- Ruthenium-catalyzed intramolecular arene C(sp2)-H amidation for synthesis of 3,4-dihydroquinolin-2(1 H)-ones
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We report the [Ru(p-cymene)(l-proline)Cl] ([Ru1])-catalyzed cyclization of 1,4,2-dioxazol-5-ones to form dihydroquinoline-2-ones in excellent yields with excellent regioselectivity via a formal intramolecular arene C(sp2)-H amidation. The reactions of the 2- and 4-substituted aryl dioxazolones proceeds initially through spirolactamization via electrophilic amidation at the arene site, which is para or ortho to the substituent. A Hammett correlation study showed that the spirolactamization is likely to occur by electrophilic nitrenoid attack at the arene, which is characterized by a negative ρ value of -0.73.
- Au, Chi-Ming,Ling, Cho-Hon,Sun, Wenlong,Yu, Wing-Yiu
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supporting information
p. 3310 - 3314
(2021/05/29)
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- Copper-Catalyzed Intermolecular Enantioselective Radical Oxidative C(sp3)?H/C(sp)?H Cross-Coupling with Rationally Designed Oxazoline-Derived N,N,P(O)-Ligands
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The intermolecular asymmetric radical oxidative C(sp3)?C(sp) cross-coupling of C(sp3)?H bonds with readily available terminal alkynes is a promising method to forge chiral C(sp3)?C(sp) bonds because of the high atom and step economy, but remains underexplored. Here, we report a copper-catalyzed asymmetric C(sp3)?C(sp) cross-coupling of (hetero)benzylic and (cyclic)allylic C?H bonds with terminal alkynes that occurs with high to excellent enantioselectivity. Critical to the success is the rational design of chiral oxazoline-derived N,N,P(O)-ligands that not only tolerate the strong oxidative conditions which are requisite for intermolecular hydrogen atom abstraction (HAA) processes but also induce the challenging enantiocontrol. Direct access to a range of synthetically useful chiral benzylic alkynes and 1,4-enynes, high site-selectivity among similar C(sp3)?H bonds, and facile synthesis of enantioenriched medicinally relevant compounds make this approach very attractive.
- Gu, Qiang-Shuai,Guo, Kai-Xin,Li, Zhong-Liang,Liu, Lin,Liu, Xin-Yuan,Tian, Yu,Yang, Chang-Jiang,Ye, Liu
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supporting information
p. 26710 - 26717
(2021/11/18)
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- Synthesis and antitumor activity of aza-brazilan derivatives containing imidazolium salt pharmacophores
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The synthesis of a series of novel aza-brazilan derivatives containing imidazolium salt pharmacophores is presented. The biological activity of such imidazolium salts was further evaluated in vitro against a panel of human tumor cell lines. The results suggest that the electron-withdrawing group on the aza-brazilan moiety, substituted 5,6-dimethyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-methylbenzyl group were essential for modulating the cytotoxic activity. Compounds 55 and 39, bearing a 4-methylbenzyl substituent at position-3 of 5,6-dimethyl-benzimidazole, were found to be the most potent compounds with IC50 values of 0.52-1.30 μM and 0.56-1.51 μM against four human tumor cell lines investigated. Particularly, compound 57 exhibited inhibitory activity against the MCF-7 cell line with an IC50 value of 0.35 μM and was 56-fold more sensitive than DDP. Moreover, compound 55 inhibited cell proliferation through inducing G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells.
- Huang, Mingqin,Duan, Shengzu,Ma, Xueqiong,Cai, Bicheng,Wu, Dongmei,Li, Yan,Li, Liang,Zhang, Hongbin,Yang, Xiaodong
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supporting information
p. 1027 - 1036
(2019/06/27)
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- Modular synthesis and biological investigation of 5-hydroxymethyl dibenzyl butyrolactones and related lignans
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Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.
- Davidson, Samuel J.,Pilkington, Lisa I.,Dempsey-Hibbert, Nina C.,El-Mohtadi, Mohamed,Tang, Shiying,Wainwright, Thomas,Whitehead, Kathryn A.,Barker, David
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- Total Synthesis of Ovafolinins A and B: Unique Polycyclic Benzoxepin Lignans through a Cascade Cyclization
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Ovafolinins A and B, isolated from Lyonia ovalifolia var. elliptica, are lignans that contain a unique bridged structure containing a penta- and tetracyclic benzoxepin and an aryl tetralin. We report the first total synthesis of these natural products in which an acyl-Claisen rearrangement was initially utilized to construct the lignan backbone with correct relative stereochemistry. Judicious use of a bulky protecting group placed reactive moieties in the correct orientation, thereby resulting in a cascade reaction to form the bridged benzoxepin/aryl tetralin from a linear precursor in a single step. Modification of this route allowed the enantioselective synthesis of (+)-ovafolinins A and B, which confirmed the absolute stereochemistry, and comparison of optical rotation suggests that these compounds are found as scalemic mixtures in nature.
- Davidson, Samuel J.,Barker, David
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supporting information
p. 9483 - 9486
(2017/08/01)
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- Photoassisted Synthesis of Complex Molecular Architectures: Dearomatization of Benzenoid Arenes with Aza-o-xylylenes via an Unprecedented [2+4] Reaction Topology
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A new method was developed for the photoinduced dearomatization of arenes through an intramolecular cycloaddition with aza-o-xylylenes generated by excited-state intramolecular proton transfer (ESIPT) in the readily available photoprecursors. The [2+4] topology of this cycloaddition is unprecedented for photo-dearomatizations of benzenoid aromatic carbocycles. It provides rapid access to novel heterocycles, cyclohexadieno-oxazolidino-quinolinols, as valuable synthons for a broad range of post-photochemical transformations. I'm so excited: Photoinduced dearomatization of arenes was achieved through intramolecular cycloaddition with aza-o-xylylenes generated by excited-state intramolecular proton transfer in the readily available photoprecursors. The [2+4] topology of this cycloaddition is unprecedented for photo-dearomatizations of benzenoid aromatic carbocycles and produces the novel heterocycles cyclohexadieno-oxazolidino-quinolinols.
- Kuznetsov, Dmitry M.,Mukhina, Olga A.,Kutateladze, Andrei G.
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supporting information
p. 6988 - 6991
(2016/06/13)
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- Synthesis of the Enantiomers of Tedanalactam and the First Total Synthesis and Configurational Assignment of (+)-Piplaroxide
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Highlighting the recently established methodology for the direct synthesis of glycidic amides from tertiary allyl amines, the synthesis of the enantiomers of tedanalactam were completed in two steps from the corresponding chiral dihydropiperidine. Additio
- Romero-Ibaez, Julio,Xochicale-Santana, Leonardo,Quintero, Leticia,Fuentes, Lilia,Sartillo-Piscil, Fernando
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p. 1174 - 1178
(2016/05/24)
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- Polyamine derivative medicinal salt and its preparation method and use
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The invention relates to a polyamine derivative medicinal salt and its preparation method and use in preparation of a drug for treating pyemia. The novel compound has good antagonistic action on a plurality of pyemia-causing pathogen-related molecules such as bacterial lipopolysaccharide (endotoxin), bacterial genome DNA, peptidoglycan, teichoic acid, virus RNA and zymosan, and can be used for preparation of a drug for treating pyemia.
- -
-
Paragraph 0048; 0050
(2016/10/17)
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- Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents
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The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Aβ1–42) inhibition activities as multifunctional drug candidates for the treatment of Alzheimer’s disease (AD). A series of 5,6-dimethoxy-1H-indene-2-carboxamides (1–22) was synthesized; cholinesterase inhibitory activities of the compounds were measured according to Ellman’s colorimetric assay, while the thioflavin T assay was used for measuring the inhibition of Aβ1–42 aggregation. The results revealed that most compounds showed higher inhibitory activity against BuChE than AChE. Compounds 20 and 21 were found to be the most potent BuChE inhibitors with respective IC50 values of 1.08 and 1.09 μM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Aβ1–42 aggregation. Kinetic analysis showed that the most potent BuChE inhibitor (20) acted as a noncompetitive inhibitor. Docking studies suggested that inhibitor 20 displayed many potential hydrogen-bondings with the PAS of BuChE. These results suggest that compound 20 may be an especially promising multifunctional drug for the prevention and treatment of AD.
- Koca, Mehmet,Yerdelen, Kadir Ozden,Anil, Baris,Kasap, Zeynep,Sevindik, Handan,Ozyurek, Ibrahim,Gunesacar, Gulsen,Turkaydin, Kubra
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- Synthesis of donepezil-based multifunctional agents for the treatment of Alzheimer's disease
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Amyloid beta (Aβ) and cholinesterase enzymes (AChE, BuChE) are important biological targets for the effective treatment of Alzheimer's disease. In this study, the aim was to synthesize new donepezil-like secondary amide compounds that display a potent inhibition of cholinesterases and Aβ with antioxidant and metal chelation abilities. All test compounds showed activities against both ChEs and β1-42 inhibition. The most encouraging compound, 20, is an AChE inhibitor with high anti-aggregation activity (55.3%). Based on the results, compound 20 may be a promising structure in further research for new anti-Alzheimer's agents.
- Yerdelen, Kadir Ozden,Koca, Mehmet,Anil, Baris,Sevindik, Handan,Kasap, Zeynep,Halici, Zekai,Turkaydin, Kubra,Gunesacar, Gulsen
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supporting information
p. 5576 - 5582
(2015/11/17)
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- Enantioselective total synthesis of (+)-brazilin, (-)-brazilein and (+)-brazilide A
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An enantioselective strategy for the synthesis of (+)-brazilin, (-)-brazilein and (+)-brazilide A has been developed. A Lewis acid mediated lactonization established the novel fused bis-lactone core of brazilide A and finalized the first total synthesis of (+)-brazilide A.
- Wang, Xuequan,Zhang, Hongbin,Yang, Xiaodong,Zhao, Jingfeng,Pan, Chengxue
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supporting information
p. 5405 - 5407
(2013/06/27)
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- New orally effective 3-(2-nitro)phenylpropanamide analgesic derivatives: Synthesis and antinociceptive evaluation
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A series of substituted 6-nitrophenylpropanamide derivatives (1-20) were synthesized using either the TDAE strategy or classical organic reactions. All these compounds were characterized by fusion point, 1H NMR, 13C NMR, elemental an
- Since, Marc,Freret, Thomas,Nee, Gerald,Terme, Thierry,Vanelle, Patrice,Boulouard, Michel
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p. 728 - 734
(2013/10/22)
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- Concise synthesis of 2-benzazepine derivatives and their biological activity
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Figure Persented: 2-Benzazepines, which are potentially good candidates for new drug therapies to treat skin wounds, were readily prepared from substituted cinnamylamide via an intramolecular Friedel-Crafts reaction. With few steps and effective reactions
- So, Masahiro,Kotake, Tomoko,Matsuura, Kenji,Inui, Makoto,Kamimura, Akio
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experimental part
p. 4017 - 4028
(2012/06/15)
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- A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates
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A Ru-catalyzed direct thermal trifluoromethylation and perfluoroalkylation of N-acyloxazolidinones has been developed. The reaction is experimentally simple and requires inexpensive reagents while providing good yields of products with good levels of stereocontrol. Preliminary studies have shown notable compatibility with functional groups, aromatics, and certain heteroaromatic substituents. The described method provides a useful alternative for the synthesis of fluorinated materials in an experimentally convenient manner.
- Herrmann, Aaron T.,Smith, Lindsay L.,Zakarian, Armen
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supporting information; experimental part
p. 6976 - 6979
(2012/06/15)
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- Design and synthesis of brazilin-like compounds
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A general and flexible synthetic route, which leads to the synthesis of brazilin-like compounds, was developed. The aza-brazilin derivatives show strong anticancer activities in MTT assay towards a number of human cancer cell lines including HT29, A549, HL60, and K562. Georg Thieme Verlag Stuttgart New York.
- Pan, Chengxue,Zeng, Xianghui,Guan, Yifu,Jiang, Xiangliu,Li, Liang,Zhang, Hongbin
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supporting information; experimental part
p. 425 - 429
(2011/04/22)
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- 2,4,5-TRISUBSTITUTED THIAZOLE COMPOUNDS,PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS AND MEDICAL USES THEREOF
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The present invention relates to 2,4,5-trisubstituted thiazole compounds of formula (I) or all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof for the inhibition of plasma PLTP activity and/or plasma CETP activity, wherein the substituents are as defined in the specification; a process for the preparation of the compounds of formula (I); a pharmaceutical composition comprising the compound of formula (I) and its use for the preparation of a medicament for treatment and/or prevention of diseases associated with the increased plasma PLTP activity and/or the increased plasma CETP activity in a mammal, such as atherosclerosis, cardiovascular diseases and peripheral vascular diseases, etc.
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Page/Page column 54
(2009/04/23)
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- TRISUBSTITUTED THIAZOLE COMPOUNDS, PREPARATIONS METHODS, PHARMACEUTICAL COMPOSITIONS AND MEDICALS USES THEREOF
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The present invention relates to 2,4,5-trisubstituted thiazole compounds of formula (I) or all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof for the inhibition of plasma PLTP activity and/or plasma CETP activity, wherein the substituents are as defined in the specification; a process for the preparation of the compounds of formula (I); a pharmaceutical composition comprising the compound of formula (I) and its use for the preparation of a medicament for treatment and/or prevention of diseases associated with the increased plasma PLTP activity and/or the increased plasma CETP activity in a mammal, such as atherosclerosis, cardiovascular diseases and peripheral vascular diseases, etc.
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Page/Page column 37
(2009/12/23)
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- An investigation into the electrophilic cyclisation of N-acyl-pyrrolidinium ions: A facile synthesis of Pyrrolo-tetrahydroisoquinolones and Pyrrolo-benzazepinones
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The triflic acid-mediated cyclisation of N-arylmethyl- and N-arylethyl-acylpyrrolidinium ions gave moderate to good yields of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones respectively. Electron-donating R substituents enhanced the rate of reaction and gave higher yields than electron-withdrawing substituents. Substituents on the methyl or ethyl chain in general enhanced the reaction, unless sterically encumbered. The equivalent acylpiperidinium ions cyclised much slower and in lower yield.
- King, Frank D.,Aliev, Abil E.,Caddick, Stephen,Copley, Royston C. B.
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experimental part
p. 3561 - 3571
(2010/01/06)
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- Discovery and biological evaluation of novel cyanoguanidine P2X7 antagonists with analgesic activity in a rat model of neuropathic pain
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We disclose the design of a novel series of cyanoguanidines that are potent (IC50 ? 10-100 nM) and selective (≥100-fold) P2X7 receptor antagonists against the other P2 receptor subtypes such as the P2Y2, P2X4, and P2X3. We also found that these P2X7 antagonists effectively reduced nociception in a rat model of neuropathic pain (Chung model). Particularly, analogue 53 proved to be effective in the Chung model, with an ED50 of 38 μmol/kg after intraperitoneal administration. In addition compound 53 exhibited antiallodynic effects following oral administration and maintained its efficacy following repeated administration in the Chung model. These results suggest an important role of P2X7 receptors in neuropathic pain and therefore a potential use of P2X7 antagonists as novel therapeutic tools for the treatment of this type of pain.
- Perez-Medrano, Arturo,Donnelly-Roberts, Diana L.,Honore, Prisca,Hsieh, Gin C.,Namovic, Marian T.,Peddi, Sridhar,Shuai, Qi,Wang, Ying,Faltynek, Connie R.,Jarvis, Michael F.,Carroll, William A.
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scheme or table
p. 3366 - 3376
(2010/04/03)
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- Inter- and intraspecific comparisons of antiherbivore defenses in three species of rainforest understory shrubs
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Plants defend themselves against herbivores and pathogens with a suite of morphological, phenological, biochemical, and biotic defenses, each of which is presumably costly. The best studied are allocation costs that involve trade-offs in investment of resources to defense versus other plant functions. Decreases in growth or reproductive effort are the costs most often associated with antiherbivore defenses, but trade-offs among different defenses may also occur within a single plant species. We examined trade-offs among defenses in closely related tropical rain forest shrubs (Piper cenocladum, P. imperiale, and P. melanocladum) that possess different combinations of three types of defense: ant mutualists, secondary compounds, and leaf toughness. We also examined the effectiveness of different defenses and suites of defenses against the most abundant generalist and specialist Piper herbivores. For all species examined, leaf toughness was the most effective defense, with the toughest species, P. melanocladum, receiving the lowest incidence of total herbivory, and the least tough species, P. imperiale, receiving the highest incidence. Although variation in toughness within each species was substantial, there were no intraspecific relationships between toughness and herbivory. In other Piper studies, chemical and biotic defenses had strong intraspecific negative correlations with herbivory. A wide variety of defensive mechanisms was quantified in the three Piper species studied, ranging from low concentrations of chemical defenses in P. imperiale to a complex suite of defenses in P. cenocladum that includes ant mutualists, secondary metabolites, and moderate toughness. Ecological costs were evident for the array of defensive mechanisms within these Piper species, and the differences in defensive strategies among species may represent evolutionary trade-offs between costly defenses.
- Fincher,Dyer,Dodson,Richards,Tobler,Searcy,Mather,Reid,Rolig,Pidcock
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p. 558 - 574
(2008/09/20)
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- Intermolecular oxidative enolate heterocoupling
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(Chemical Equation Presented) No priming necessary: The intermolecular oxidative heterocoupling of imides and oxindoles to esters, ketones, and lactones is shown for the first time to be synthetically viable. Strategic use of the initial oxidation state o
- Baran, Phil S.,DeMartino, Michael P.
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p. 7083 - 7086
(2007/10/03)
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- Dopamine D3 receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-Dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans
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5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure- activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D3 antagonists. Thus, combinations of various alkyl groups were generally inactive at the D3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D3 binding affinity, the D2 affinity is also enhanced, resulting in a less than 4-fold preference for the D3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D3 antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH3·Me2S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et3SiH to give the desired product 3 in good overall yield of (~65%) from the indanone 5c.
- Haadsma-Svensson,Cleek,Dinh,Duncan,Haber,Huff,Lajiness,Nichols,Smith,Svensson,Zaya,Carlsson,Lin
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p. 4716 - 4732
(2007/10/03)
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- IMDAF Cycloaddition as a Method for the Preparation of Pyrrolophenanthridine Alkaloids
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Acylation of 5-amino-2-furancarboxylic acid methyl ester with alkenoyl acid chlorides gives 2-amidofurans that undergo intramolecular Diels-Alder cycloadditions. The reactions occur at 165°C in toluene or at 100°C when 4 M ethereal LiClO4 was u
- Padwa, Albert,Dimitroff, Martin,Waterson, Alex G.,Wu, Tianhua
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p. 3986 - 3997
(2007/10/03)
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- Intramolecular Reactions of N-Nitrenes: Oxidation of 3-Amino-2-(arylalkyl)quinazolin-4(3H)-ones
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Oxidation of the title compounds yields N-nitrenes which react intramolecularly with methoxy-substituted aryl rings.The particular substitution pattern in the aryl rings which is required for effective trapping of the nitrenes is in accord with an electro
- Atkinson, Robert S.,Malpass, John R.,Woodthorpe, Katherine L.
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p. 2407 - 2412
(2007/10/02)
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