- 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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- Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent
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We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4′-position, the basicity of the 4-position amino moiety, and conformational restriction. The potential metabolites of the active compounds were also synthesized. Some compounds demonstrated single digit nanomolar IC50 values for antiproliferative effects in MDA-MB-435 melanoma cells. Particularly, the S-methyl analog 3 was more potent than 1 in MDA-MB-435 cells (IC50 = 4.6 nM). Incubation of 3 with human liver microsomes showed that the primary metabolite of the S-methyl moiety of 3 was the methyl sulfinyl group, as in analog 5. This metabolite was equipotent with the lead compound 1 in MDA-MB-435 cells (IC50 = 7.9 nM). Molecular modeling and electrostatic surface area were determined to explain the activities of the analogs. Most of the potent compounds overcome multiple mechanisms of drug resistance and compound 3 emerged as the lead compound for further SAR and preclinical development.
- Xiang, Weiguo,Choudhary, Shruti,Hamel, Ernest,Mooberry, Susan L.,Gangjee, Aleem
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p. 2437 - 2451
(2018/04/16)
-
- 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)
-
- Selective Monomethylation of Amines with Methanol as the C1 Source
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The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.
- Choi, Geunho,Hong, Soon Hyeok
-
supporting information
p. 6166 - 6170
(2018/04/30)
-
- A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931)
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The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-cataly
- Thaisrivongs, David A.,Morris, William J.,Tan, Lushi,Song, Zhiguo J.,Lyons, Thomas W.,Waldman, Jacob H.,Naber, John R.,Chen, Wenyong,Chen, Lu,Zhang, Baoyun,Yang, Jun
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p. 1568 - 1571
(2018/03/23)
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- HALOALLYLAMINE PYRAZOLE DERIVATIVE INHIBITORS OF LYSYL OXIDASES AND USES THEREOF
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The present invention relates to novel compounds which are capable of inhibiting certain amine oxidase enzymes. These compounds are useful for treatment of a variety of indications, e.g., fibrosis, cancer and/or angiogenesis in human subjects as well as i
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- Alkyl-guanidine Compounds as Potent Broad-Spectrum Antibacterial Agents: Chemical Library Extension and Biological Characterization
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Nowadays, the increasing of multidrug-resistant pathogenic bacteria represents a serious threat to public health, and the lack of new antibiotics is becoming a global emergency. Therefore, research in antibacterial fields is urgently needed to expand the currently available arsenal of drugs. We have recently reported an alkyl-guanidine derivative (2), characterized by a symmetrical dimeric structure, as a good candidate for further developments, with a high antibacterial activity against both Gram-positive and Gram-negative strains. In this study, starting from its chemical scaffold, we synthesized a small library of analogues. Moreover, biological and in vitro pharmacokinetic characterizations were conducted on some selected derivatives, revealing notable properties: broad-spectrum profile, activity against resistant clinical isolates, and appreciable aqueous solubility. Interestingly, 2 seems neither to select for resistant strains nor to macroscopically alter the membranes, but further studies are required to determine the mode of action.
- Pasero, Carolina,D'Agostino, Ilaria,De Luca, Filomena,Zamperini, Claudio,Deodato, Davide,Truglio, Giuseppina I.,Sannio, Filomena,Del Prete, Rosita,Ferraro, Teresa,Visaggio, Daniela,Mancini, Arianna,Guglielmi, Mario B.,Visca, Paolo,Docquier, Jean-Denis,Botta, Maurizio
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p. 9162 - 9176
(2018/10/24)
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- Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors
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Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC50 > 5 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results.
- Park, Sun You,Oh, Yong Jin,Lho, Yunmee,Jeong, Ju Hui,Liu, Kwang-Hyeon,Song, Jaeyoung,Kim, Soong-Hyun,Ha, Eunyoung,Seo, Young Ho
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p. 390 - 401
(2017/12/07)
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- Photocatalyzed cascade Meerwein addition/cyclization of: N -benzylacrylamides toward azaspirocycles
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A visible-light-induced cascade Meerwein addition/cyclization of alkenes involving C-F bond cleavage was developed. This method offers a rapid access to azaspirocyclic cyclohexadienones from N-benzylacrylamides via C-F bond cleavage applying H2O as an external oxygen source, allowing for the incorporation of various aromatic moieties originating from aryldiazonium salts.
- Yuan, Li,Jiang, Sheng-Ming,Li, Zeng-Zeng,Zhu, Yong,Yu, Jian,Li, Lan,Li, Ming-Zhu,Tang, Shi,Sheng, Rui-Rong
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supporting information
p. 2406 - 2410
(2018/04/12)
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- Reductive N-methylation of amines with calcium hydride and Pd/C catalyst
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The methylation of amines by paraformaldehyde in the presence of calcium hydride as a source of hydrogen and palladium on charcoal as catalyst was studied. Depending on the quantity of paraformaldehyde, monomethylated and dimethylated amines were selectively and efficiently prepared in one pot with good yields.
- Guyon, Carole,Duclos, Marie-Christine,Métay, Estelle,Lemaire, Marc
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p. 3002 - 3005
(2016/07/06)
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- Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family
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Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.
- Tintori, Cristina,Brai, Annalaura,Dasso Lang, Maria Chiara,Deodato, Davide,Greco, Antonia Michela,Bizzarri, Bruno Mattia,Cascone, Lorena,Casian, Alexandru,Zamperini, Claudio,Dreassi, Elena,Crespan, Emmanuele,Maga, Giovanni,Vanham, Guido,Ceresola, Elisa,Canducci, Filippo,Ari?n, Kevin K.,Botta, Maurizio
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p. 2747 - 2759
(2016/04/10)
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- Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease
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Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The s
- Thaisrivongs, David A.,Miller, Steven P.,Molinaro, Carmela,Chen, Qinghao,Song, Zhiguo J.,Tan, Lushi,Chen, Lu,Chen, Wenyong,Lekhal, Azzeddine,Pulicare, Sarah K.,Xu, Yanke
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p. 5780 - 5783
(2016/11/29)
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- Visible light-induced intramolecular dearomative cyclization of α-bromo-N-benzyl-alkylamides: Efficient construction of 2-azaspiro[4.5]decanes
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An efficient intramolecular dearomative cyclization via visible light-induced photoredox catalysis allows for a highly regioselective dearomative cyclization of α-bromo-N-benzyl-alkylamides to construct 2-azaspiro[4.5]decanes in the presence of an iridium catalyst.
- Hu, Bei,Li, Yuyuan,Dong, Wuheng,Ren, Kai,Xie, Xiaomin,Wan, Jun,Zhang, Zhaoguo
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supporting information
p. 3709 - 3712
(2016/03/05)
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- RESORCINOL N-ARYL AMIDE COMPOUNDS, FOR USE AS PYRUVATE DEHYDROGENASE KINASE INHIBITORS
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A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Y is –CONR1- or optionally substituted arylene or optionally substituted heteroarylene; R1 is H, Cl, F, CH3 or CF3; 10 each R4 is independently H, CH3 or F; R5 is H or CH3; and each R2 and R6 is independently (Alk)n-Rn-(Alk)n-Rn-(Alk)n-X; The compounds of the invention are useful as resorcinol N-aryl amide (NAA) compounds, which are suitable for use as PDK inhibitors, for example for 15 inhibition of cancer cell proliferation.
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Page/Page column 81
(2015/04/15)
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- Selective monomethylation of primary amines with simple electrophiles
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Direct monomethylation of primary amines with methyl triflate was achieved with high selectivity (up to 96%). The key point of this single methyl transfer stems from the use of HFIP as the solvent that interferes with amines and avoids overmethylation.
- Lebleu, Thomas,Ma, Xiaolu,Maddaluno, Jacques,Legros, Julien
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supporting information
p. 1836 - 1838
(2014/02/14)
-
- Smooth isoindolinone formation from isopropyl carbamates via bischler-napieralski-type cyclization
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Isopropyl carbamates derived from benzylamines provide isoindolinones by treatment with phosphorus pentoxide at room temperature. Utility of this Bischler-Napieralski-type cyclization and a new mechanism involving a carbamoyl cation for rationalization of this smooth conversion are discussed.
- Adachi, Satoshi,Onozuka, Masao,Yoshida, Yuko,Ide, Mitsuaki,Saikawa, Yoko,Nakata, Masaya
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supporting information
p. 358 - 361
(2014/04/03)
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- SYNERGISTIC COMBINATION OF IMMUNOLOGIC INHIBITORS FOR THE TREATMENT OF CANCER
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In some embodiments, the methods involve the use of a combination of at least two of the following: an inhibitor of indoleamine-2,3-dioxygenase (IDO), an inhibitor of the PD-L1/PD-1 pathway, an inhibitor of CTLA-4, an inhibitor of CD25, or IL-7. The inven
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Paragraph 00313
(2014/05/24)
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- Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl groups
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Sulfamates are important functional groups in certain areas of current medicinal chemistry and drug development. Alcohols and phenols are generally converted into the corresponding primary sulfamates (ROSO2NH 2 and ArOSO2NH2, respectively) by reaction with sulfamoyl chloride (H2NSO2Cl). The lability of the O-sulfamate group, especially to basic conditions, usually restricts this method to a later stage of a synthesis. To enable a more flexible approach to the synthesis of phenolic O-sulfamates, a protecting group strategy for sulfamates has been developed. Both sulfamate NH protons were replaced with either 4-methoxybenzyl or 2,4-dimethoxybenzyl. These N-protected sulfamates were stable to oxidising and reducing agents, as well as bases and nucleophiles, thus rendering such masked sulfamates suitable for multi-step synthesis. The protected sulfamates were synthesised by microwave heating of 1,1′-sulfonylbis(2-methyl-1H-imidazole) with a substituted phenol to give an aryl 2-methyl-1H-imidazole-1-sulfonate. This imidazole-sulfonate was N-methylated by reaction with trimethyloxonium tetrafluoroborate, which enabled subsequent displacement of 1,2-dimethylimidazole by a dibenzylamine (e.g. bis-2,4-dimethoxybenzylamine). The resulting N-diprotected, ring-substituted phenol O-sulfamates were further manipulated through reactions at the aryl substituent and finally deprotected with trifluoroacetic acid to afford a phenol O-sulfamate. The use of 2,4-dimethoxybenzyl was particularly attractive because deprotection occurred quantitatively within 2 h at room temperature with 10% trifluoroacetic acid in dichloromethane. The four key steps in the protocol described [reaction of 1,1′-sulfonylbis(2-methyl-1H-imidazole) with a phenol, methylation, displacement with a dibenzylamine and deprotection] all proceeded in very high yields.
- Reuillon, Tristan,Bertoli, Annalisa,Griffin, Roger J.,Miller, Duncan C.,Golding, Bernard T.
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p. 7610 - 7617
(2012/10/29)
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- 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors
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Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
- Pechulis, Anthony D.,Beck, James P.,Curry, Matt A.,Wolf, Mark A.,Harms, Arthur E.,Xi, Ning,Opalka, Chet,Sweet, Mark P.,Yang, Zhicai,Vellekoop, A. Samuel,Klos, Andrew M.,Crocker, Peter J.,Hassler, Carla,Laws, Mia,Kitchen, Douglas B.,Smith, Mark A.,Olson, Richard E.,Liu, Shuang,Molino, Bruce F.
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p. 7219 - 7222
(2013/01/15)
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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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- A domino microwave-assisted protocol for the synthesis of 2,6-disubstituted pyrimidinones
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A practical microwave-assisted protocol for the synthesis of 2,6-disubstituted pyrimidinones has been developed. This approach is based on a domino Michael addition-cyclocondensation reaction between substituted thioureas/guanidines and acetylenecarboxyla
- Radi, Marco,Casaluce, Gianni,Botta, Maurizio
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supporting information; experimental part
p. 1997 - 2000
(2011/10/09)
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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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- 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; 26-27
(2010/04/03)
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- Argifin; efficient solid phase total synthesis and evalution of analogues of acyclic peptide
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An effective solid phase synthesis of Argifin, providing subsequent access to effective synthesis of analogues, was developed in 13% overall yield, as well as elucidating structure-activity relationships. The novel acyclic peptide 18b, prepared from a synthetic intermediate of Argifin, was found to be 70 times more potent as an inhibitor of Serratia marcescens chitinases B than Argifin itself.
- Sunazuka, Toshiaki,Sugawara, Akihiro,Iguchi, Kanami,Hirose, Tomoyasu,Nagai, Kenichiro,Noguchi, Yoshihiko,Saito, Yoshifumi,Yamamoto, Tsuyoshi,Ui, Hideaki,Gouda, Hiroaki,Shiomi, Kazuro,Watanabe, Takeshi,Omura, Satoshi
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experimental part
p. 2751 - 2758
(2009/08/15)
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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)
-
- Potent and selective adenosine A2A receptor antagonists: 1,2,4-Triazolo[1,5-c]pyrimidines
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Antagonism of the adenosine A2a receptor offers great promise in the treatment of Parkinson's disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A1) A2a antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure-activity relationships and plasma levels are described for this series.
- Neustadt, Bernard R.,Liu, Hong,Hao, Jinsong,Greenlee, William J.,Stamford, Andrew W.,Foster, Carolyn,Arik, Leyla,Lachowicz, Jean,Zhang, Hongtao,Bertorelli, Rosalia,Fredduzzi, Silva,Varty, Geoffrey,Cohen-Williams, Mary,Ng, Kwokei
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scheme or table
p. 967 - 971
(2009/09/06)
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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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- Synthesis, CNS and chloroquin resistance reversal activity of benzenepropanamines
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Several benzenepropanamines with a benzyl group attached to the 3-amino function are synthesized and evaluated for their CNS and chloroquin resistant reversal activity. The compounds are fully characterized by spectral and elemental analyses. These compounds are tested for their effect on gross behaviour and for antidepressant, anticonvulsant and anorexigenic activity. No effect is observed on gross behaviour where as most of them show fluoxetine like antireserpine and anorexigenic activity. Since this class of compounds have been reported to modulate the chloroquin resistance in P. falciparum, therefore these compounds are tested for chloroquin resistance reversal activity in vitro. Five compounds selectively inhibit P. falciparum heme oxygenase like fluoxetine.
- Sharma,Bhandari, Kalpana,Shankar, Girija,Singh,Srivastava, Pratima,Pandey
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p. 207 - 211
(2007/10/03)
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- IMIDAZO-FUSED OXAZOLO[4,5-B]PYRIDINE AND IMIDAZO-FUSED THIAZOLO[4,5-B]PYRIDINE BASED TRICYCLIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME
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The present invention provides for pyrazolopurine-based tricyclic compounds having the formula (I),[chemical structure] wherein R1, R2, R3, R4, R5 and R6 are as described herein. The present invention further provides pharmaceutical compositions comprising such compounds, as well as the use of such compounds for treating inflammatory and immune diseases.
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- Selective N-methylation of primary aliphatic amines with dimethyl carbonate in the presence of alkali cation exchanged Y-faujasites
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The N-methylation of aliphatic amines [XC6H4(CH 2)nNH2; n=1, X=H (1a), o-MeO (1b), p-MeO (1c); n=2, X=H (2a), o-MeO (2b); 1d: PhCH(Me)NH2] with dimethyl carbonate (DMC) is efficiently catalysed by NaY faujasite: on condition that CO 2 (a co-product of the reaction) is carefully removed, N-methyl- and N,N-dimethyl-amines (RNHMe and RNMe2) are obtained in good overall yields (70-90%). Otherwise, in the presence of CO2, carbamates (RNHCO2Me) form competitively to a large extent. The reaction probably proceeds through a BAl2 displacement of the amine on DMC.
- Selva, Maurizio,Tundo, Pietro
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p. 8139 - 8142
(2007/10/03)
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- Practical and efficient synthesis of C2 symmetrical diamines with Zn / Me3SiCl
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C2 symmetrical diamines are efficiently obtained by reductive coupling of imines with the couple Zn/Me3SiCl. This high yielding method is very practical and cheap for large scale preparation.
- Alexakis, Alexandre,Aujard, Isabelle,Mangeney, Pierre
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p. 873 - 874
(2007/10/03)
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- Isomerization of meso diamines into their C2 symmetrical d,l isomers
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An efficient isomerization method is disclosed which allows the obtention of the useful d,l isomers of C2 symmetrical diamines, starting from their meso isomer.
- Alexakis, Alexandre,Aujard, Isabelle,Mangeney, Pierre
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p. 875 - 876
(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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- Facile preparation of N-methyl secondary amines by titanium(IV) isopropoxide-mediated reductive animation of carbonyl compounds
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A simple, mild and efficient procedure for obtaining N-methyl secondary amines from aldehydes and ketones is reported. Treatment of carbonyl compounds with methylamine hydrochloride, triethylamine and titanium(IV) isopropoxide, followed by in situ sodium borohydride reduction and straightforward aqueous work-up, affords clean products in good to excellent yields.
- Neidigh, Kurt A.,Avery, Mitchell A.,Williamson, John S.,Bhattacharyya, Sukanta
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p. 2527 - 2531
(2007/10/03)
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- A New Synthesis of 1,2,3,4-Tetrahydro-2-methyl-4-phenylisoquinolines
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1,2,3,4-Tetrahydro-2-methyl-4-phenylisoquinolines 6 are obtained from aromatic aldehydes 1, methyl amine and α-haloacetophenones 2 in the presence of sodium borohydride followed by cyclization with sulfuric acid and zinc in methanol.
- Venkov, Atanas P.,Vodenicharov, Daniel M.
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p. 253 - 255
(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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- A MECHANISTIC APPROACH TO THE REACTION BETWEEN IMINES AND SODIUM HYDROGEN TELLURIDE
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A study of the mechanism of the action of sodium hydrogen telluride on imines is presented.It accounts for the observed reduction of the imine function to secondary amino or methylene groups depending on the structure of the substrate.
- Barton, Derek H. R.,Bohe, Luis,Lusinchi, Xavier
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p. 2571 - 2574
(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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- Model Systems for Cytochrome P450-dependent Mono-oxygenases. Part 5. Amine Oxidation. Part 17. Oxidative N-Dealkylation of Tertiary Amines by Metalloporphyrin-catalysed Model Systems for Cytochrome P450 Monooxygenases
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NN-Dimethylbenzylamine has been oxidatively demethylated to N-methylbenzylamine and debenzylated to benzaldehyde by iodosylbenzene and by t-butyl hydroperoxide catalysed by tetraphenylporphinato-iron(III) or -manganese(III) chloride.The influence of substituents on the aromatic ring and of deuteration of the benzylic hydrogens on the relative reactivity of the substrates and on the product distribution has been stidied.The results suggest that the initial step in the metalloporphyrin-catalysed iodosylbenzene oxidations is an electron-transfer from the amine to a high valent oxometal species, whereas, with t-butyl hydroperoxide the mechanism is one of hydrogen abstraction from the amine by the t-butoxyl radical.The mechanisms of the subsequent steps are discussed.
- Smith, John R. Lindsay,Mortimer, David N.
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p. 1743 - 1750
(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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- Reactions of N-Halobenzylalkylamines with Sodium Methoxide in Methanol
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Reactions of N-halobenzylmethylamines 1 and 2 (X = Cl and Br) with MeONa-MeOH have been investigated.Eliminations from 1 were quantitative, producing only benzylidenemethylamines.Reaction of 2 with MeONa-MeOH produced benzylidenemethylamines and benzylmethylamines.The yield of benzylidenemethylamine increased with electron-withdrawing aryl substituents and increased base concentration and became quantitative when pentane was used as a solvent.The results are interpreted as competing bimolecular elimination and nucleophilic substitution by methoxide on bromine.Product studies for reaction of N-halobenzyl-tert-butylamines with MeONa-MeOH and EtSNa-MeOH establish that the substitution reaction is a general reaction pathway available for the N-haloamines.Transition states for eliminations from 1 and 2 are characterized by Hammett ρ and primary deuterium isotope effect values.
- Cho, Bong Rae,Yoon, Jong Chan,Bartsch, Richard A.
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p. 4943 - 4946
(2007/10/02)
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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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- ELECTROCATALYTIC HYDROGENATION OF ORGANIC COMPOUNDS ON DEVARDA COPPER AND RANEY NICKEL ELECTRODES IN BASIC MEDIA
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Using Devarda copper and Raney nickel electrodes, nitrobenzene, nitrocyclohexane, p-nitroacetophenone, N-methyl-p-anisaldehyde imine, benzophenone, and phenanthrene have been electrocatalytically hydrogenated with high chemical and current efficiency.
- Belot, Gerard,Desjardins, Sylvie,Lessard, Jean
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p. 5347 - 5350
(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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- N,N'-Dialkyl-1,2-bis(hydroxyphenyl)ethylenediamines and N,N'-Dialkyl-4,5-bis(4-hydroxyphenyl)imidazolidines: Syntheses and Evaluation of Their Mammary Tumor Inhibiting Activity
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Diastereomeric N,N'-dialyl-1,2-bis(hydroxyphenyl)ethylenediamines (5) were synthesized and tested for their affinity for the estradiol receptor.Only the (+/-)-1,2-bis(4-hydroxyphenyl)ethylenediamines with the alkyl groups C3H7 a=1.1
- Angerer, Erwin von,Egginger, Guenter,Kranzfelder, Gerhard,Bernhauer, Horst,Schoenenberger, Helmut
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p. 832 - 837
(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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