- A new multifunctional hydroxytyrosol-fenofibrate with antidiabetic, antihyperlipidemic, antioxidant and antiinflammatory action
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Dyslipidemia, oxidative stress and inflammation are major risky factors involved in the pathophysiology of type 2 diabetes mellitus and atherosclerosis. Multifunctional intervene is more meaningful. The aim of this study was to evaluate the multifunctional effects of two new compounds, combination of fenofibric acid (FA) with tyrosol (T) or hydroxytyrosol (HT). Compared with fenofibrate (FF), FF-HT exhibited excellent antioxidant capacities in vitro and much improved hypolipidemia, reducing plasma triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 76%, 54%, and 28%, while FF-T decreased the plasma parameters by 16%, 10%, and 20% in hyperlipidemic mice induced by Triton WR 1339. Furthermore, compound FF-HT exhibited significant antihyperglycemic, antihyperlipidemic, antioxidant and anti-inflammatory activities as well as attenuating hepatotoxicity in a type 2 diabetes experimental mouse model. The histological findings showed that FF-HT suppressed the development of hepatic lipid accumulation and ameliorated the damage in hepatic and pancreatic tissues compared to model mice. This study indicates for the first time that reasonable optimized drug design produce a compound entity which is conducive to the prevention of type 2 diabetes mellitus and its complications.
- Xie, Yundong,Xu, Yanhong,Chen, Zizhang,Lu, Wenfang,Li, Na,Wang, Qiutang,Shao, Lihua,Li, Yiping,Yang, Guangde,Bian, Xiaoli
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Read Online
- Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents
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The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondria-directed vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 μM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon co-administration with a pump-efflux inhibitor.
- Hicke, Francisco J.,Puerta, Adrián,Dini?, Jelena,Pe?i?, Milica,Padrón, José M.,López, óscar,Fernández-Bola?os, José G.
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- Preparation method of 2-(4-benzyloxyphenyl)ethanol
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The invention provides a preparation method of 2-(4-benzyloxyphenyl)ethanol. The preparation method comprises the following steps: 1) subjecting phenol to reacting with chloroacetyl chloride under the catalysis of aluminum trichloride to obtain a compound as shown in a formula II; 2) subjecting the compound as shown in the formula II to reacting with benzyl halide under an alkaline condition to obtain a compound as shown in a formula III, wherein the benzyl halide is one selected from benzyl bromide and benzyl chloride; 3) performing reduction treatment on the compound as shown in the formula III, and adjusting a reaction system to be an alkaline system to obtain a compound as shown in a formula IV; and 4) under the action of a catalyst, reducing the compound as shown in the formula IV under a hydrogen condition to obtain the 2-(4-benzyloxyphenyl)ethanol as shown in the formula I. The preparation method has the advantages of low cost, mild reaction conditions, safety in operation and less three-waste pollution, and is beneficial to being applied to industrial production.
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- Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents
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Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (MtbTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis. Therefore, this enzyme constitutes a potential Achilles heel of the pathogen. Based on a previously reported MtbTMPK 6-aryl-substituted pyridone inhibitor and guided by two co-crystal structures of MtbTMPK with pyridone- and thymine-based inhibitors, we report the synthesis of a series of aryl-shifted cyanopyridone analogues. These compounds generally lacked significant MtbTMPK inhibitory potency, but some analogues did exhibit promising antitubercular activity. Analogue 11i demonstrated a 10-fold increased antitubercular activity (MIC H37Rv, 1.2 μM) compared to literature compound 5. Many analogues with whole-cell antimycobacterial activity were devoid of significant cytotoxicity.
- Boshoff, Helena I. M.,Caljon, Guy,Forbes, He Eun,Hulpia, Fabian,Jian, Yanlin,Munier-Lehmann, Héle?ne,Risseeuw, Martijn D. P.,Van Calenbergh, Serge
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- Butenolide derivative as well as preparation method and application thereof
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The invention discloses a butenolide compound as well as a preparation method and an application thereof. The butenolide derivative has the inhibitory activity of protein tyrosine phosphatase 1B (PTP1B), improves insulin resistance of HepG2 cells, generates a remarkable hypoglycemic effect and can be used for preparing a medicine for treating diabetes mellitus.
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Paragraph 0052-0054; 0056
(2020/07/21)
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- 1-(4-(2-cyclobutoxyethyl) phenoxy)-3-(isopropylamino) propyl-2-ol and preparation method thereof
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The invention belongs to the technical field of medicine preparation, and mainly relates to a new compound 1-(4-(2-cyclobutoxyethyl) phenoxy)-3-(isopropylamino) propyl-2-ol, a preparation method and application in detection of betaxolol hydrochloride and betaxolol hydrochloride eye drops related substances. The structure of the compound is as shown in the specification. The 1-(4-(2-cyclobutoxyethyl) phenoxy)-3-(isopropylamino) propyl-2-ol prepared by the preparation method disclosed by the invention can be used as a reference substance for detecting the content of 1-(4-(2-cyclobutoxyethyl) phenoxy)-3-(isopropylamino) propyl-2-ol in betaxolol hydrochloride and eye drops of betaxolol hydrochloride. Technical support and material guarantee are provided for improving the quality standard of betaxolol hydrochloride and eye drops thereof and controlling the safety of product quality, so that the national standard of betaxolol hydrochloride is at the world leading level, and the product has good economic benefits and social benefits.
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Paragraph 0007-0008; 0024-0026
(2020/10/14)
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- Access to β-Ketonitriles through Nickel-Catalyzed Carbonylative Coupling of α-Bromonitriles with Alkylzinc Reagents
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Herein, we report a nickel-catalyzed carbonylative coupling of α-bromonitriles and alkylzinc reagents with near stoichiometric carbon monoxide to give β-ketonitriles in good yields. The reaction is catalyzed by a readily available and stable nickel(II) pincer complex. The developed protocol tolerates substrates bearing a variety of functional groups, which would be problematic or incompatible with previous synthetic methods. Additionally, we demonstrate the suitability of the method for carbon isotope labeling by the synthesis of 13C-labeled β-ketonitriles and their transformation into isotopically labeled heterocycles.
- Donslund, Aske S.,Neumann, Karoline T.,Corneliussen, Nicklas P.,Grove, Ebbe K.,Herbstritt, Domenique,Daasbjerg, Kim,Skrydstrup, Troels
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supporting information
p. 9856 - 9860
(2019/07/09)
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- A New Series of Salicylic Acid Derivatives as Non-saccharide α-Glucosidase Inhibitors and Antioxidants
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In this study, a series of salicylic acid derivatives were designed and synthesized as novel non-saccharide α-glucosidase inhibitors. Biological evaluation indicated that when compared to acarbose, compounds T9, T10, and T32 exhibited a higher potency of α-glucosidase inhibitory activity with IC50 values of 0.15±0.01, 0.086±0.01 and 0.32±0.02mM, respectively. Evaluation of the inhibition kinetics indicated that T9, T10, T32, and acarbose interacted with α-glucosidase in a mixed non-competitive inhibitory manner. Moreover, T9, T10, and T32 statically quenched the fluorescence of α-glucosidase by formation of an inhibitor-α-glucosidase complex. The docking results showed that hydrogen bonds were generated between the test compounds and α-glucosidase. The antioxidant study revealed that compound T10 exhibited a higher antioxidant activity via scavenging 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH), thereby inhibiting lipid peroxidation and the total reduction capacity. In brief, the salicylic acid derivatives identified in this study were promising candidates for development as novel non-saccharide α-glucosidase inhibitors.
- Chen, Jiangang,Lu, Wenfang,Chen, Hao,Bian, Xiaoli,Yang, Guangde
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p. 231 - 246
(2019/02/19)
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- α-Amino Diphenyl Phosphonates as Novel Inhibitors of Escherichia coli ClpP Protease
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Increased Gram-negative bacteria resistance to antibiotics is becoming a global problem, and new classes of antibiotics with novel mechanisms of action are required. The caseinolytic protease subunit P (ClpP) is a serine protease conserved among bacteria that is considered as an interesting drug target. ClpP function is involved in protein turnover and homeostasis, stress response, and virulence among other processes. The focus of this study was to identify new inhibitors of Escherichia coli ClpP and to understand their mode of action. A focused library of serine protease inhibitors based on diaryl phosphonate warheads was tested for ClpP inhibition, and a chemical exploration around the hit compounds was conducted. Altogether, 14 new potent inhibitors of E. coli ClpP were identified. Compounds 85 and 92 emerged as most interesting compounds from this study due to their potency and, respectively, to its moderate but consistent antibacterial properties as well as the favorable cytotoxicity profile.
- Moreno-Cinos, Carlos,Sassetti, Elisa,Salado, Irene G.,Witt, Gesa,Benramdane, Siham,Reinhardt, Laura,Cruz, Cristina D.,Joossens, Jurgen,Van Der Veken, Pieter,Br?tz-Oesterhelt, Heike,Tammela, P?ivi,Winterhalter, Mathias,Gribbon, Philip,Windshügel, Bj?rn,Augustyns, Koen
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p. 774 - 797
(2019/01/30)
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- Metabolism of fentanyl and acetylfentanyl in human-induced pluripotent stem cell-derived hepatocytes
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To evaluate the capability of human-induced pluripotent stem cell-derived hepatocytes (h-iPS-HEP) in drug metabolism, the profiles of the metabolites of fentanyl, a powerful synthetic opioid, and acetylfentanyl, an N-acetyl analog of fentanyl, in the cells were determined and analyzed. Commercially available h-iPSHEP were incubated with fentanyl or acetylfentanyl for 24 or 48 h. After enzymatic hydrolysis, the medium was deproteinized with acetonitrile, then analyzed by LC/MS. Desphenethylated metabolites and some hydroxylated metabolites, including 4′-hydroxy-fentanyl and β-hydroxy-fentanyl, were detected as metabolites of fentanyl and acetylfentanyl in the medium. The main metabolite of fentanyl with h-iPS-HEP was the desphenethylated metabolite, which was in agreement with in vivo results. These results suggest that h-iPSHEP may be useful as a tool for investigating drug metabolism.
- Kanamori, Tatsuyuki,Iwata, Yuko Togawa,Segawa, Hiroki,Yamamuro, Tadashi,Kuwayama, Kenji,Tsujikawa, Kenji,Inoue, Hiroyuki
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p. 106 - 114
(2018/01/11)
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- Exploring physicochemical space: Via a bioisostere of the trifluoromethyl and ethyl groups (BITE): Attenuating lipophilicity in fluorinated analogues of Gilenya for multiple sclerosis
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The direct, catalytic vicinal difluorination of terminal alkenes via an I(i)/I(iii) manifold was exploited to install a chiral, hybrid bioisostere of the CF3 and Et groups (BITE) in Gilenya; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (logD) to be tempered compared to the corresponding CF3 and Et derivatives (CH2CH3 > CH2CF3 > CHFCH2F).
- Erdeljac, Nathalie,Kehr, Gerald,Ahlqvist, Marie,Knerr, Laurent,Gilmour, Ryan
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p. 12002 - 12005
(2018/11/21)
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- To the methoxy ethyl phenol synthesis method (by machine translation)
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The invention discloses a method for synthesizing methoxy ethyl phenol, to the chlorophenol as the starting material, through the phenolic hydroxyl protection, format reaction, methylation and hydrogenation debenzylation reaction to obtain the target product to the methoxy ethyl phenol process, the methylation reaction is just a simple filtering operation that can be used for the next step reaction, without any other operation. This invention adopts the [...] as the starting material to synthesize to methoxy ethyl phenol, reduce the difficulty of after treatment, reduce the reaction time, the product has high purity, high yield, good stability of the product. (by machine translation)
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Paragraph 0031-0032; 0033-0036
(2018/11/04)
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- Method for synthesizing salidroside by using [Rmim][OSO2OR]-Lewis acid ionic liquid system
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The invention belongs to the technical field of catalytic synthesis and particularly relates to a method for synthesizing salidroside by using a [Rmim][OSO2OR]-Lewis acid ionic liquid system. According to the method, the salidroside compound is synthesized by using ionic liquid [Rmim][OSO2OR]. The synthesis of the ionic liquid provided by the invention needs only a one-step reaction, and atoms ofraw materials in a synthetic reaction of the ionic liquid are utilized by 100%, and thus, the reaction is an atomic-economical-efficiency reaction with simple and convenient operation. The method provided by the invention is environmentally friendly and is mild in reaction conditions and simple in aftertreatment, the problems such as environmental pollution caused by tedious synthesis of the ionicliquid used during the existing O-Glycosylation of a glycosyl trichloroacetimidate donor by using an ionic liquid system, thermal energy consumption, atom waste and a non-atomic-economical-efficiencyreaction are solved, and meanwhile, the problems such as environmental pollution and tedious aftertreatment caused by the existing salidroside drug chemical-synthesis in organic solvents are solved.
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- Synthesis and in vitro evaluation of diverse heterocyclic diphenolic compounds as inhibitors of DYRK1A
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Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual-specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A. None of these derivatives showed significant DYRK1A inhibition but provide valuable knowledge around the importance of the 7-azaindole moiety. These data will be of use for developing further structure-activity relationship studies to improve the selective inhibition of DYRK1A.
- Zhou, Qingqing,Reekie, Tristan A.,Abbassi, Ramzi H.,Indurthi Venkata, Dinesh,Font, Josep S.,Ryan, Renae M.,Munoz, Lenka,Kassiou, Michael
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p. 5852 - 5869
(2018/11/10)
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- Efficient Difluoromethylation of Alcohols Using TMSCF2Br as a Unique and Practical Difluorocarbene Reagent under Mild Conditions
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A general method for the efficient difluoromethylation of alcohols using commercially available TMSCF2Br (TMS=trimethylsilyl) as a unique and practical difluorocarbene source is developed. This method allows primary, secondary, and even tertiary alkyl difluoromethyl ethers to be synthesized under weakly basic or acidic conditions. The reaction mainly proceeds through the direct interaction between a neutral alcohol and difluorocarbene, which is different from the difluoromethylation of phenols. Moreover, alcohols containing other moieties that are also reactive toward difluorocarbene can be transformed divergently by using TMSCF2Br. This research not only solves the synthetic problem of difluorocarbene-mediated difluoromethylation of alcohols, it also provides new insights into the different reaction mechanisms of alcohol difluoromethylation and phenol difluoromethylation with difluorocarbene species.
- Xie, Qiqiang,Ni, Chuanfa,Zhang, Rongyi,Li, Lingchun,Rong, Jian,Hu, Jinbo
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supporting information
p. 3206 - 3210
(2017/03/17)
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- DDQ-Promoted Benzylic/Allylic sp3 C-H Activation for the Stereoselective Intramolecular C-N Bond Formation: Applications to the Total Synthesis of (-)-Codonopsinine, (+)-5-epi-Codonopsinine, (+)-Radicamine B, and (-)-Codonopsinol
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This is the first report on an intramolecular C-N bond formation of an amide-tethered benzylic/allylic system using DDQ under neutral conditions which has been successfully applied to the total synthesis of naturally occurring pyrolidine alkaloids. The key steps for the synthesis of corresponding precursors involve Julia-Kociensky olefination/cross-metathesis and dihydroxylation reactions, and this methodology is also extended to the ω-unsaturated N-sulfanilamide to furnish piperidines.
- Lingamurthy, Macha,Jagadeesh, Yerri,Ramakrishna, Katakam,Rao, Batchu Venkateswara
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p. 1367 - 1377
(2016/03/01)
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- Mild deprotection of PMB ethers using tert-butyl bromide
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A convenient and high yielding method for the cleavage and scavenging of p-methoxybenzyl protecting group of several alcohols using tert-butyl bromide in refluxing acetonitrile is described. Under these mild conditions other protecting groups such as acid sensitive allyl, benzyl, and Me3CPh2Si ethers, or isopropylidene acetals were unchanged. Interestingly, a selective alkoxy-PMB cleavage was observed in the presence of a PMB phenoxy ether.
- Rival, Nicolas,Albornoz Grados, Arantxa,Schiavo, Lucie,Colobert, Fran?oise,Hanquet, Gilles
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p. 6823 - 6826
(2015/11/27)
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- HYDROXY ALIPHATIC SUBSTITUTED PHENYL AMINOALKYL ETHER DERIVATIVES
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New hydroxy aliphatic substituted phenyl aminoalkyl ether compounds of formula (I), compositions thereof and their use as a medicament in the treatment of nervous system diseases and/or the treatment of developmental, behavioral and/or mental disorders associated with cognitive deficits.
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Paragraph 0271-0272
(2015/12/24)
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- THIOARYL DERIVATIVES AS GPR120 AGONISTS
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The present invention relates to thioaryl derivatives of Formula 1 as defined in the specification, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof. The thioaryl derivatives of Formula 1 according to the present invention promote GLP-1 formation in the gastrointestinal tract and improve insulin resistance in macrophages, pancreas cells, etc. due to anti-inflammatory action, and can accordingly be effectively used for preventing or treating diabetes, complications of diabetes, inflammation, obesity, non-alcoholic fatty liver, steatohepatitis or osteoporosis.
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Paragraph 468-470
(2014/05/24)
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- Hydroxy aliphatic substituted phenyl aminoalkyl ether derivatives
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New hydroxy aliphatic substituted phenyl aminoalkyl ether compounds of formula (1), compositions thereof and their use as a medicament in the treatment of nervous system diseases and/or the treatment of developmental, behavioral and/or mental disorders associated with cognitive deficits.
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Page/Page column
(2014/07/08)
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- Stereoselective total synthesis of phenolic nonadecanediol
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A simple and highly efficient synthetic route has been developed for synthesis of 1-(4-hydroxyphenyl)nonadecane-3,5-diol (1). The two stereogenic centers were generated by employing proline asymmetric α-hydroxylation (MacMillan α-hydroxylation), Jacobsen's hydrolytic kinetic resolution (HKR), and, finally, Yamaguchi oxirane opening as key steps (Scheme 2). Copyright
- Chinnababu, Baggu,Purushotham Reddy, Sudina,Venkatesham, Kunuru,Chandra Rao, Dasireddi,Venkateswarlu, Yenamandra
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p. 613 - 618
(2014/06/09)
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- MATRIX METALLOPROTEINASE INHIBITORS
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This invention also relates to pharmacological compositions containing the compounds of the present invention, and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, periodontitis, multiple sclerosis, gingivitis, gingivitis, atherosclerosis, dry eye, neointimal proliferation, which leads to restenosis and ischemic heart failure, stroke, renal diseases, tumor metastasis, and pounds.
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Paragraph 0403; 0404
(2014/06/11)
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- Total synthesis of zyzzyanones A-D
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Zyzzyanones A-D is a group of biologically active marine alkaloids isolated from Australian marine sponge Zyzzya fuliginosa. They contain a unique bispyrroloquinone ring system as the core structure. The first total synthesis of all four zyzzyanones is described here. The synthesis of these alkaloids started from a previously known 6-benzylamino indole-4,7-quinone derivative and involves 6-7 steps. The key step in the synthesis involves the construction of a pyrrole ring in one step using a Mn(OAc)3 mediated oxidative free radical cyclization reaction of a 6-benzylamino indole-4,7-quinone derivative with 4-benzyloxyphenyl acetaldehyde diethyl acetal in CH3CN.
- Nadkarni, Dwayaja H.,Murugesan, Srinivasan,Velu, Sadanandan E.
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p. 4105 - 4113
(2013/07/04)
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- Total synthesis of dictyodendrins A-E
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A highly efficient total synthesis of dictyodendrins A-E was accomplished. The synthesis features a novel benzyne-mediated one-pot indoline formation/cross-coupling sequence for the construction of a highly substituted key indoline intermediate. Peripheral substituents were introduced onto this intermediate in a modular fashion to complete the total synthesis of dictyodendrins A-E. A benzyne-mediated one-pot indoline formation/cross-coupling sequence is used for the construction of a highly substituted common indole intermediate. The peripheral substituents were introduced using a Friedel-Crafts reaction on the indole intermediate in a modular fashion to complete the total synthesis. Copyright
- Tokuyama, Hidetoshi,Okano, Kentaro,Fujiwara, Hideto,Noji, Toshiharu,Fukuyama, Tohru
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supporting information; experimental part
p. 560 - 572
(2011/10/03)
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- Preparation and antioxidant activity of tyrosyl and homovanillyl ethers
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Preparation of tyrosyl and homovanillyl lipophilic derivatives was carried out as a response to the food industry's increasing demand for new synthetic lipophilic antioxidants. Tyrosyl and homovanillyl ethers were synthesized in high yields by a three-step procedure starting from tyrosol (Ty) and homovanillic alcohol (HMV). The antioxidant activity of these new series of alkyl tyrosyl and homovanillyl ethers was evaluated by the Rancimat test in a lipophilic food matrix and by the FRAP, ABTS and ORAC assays and compared to free Ty and HMV as well as two antioxidants widely used in the food industry, butylhydroxytoluene (BHT) and α-tocopherol. The results pointed out the higher activity of homovanillyl series in comparison with tyrosyl series with all the assayed methods. However, while both synthetic series were less antioxidant than BHT and α-tocopherol in a lipophilic matrix after their Rancimat test evaluation, homovanillyl alkyl ethers showed the best reducing power and radical scavenging activity of all evaluated compounds. This batch of synthetic lipophilic compounds, derived from biologically active compounds such as Ty and HMV, provide interesting and potentially bioactive compounds.
- Madrona,Pereira-Caro,Bravo,Mateos,Espartero
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scheme or table
p. 1169 - 1178
(2012/05/05)
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- DEUTERATED AMINOGLYCIDYL COMPOUNDS
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Provided herein are substituted aminoglycidyl compounds of Formula (1), processes of preparation, and pharmaceutical compositions thereof and methods of their use for treating, preventing, or ameliorating one or more symptoms of a social anxiety disorder, an anxiety disorder, hyperthyroidism, tremor, glaucoma, hypertension, coronary artery bypass graft, chronic stable angina, atrial arrhythmia, migraine, bleeding esophageal varices, hypertrophic subaortic stenosis, heart failure, post-myocardial infarction, decreased left ventricular function after recent myocardial infarction, and/or any disorder ameliorated by beta adrenergic receptor modulators.
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Page/Page column 77
(2008/06/13)
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- Synthesis and biological evaluation of analogues of the anti-tumor alkaloid naamidine A
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A small series of derivatives of the alkaloid naamidine A was synthesized and tested in vitro for their ability to inhibit mitogenesis in BaF/ERX cells. Replacement of the imidazole core with a thiazole was found to have only a minor effect on potency, and the 4-methoxybenzyl substituent of the natural product was shown to be unnecessary for activity.
- Aberle, Nicholas,Catimel, Jenny,Nice, Edouard C.,Watson, Keith G.
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p. 3741 - 3744
(2008/02/12)
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- Synthesis of a benzyl-protected analog of arenarioside, a trisaccharide phenylpropanoid glycoside
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A benzyl-protected analog of the phenylpropanoid glycoside arenarioside, (4-benzyloxyphenyl)ethyl α-l-rhamnopyranosyl-(1→3)-4-O-[(E)-3,4-di-O-benzyl-caffeoyl]-[β-d-xylopyranosyl-(1→6)]-β-d-glucopyranoside (22), was synthesized through two different routes from d-glucose. This is the first approach on the synthesis of a trisaccharide phenylpropanoid glycoside, although the benzyl-protecting group in the backbone of the arenarioside analog could not be removed by conventional debenzylation procedures.
- Zhou, Feng-Yan,She, Jin,Wang, Yan-Guang
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p. 2469 - 2477
(2007/10/03)
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- PROCESS FOR PREPARATION OF S-(-)-BETAXOLOL AND SALTS THEREOF
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The present invention relates to an improved process for preparation of S-(?)-betaxolol salts. More particularly the present invention relates to the preparation of hydrochloride salt of S-(?)-betaxolol of formula (1).
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Page/Page column 2-4
(2010/02/15)
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- AMINOPROPANOL DERIVATIVES
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Compounds of formula (I): wherein R1, R2, n and m are as defined in the specification, processes for their production, their uses and pharmaceutical compositions containing them.
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Page/Page column 13; 18
(2008/06/13)
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- A convenient synthesis of the enantiomerically pure β-blocker (S)-betaxolol using hydrolytic kinetic resolution
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Enantiopure (S)-betaxolol was prepared in an extremely simple and practical way using hydrolytic kinetic resolution of a terminal epoxide by Jacobsen's catalyst. High enantiomeric purity (99% ee) has been achieved and the method is amenable to industrial scale-up.
- Joshi, Ramesh A.,Garud, Dinesh R.,Muthukrishnan,Joshi, Rohini R.,Gurjar
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p. 3802 - 3806
(2007/10/03)
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- Novel benzopyridothiadiazepines as potential active antitumor agents
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The synthesis of novel thiadiazepine derivatives, that could be considered as constraint analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on L1210 cells with the most cytotoxic compounds showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with IC50 of respectively 3.8 and 2.4 μM compared to 2.4 μM for desoxypodophyllotoxin. A 4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine was found to be essential for the antiproliferative activity. The in vitro activities of compounds 2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders which warrant further in vivo evaluation.
- Lebegue, Nicolas,Gallet, Sebastien,Flouquet, Nathalie,Carato, Pascal,Pfeiffer, Bruno,Renard, Pierre,Léonce, Stéphane,Pierré, Alain,Chavatte, Philippe,Berthelot, Pascal
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p. 7363 - 7373
(2007/10/03)
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- DIARYL ETHER DERIVATIVE, ADDITION SALT THEREOF, AND IMMUNOSUPPRESSANT
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The present invention provides diaryl ether derivatives that exhibit significant immunosuppressive effects with less side effects. The diaryl derivatives of the present invention are represented by the following general formula (1): ???one example is 2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl)propyl-1,3-propanediol.
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- THERAPEUTIC AGENTS
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Substituted 3-phenylpropionic acid derivatives, processes for preparing such compounds, their utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance, methods for their therapeutic use and pharmaceutical compositions containing them.
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- Compound
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There is provided a compound of Formula I 1 wherein each T is independently selected from H, hydrocarbyl, —F—R, and a bond with one of D, E, P or Q, or together with one of P and Q forms a ring; Z is a suitable atom the valency of which is m; D, E and F are each independently of each other an optional linker group, wherein when Z is nitrogen E is other than CH2 and C═O; P, Q and R are independently of each other a ring system; and at least Q comprises a sulphamate group.
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Page/Page column 35
(2008/06/13)
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- AMINO-PROPANOL DERIVATIVES
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Compounds of formula (I) wherein R1, R2, R3, R4 and R5 are as defined in the specification, processes for their production, their uses and pharmaceutical compositions containing them.
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- Asymmetric dihydroxylation and regioselective C-3 indole coupling routes to the anticoccidial antibiotic (+)-diolmycin A2
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A highly enantioselective synthesis of (+)-diolmycin A2 starting from 4-hydroxybenzaldehyde and employing the Sharpless asymmetric dihydroxylation and CH3NO2 solvent assisted regioselective C-3 coupling of indole as the key steps is described.
- Fernandes, Rodney A,Bodas, Mandar S,Kumar, Pradeep
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p. 1223 - 1227
(2007/10/03)
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- Differential inhibition of polymerase and strand-transfer activities of HIV-1 reverse transcriptase
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A new class of inhibitors of HIV-1 reverse transcriptase obtained by the systematic structural simplification of epicatechin and epigallocatechin gallates are also shown here to inhibit DNA-strand-transfer, a process critical to the completion of the HIV-1-RT reproduction and to recombination-associated mutation of the virus. Up to 80-fold selectivity for DNA-strand-transfer inhibition over polymerase inhibition was observed for a defined subset of these agents. Such specific DNA-strand-transfer inhibitors may have important therapeutic potential.
- Tillekeratne,Sherette, Angela,Fulmer, Jennifer A,Hupe, Lynn,Hupe, Donald,Gabbara, Sam,Peliska, James A,Hudson, Richard A
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p. 525 - 528
(2007/10/03)
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- Head-to-Tail Connected Double Calix[4]arenes
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New macrotricyclic compounds consisting of two calix[4]arene substructures connected by aliphatic chains of various length (three to five carbon atoms) between two opposite p-positions and two distal phenolic oxygens have been synthesized. Starting with p-tert-butyl-calix[4]arene, two O-protected phenolic units are attached via ether links in 1,3-position by reaction with the corresponding tosylates. After deprotection, the new calix[4]arene is formed by fragment condensation with 2,6-tobromomethylated 4-alkylphenols. The structure of one example (8c) has been confirmed by single crystal X-ray analysis. Both calixarene parts assume the cone conformation, a molecule of acetonitrile being included in both cavities.
- Wasikiewicz,Rokicki,Kielkiewicz,Paulus,Boehmer
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p. 863 - 879
(2007/10/03)
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- Structure-activity relationship studies of the amide functionality in (p-O-sulfamoyl)-N-alkanoyl tyramines as estrone sulfatase inhibitors
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Recently, we reported the synthesis and biochemical studies of a series of (p-O-sulfamoyl)-N-alkanoyl tyramines as nonsteroidal estrone sulfatase inhibitors. One of the most potent inhibitors in this series is (p-O- sulfamoyl)-N-tridecanoyl tyramine 1 with an IC50 value of 61.3 nM. In this study, we synthesized four analogs of 1 (compounds 2-5) to investigate the structure-activity relationships of the amide functionality in (p-O- sulfamoyl)-N-tridecanoyl tyramine. Replacement of the amide functionality in 1 with an ethylene moiety to form the alkyl analog 5 resulted in complete loss of sulfatase inhibitory activity (IC50 of 61.3 nM vs. >20 μM). The keto, hydroxy, and ester analogs (inhibitors 2-4) are 8-15 times less in affinity to the sulfatase than inhibitor 1. However, their inhibitory activities are significantly higher than the alkyl analog 5. The results suggest that the amide functionality is favorable for sulfatase inhibitory activity and that there may be a hydrogen bonding component to the enzyme interaction in this region.
- Chu, Guo-Hua,Milano, Shawn,Kluth, Lisa,Rhodes, Michael,Boni, Riccardo,Johnson, David A.,Li, Pui-Kai
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p. 530 - 535
(2007/10/03)
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- Catalytic asymmetric synthesis of arbutamine
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An efficient catalytic asymmetric synthesis of (R)-arbutamine has been achieved using a catalytic asymmetric nitroaldol reaction promoted by a heterobimetallic multifunctional asymmetric catalyst as a key step.
- Takaoka, Eiji,Yoshikawa, Naoki,Yamada, Yoichi M.A.,Sasai, Hiroaki,Shibasaki, Masakatsu
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p. 157 - 163
(2007/10/03)
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- Polymers with alkyl- or heteroalkyl -aryl backbone and pharmaceutical compositions incorporating same
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A biologically active polymeric compound comprising an alkylaryl or heteroalkylaryl backbone having about 5 to about 50 repeating aromatic ring-containing units and which, according to the computer program marketed as SYBYL version 5.2 running on a DEC VAX 11/750 computer, is capable of forming a linear backbone having a helical secondary structure, and wherein the maximum diameter of the helical structure, as measured by the alkylaryl or heteroalkylaryl backbone, is less than 3 times greater than the maximum diameter of the aryl group of the alkylaryl or heteroalkylaryl backbone.
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- Synthesis of 3-Substituted Pentane-2,4-diones: Valuable Intermediates for Liquid Crystals
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General procedures for the synthesis of six series of 3-substituted pentane-2,4-diones are described.The diones were used as intermediates in the preparation of pyrazoles, isoxazoles, and coordination complexes whose mesogenic properties have been studied.Nematic and smectic phases have been obtained in a number of cases, and relationship between molecular structure and mesogenic properties has been explored.
- Cativiela, Carlos,Serrano, Jose L.,Zurbano, Maria M.
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p. 3074 - 3083
(2007/10/02)
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- 3-aryl-2-hydroxypropionic acid derivatives and analogs as antihypertensives
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A method of using certain 3-aryl-2-hydroxypropionic acid derivatives and analogs in the treatment of hypertension.
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- The Effect of Carbonyl Containing Terminal Chains on Mesomorphic Properties in 4,4'-Disubstituted Phenylbenzoates and Phenylthiobenzoates. 5. Phenylbenzoates Containing a (CH2)nO2CR' Group (n = 1,2) on the Phenolic End
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A few homologs of the esters 2 (R' = C8H17, n= 1 or 2) and 4 (R' = C7H15) were synthesized and their mesomorphic properties determined using hot-stage polarizing microscopy.No mesophases were observed for series 2 (n = 1) or 4.This was also true for the previously reported series 1 (n = 1) and 3.Transitions temperatures for series 2 with n = 2 were lower than when n = 1 but higher than for the reverse ester series I with n = 2.In both series 1 and 2 with n = 2, only short range monotropic phases were observed.Like its parent sereis 2 (n = 0), the n = 2 esters showed various combination of nematic and smectic A, B and C, whereas the reverse esters 1 (n = 2) have only nematic and smectic A phases.The phenols required for synthesizing the esters 2 (n = 2) and 4 were prepared from the analogous protected phenolic alcohols.No suitable protecting group which could be selectively removed from the phenol could be found for synthesizing the precursor alcohol for series 2 when n = 1.Instead these esters were prepared by esterification of the appropriately 4-substituted benzoic acid with 4-hydroxybenzaldehyde, reduction to the alcohol and esterification.NMR spectra were used to confirm the structures of all intermediates and esters. Keywords: liquid crystals, phenylbenzoates, 4-substituted phenols, NMR
- Neubert, M. E.,Citano, C. M.,Ezenyilimba, M. C.,Jirousek, M. R.,Sabol-Keast, S.,Sharma, R. B.
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p. 103 - 116
(2007/10/02)
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- Antihypertensive dihydropyridine derivatives
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Compound of formula 1 are calcium entry antagonists useful for treating hypertension, congestive heart failure, angina, and vasospastic disorders: STR1 wherein n is an integer from 1 to 4; R1 and R2 are lower alkyl; R3 is lower alkyl or alkoxyalkyl; A is alkylene of two to eight carbon atoms; X1 and X2 are each independently --NO2, --CF3, CH3 O--, --CN, --H, lower alkyl or halo; Y is --O--, --S--, --S(O)--, or --S(O)2 --; and R is H, lower alkyl, cycloalkyl, alkoxyalkyl, cycloalkyloxy-alkyl, alkoxycycloalkyl, acyl, or saturated or unsaturated 5- or 6-membered heterocyclyl optionally substituted with lower alkyl or alkoxy, wherein the heteroatom is one oxygen atom.
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- Hypoglycemic thiazolidinediones
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Hypoglycemic 5-[1-(5,6,7,8-tetrahydro-2-napthyl-; 1,2,3,4-tetrahydro-6-quinolyl-; 2-indanyl-; and 2-indolyl)alkyl]thiazolidine-2,4-dione derivatives, pharmaceutically acceptable salts thereof, and a method for their use in the treatment of hyperglycemic mammals.
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- Antihypertensive dihydropyridine compositions, optical isomers and intermediates
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Compositions containing dihydropyridine derivatives which are useful for treating congestive heart failure, hypertension, or angina have the formula: STR1 or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is --O--, --NH--, --NR2 --, --S--, --S(O)--, --S(O)2 --, or a bond; R1 and R2 are each independently A1, A2, A3 or A4 where A1 is --(CH2)m (CHOH)p CH2 OH; A2 is --(CH2)q CH(3-r) [(CH2)s OH]r ; A3 is --(CH2)q CH(3-r) [(CH2)p COOR3 ]r ; and A4 is --(CH2)m COOR3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R3 is H or alkyl of 1 to 18 carbon atoms; R4 is --NO2, --CF3, or halo; and R5 is lower alkyl or --CH2 CH2 OCH3. Also disclosed are optical isomers of the above compounds, as well as intermediates in the preparation of these final products.
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