine. Several kinetic experiments and DFT studies were carried out to understand the mechanism of this transformation.
- Chakrabarti, Kaushik,Mishra, Anju,Panja, Dibyajyoti,Paul, Bhaskar,Kundu, Sabuj
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supporting information
p. 3339 - 3345
(2018/07/29)
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- Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands
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In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new σ1 receptor (σ1R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based σ1 ligands, the three-dimensional homology model of the σ1R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the σ1R binding cavity was explored, and the effect on σ1R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward σ1and σ2receptors were tested. Finally, a representative series of best σ1R binders were assayed for cytotoxic activity on the SH-SY5Y human neuroblastoma cell line. Specifically, the new 4-phenyloxazolidin-2-one derivatives 2b (i.e., (R)-2b and (S)-2b) emerged as potential leads for further development as σ1R agents, as they were found endowed with the highest σ1R affinity (Kiσ1 values in the range 0.95–9.3?nM), and showed minimal cytotoxic levels exhibited in the selected, cell-based test, in line with a σ1R agonist behavior.
- Zampieri, Daniele,Vio, Luciano,Fermeglia, Maurizio,Pricl, Sabrina,Wünsch, Bernhard,Schepmann, Dirk,Romano, Maurizio,Mamolo, Maria Grazia,Laurini, Erik
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p. 712 - 726
(2016/07/06)
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- Tandem C(sp3)?H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones
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Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of isoindolinones with aryl bromides (22 examples) using a palladium(II) acetate/NIXANTPHOS-based catalyst system. Additionally 3-aryl-3-hydroxyisoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxy group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials. (Figure presented.).
- Jiménez, Jacqueline,Kim, Byeong-Seon,Walsh, Patrick J.
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supporting information
p. 2829 - 2837
(2016/09/13)
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- AZETIDINE DERIVATIVES USEFUL FOR THE TREATMENT OF METABOLIC AND INFLAMMATORY DISEASES
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Compounds are disclosed that have a formula represented by the following: These compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example inflammatory conditions, infectious diseases, autoimmune diseases, diseases involving impairment of immune cell functions, cardiometabolic diseases, and/or proliferative diseases.
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Page/Page column 93
(2012/08/07)
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- A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT
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A series of 12 new dibemethin (N-benzyl-N-methyl-1-phenylmethanamine) derivatives bearing an N-aminomethyl group attached to the one phenyl ring and an H, Cl, OCH3 or N(CH3)2 group on the other have been synthesized. These compounds all showed strong chloroquine chemosensitizing activity, comparable to verapamil, when present at 1 μM in an in vitro culture of the chloroquine-resistant W2 strain of the human malaria parasite, Plasmodium falciparum. Their N-formylated derivatives also exhibited resistance-reversing activity, but only at substantially higher IC10 concentrations. A number of the dibemethin derivatives were shown to inhibit chloroquine transport via the parasite's 'chloroquine resistance transporter' (PfCRT) in a Xenopus laevis oocyte expression system. The reduced resistance-reversing activity of the formylated compounds relative to their free amine counterparts can probably be ascribed to two factors: decreased accumulation of the formylated dibemethins within the parasite's internal digestive vacuole (believed to be the site of action of chloroquine), and a reduced ability to inhibit PfCRT. The resistance-reversing activity of the compounds described here demonstrates that the amino group need not be attached to the two aromatic rings via a three or four carbon chain as has been suggested by previous QSAR studies. These compounds may be useful as potential side chains for attaching to a 4,7-dichloroquinoline group in order to generate new resistance-reversing chloroquine analogues with inherent antimalarial activity.
- Zishiri, Vincent K.,Hunter, Roger,Smith, Peter J.,Taylor, Dale,Summers, Robert,Kirk, Kiaran,Martin, Rowena E.,Egan, Timothy J.
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experimental part
p. 1729 - 1742
(2011/05/06)
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- Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization
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A chiral catalyst prepared from N,N′-dioxide and Co(BF 4)2·6H2O was applied in the asymmetric hydride transfer initiated cyclization reaction, giving optically active tetrahydroquinolines in good yields with high enantioselectivities under mild reaction conditions. Meanwhile, in light of the absolute configuration of the product, a possible working model was proposed to explain the origin of the activation and asymmetric induction.
- Cao, Weidi,Liu, Xiaohua,Wang, Wentao,Lin, Lili,Feng, Xiaoming
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p. 600 - 603
(2011/04/15)
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- QUINOLINE COMPOUNDS CONTAINING A DIBEMETHIN GROUP
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4-Amino-7-chloroquinolines are described containing dibenzylmethylamine (dibemethin) side chains attached via a methylene bridge to the amino group of the quinoline showing strong antimalarial and resistance reversing activity. The compounds are of the general formula (I), wherein X1, X2, X3 and X4 are independently selected from the group consisting of H, alkoxy, amido, optionally substituted amino, cyano, halo, haloalkyl, hydroxyl, nitro, sulphonamide and trifluoromethyl; Y is CH or N; m, n, p, q, r and s are independently from 0 to 5; R1, R2, R3 and R4 are independently selected from the group consisting of H, optionally substituted alkyl, alkenyl, alkynyl cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein R3 and R4 together with the carbon atoms to which they are joined optionally form a six membered ring; or pharmaceutically acceptable salts thereof. Pharmaceutical compositions containing at least one of these compounds are also described for treating or preventing malaria.
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Page/Page column 19; 23
(2010/04/03)
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- THERAPEUTIC MACROLIDE COMPOUNDS AND THEIR USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain macrolide compounds (for convenience, collectively referred to herein as "MC compounds"), which, inter alia, are useful in treatment of cancer. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to treat proliferative conditions such as cancer, and in the treatment of diseases and conditions that are mediated by the regulation (e.g. inhibition) of cell proliferation, optionally in combination with another agent.
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Page/Page column 90, 91
(2010/06/17)
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- Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations
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3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H37Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.
- Zampieri, Daniele,Mamolo, Maria Grazia,Laurini, Erik,Fermeglia, Maurizio,Posocco, Paola,Pricl, Sabrina,Banfi, Elena,Scialino, Giuditta,Vio, Luciano
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experimental part
p. 4693 - 4707
(2009/10/24)
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- Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists
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Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1a (MIP-1a) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC50 of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.
- Merritt, J. Robert,Liu, Jinqi,Quadros, Elizabeth,Morris, Michelle L.,Liu, Ruiyan,Zhang, Rui,Jacob, Biji,Postelnek, Jennifer,Hicks, Catherine M.,Chen, Weiqing,Kimble, Earl F.,Rogers, W. Lynn,O'Brien, Linda,White, Nicole,Desai, Hema,Bansal, Shalini,King, George,Ohlmeyer, Michael J.,Appell, Kenneth C.,Webb, Maria L.
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supporting information; experimental part
p. 1295 - 1301
(2009/12/07)
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- Cholinesterase inhibitors: SAR and enzyme inhibitory activity of 3-[ω-(benzylmethylamino)alkoxy]xanthen-9-ones
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In this work, we further investigated a previously introduced class of cholinesterase inhibitors. The removal of the carbamic function from the lead compound xanthostigmine led to a reversible cholinesterase inhibitors 3. Some new 3-[ω-(benzylmethylamino)alkoxy]xanthen-9-one analogs were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The length of the alkoxy chain of compound 3 was increased and different substituents were introduced. From the IC50 values, it clearly appears that the carbamic residue is crucial to obtain highly potent AChE inhibitors. On the other hand, peculiarity of these compounds is the high selectivity toward BuChE with respect to AChE, being compound 12 the most selective one (6000-fold). The development of selective BuChE inhibitors may be of great interest to clarify the physiological role of this enzyme and to provide novel therapeutics for various diseases.
- Piazzi, Lorna,Belluti, Federica,Bisi, Alessandra,Gobbi, Silvia,Rizzo, Stefano,Bartolini, Manuela,Andrisano, Vincenza,Recanatini, Maurizio,Rampa, Angela
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p. 575 - 585
(2008/03/12)
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- TACHYKININ RECEPTOR ANTAGONISTS
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The present invention relates to selective NK-1 receptor antagonists of Formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with an excess of tachykinins.
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- Oxidation of secondary amines by molecular oxygen and cyclohexanone monooxygenase
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Cyclohexanone monooxygenase from Acinetobacter calcoaceticus catalyzed the oxidation of tertiary and secondary amines to N-oxides and nitrones, respectively. The formation of a hydroxylamine intermediate was involved with secondary amines as starting substrates.
- Colonna, Stefano,Pironti, Vincenza,Carrea, Giacomo,Pasta, Piero,Zambianchi, Francesca
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p. 569 - 575
(2007/10/03)
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- β-lactam derivatives as inhibitors of human cytomegalovirus protease
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The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the β- lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both triand tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.
- Yoakim, Christiane,Ogilvie, William W.,Cameron, Dale R.,Chabot, Catherine,Guse, Ingrid,Haché, Bruno,Naud, Julie,O'Meara, Jeff A.,Plante, Raymond,Déziel, Robert
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p. 2882 - 2891
(2007/10/03)
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- Mono and double modified teicoplanin aglycon derivatives on the amino acid No. 7; Structure-activity relationship
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A series of 7d-aminomethylated derivatives (mono modified) and their amides (double modified) at the amino acid No. 7 of teicoplanin aglycon were prepared with the aim of obtaining activity against vancomycin-resistant VanA enterococci. Among mono modified compounds, the 7d-n-decylaminomethyl derivative was the most active against VanA enterococci (4 μg/ml). Amides of the latter with 3-dimethylamino-propylamine or methylamine were found to be up to four times more active against glycopeptide-susceptible Gram-positive bacteria, and up to four times less active against VanA enterococci than the starting compound.
- Pavlov, Andrei Y.,Preobrazhenskaya, Maria N.,Malabarba, Adriano,Ciabatti, Romeo,Colombo, Luigi
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- Synthesis of 1,2-Dihydroisoquinoline-3-carbaldehydes
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ortho-Formylation of N-(2,2-diethoxyethyl)benzylamines followed by acid-catalyzed cyclisation leads to 1,2-dihydroisoquinoline-3-carbaldehydes.
- Simig, Gyula
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p. 1613 - 1616
(2007/10/02)
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- Cross Interaction Constants As a Measure of Transition State structure. Part 7. Aminolysis of Alkyl Benzenesulphonates
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Kinetic studies of the reactions of methyl and ethyl benzenesulphonates with anilines and benzylamines in methanol and acetonitrile at 65.0 deg C have been reported.The magnitudes of cross-interaction constants between substituents in the nucleophile (X) and the leaving group (Z),ρxz and βxz, were found to be greater for the ethyl series which indicates a tighter transition state for ethyl rather than methyl derivatives.This unexpected trend has been rationalized by making the assumption that the small electron-donating polar effect, of the α-methyl substituent in the ethyl compounds, requires a tighter transition-state structure in addition to the major effect of steric repulsion on the activation barrier which is present in all SN2 reactions taking place at a carbon centre.
- Lee, Ikchoon,Choi, Young Hoon,Rhyu, Keun Woo,Shim, Chang Sub
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p. 1881 - 1886
(2007/10/02)
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- Oxidations with Cerium(IV) Sulfate: Intramolecular Cyclization of N-Benzyl-&β-aminoketones Yielding 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines
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Preparation and regiospecific cerium(IV) sulfate of the substituted N-benzyl-β-aminoketones 3 are described. 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines 4 so obtained are reduced by sodium borohydride.
- Holzgrabe, Ulrike
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p. 647 - 654
(2007/10/02)
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- Quantitative structure-activity relationship of the mutagenicity of substituted N-nitroso-N-benzylmethylamines: Possible implications of carcinogenicity
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The relative mutagenicities of substituted N-nitroso-N-benzylmethylamines have been reexamined from a quantitative structure-activity relationship point of view. Most of the compounds were mutagenic toward Salmonella typhimurium TA 1535 with Aroclor-induced male hamster liver S9 activation. The dose-response data were subjected to a multiple linear regression equation calculated in a stepwise manner, which found that the differences in mutagenicities could be explained primarily by differences in the three-bond path molecular connectivity index, with smaller contributions from σ and π. Moreover, a polynomial regression analysis showed that the maximum mutagenicity could be explained by an optimal amount of electron withdrawal by the substituent which could cause a weakening, or activation, of the methylene C-H bond. The possible relevance of these observations to carcinogenesis is discussed.
- Singer,Andrews,Guo
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- Oxidative N-Dealkylation of N,N-Dimethylbenzylamines by Metalloporphyrin-catalysed Model Systems for Cytochrome P450 Mono-oxygenases
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Iodosylbenzene, catalysed by tetraphenylporphyrinato-iron(III) or - manganese(III) chloride, oxidises tertiary amines by an initial one-electron transfer process whereas with t-butyl hydroperoxide with these catalysts the oxidation is initiated by hydrogen atom abstraction.
- Smith, John R. Lindsay,Mortimer, David N.
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- Benzylamines: Synthesis and evaluation of antimycobacterial properties
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The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are described. The most active compounds in this test, N-methyl-3-chlorobenzylamine (MIC 10.2 μg/mL), N-methyl-3,5-dichlorobenzylamine (93, MIC 10.2 μg/mL), and N-butyl-3,5-difluorobenzylamine (MIC 6.4 μg/mL), also exhibited a marked inhibitory effect on Mycobacterium marinum and Mycobacterium lufu used for the determination of antileprotic properties. The combination of 93 with aminosalicylic acid, streptomycin, or dapsone exert marked supra-additive effects on M. tuberculosis H 37 Ra.
- Meindl,Von Angerer,Schonenberger,Ruckdeschel
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p. 1111 - 1118
(2007/10/02)
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- Mutagenicity and Chemistry of N-Nitroso-N-(p-substituted-benzyl)methylamines
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The relative mutagenicities of N-nitroso-N-(p-substituted-benzyl)methylamines in Salmonella typhimurium TA 1535 were tested in order to determine whether biological activity is affected by the electron density at a nitrosamine α carbon.The order of potency was as follows: X = Cl > CN > Br > NO2 > H > CH3O > CH3 > F >> COOH.No direct correlation was apparent, nor was there obvious correlation between biological activity and the extent of base-catalysed hydrogen-deuterium exchange at the α-carbons.
- Singer, George M.,Andrews, A.W.
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p. 309 - 312
(2007/10/02)
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- Substituted 7,12-methano dibenzazocines
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Substituted 7,12-methano-dibenzazocines, e.g., 7,13-dihydro-6,12-dimethyl-7,12-methano-6H-dibenz[c,f]azocine, are prepared by cyclizing 3-benzylamino-alkyl-indan-1-ols and are useful as anti-inflammatory agents.
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- Substituted 7,12-methano dibenzazocines and 8,13-methano dibenzazonines
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Substituted 7,12-methano-dibenzazocines and 8,13-methanodibenzazonines, e.g., 7,12-dihydro-6,13-dimethyl-7,12-methano-6H-dibenz [c,f] azocine, are prepared by cyclizing 3-benzylamino or 3-phenethylamino -2-alkyl-indan-1-ols and are useful as anti-inflammatory agents.
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