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ChemInform Abstract: α-Trimethylsilylmethylamine Radical Cation in the Synthesis of Cyclic Amines and Beyond

Authors:
Ganesh Pandey at Centre of Biomedical Research
Ganesh Pandey
Debasis Dey
Debasis Dey
Debasis Dey
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Smita R Gadre
Smita R Gadre
Smita R Gadre
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Abstract

The evolution of chemistry associated with the photoinduced electron transfer (PET)-generated α-trimethylsilylmethylamine radical cation cyclization to a tethered olefin to synthesize cyclic amine structural frame works is presented in chronological order. The importance of this interesting chemistry is demonstrated by the synthesis of several novel glycosidase inhibitors.
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ChemInform 2013, 44, issue 39 © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Organic chemistry
Z 0200 DOI: 10.1002/chin.201339232
α-Trimethylsilylmethylamine Radical Cation in the Synthesis of Cyclic Amines
and Beyond — [168 refs.]. — (PANDEY, G.; DEY, D.; GADRE, S. R.; Chimia 67
(2013) 1-2, 30-38, http://dx.doi.org/10.2533/chimia.2013.30 ;
Div. Org. Chem., Natl. Chem. Lab., Pune 411 008, India; Eng.) — Koehler
39- 232
... Indolizine derivatives were also reported to have photophysical properties such as organic light-emitting devices (OLEDs) [41,42], and as organic sensitizers for solar-cell applications [43]. Different green and conventional strategies for constructing a wide range of biologically small molecules having indolizine moiety were established, most of these methods were undertaken via [3 + 2] 1,3-dipolar cycloaddition reactions [44][45][46][47][48][49][50][51][52][53][54][55][56][57]. The present work outlines the various biological activities of indolizine derivatives and their role in pharmaceutical and clinical trials. ...
Inhibitory activities of indolizine derivatives: a patent review
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  • Jul 2020
Introduction Indolizines are structural isomers with indoles. Although several indole-based commercial drugs are available in the market, none of the indolizine-based drugs are available up to-date. Natural and synthetic indolizines have a wide-range of pharmaceutical importance such as antitumor, antimycobacterial, antagonist, and antiproliferative activities. This prompted us to search and collect all possible data about the pharmacological importance of indolizine to open an avenue to the researchers in exploring more medicinal applications of such biologically important compounds. Areas covered The current review article covers the advancements about the biological and pharmacological activities of indolizine-based compounds during the last decade. The covered areas of this work involved anticancer, anti-HIV-1, anti-inflammatory, antimicrobial, anti-tubercular, larvicidal, anti-schizophrenia, CRTh2 antagonist’s activities in addition to enzymatic inhibitory activity. Expert opinion The discovery of indolizine drugs will be a major breakthrough as compared with their widely available drug-containing indole isosteres. Major work collected here was focused on anticancer, anti-tubercular, anti-inflammatory and enzymatic inhibitory activities. The SAR study of the reported biologically active indolizines are summarized throughout the review whenever highlighted to the rationale the behavior of inhibitory action. Several indolizines with certain functions provided great enhancement in the therapeutic activities comparing with reference drugs.
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ChemInform Abstract: Synthesis of Iminosugars from Tetroses.
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  • Aug 2014
  • ChemInform
Iminosugars continue receiving a great deal of attention from chemists and biochemists for their potential as pharmaceutics. This is a comprehensive review of the methods found in the literature for the synthesis of piperidine, pyrrolidine, indolizidine, and pirrol-izidine iminosugars, starting from D/L-erythrose and D/L-threose carbon chains (tetroses). This review shows the crescent popularity of small molecules to build up iminosugar molecules. Methodologies described herein utilize inexpensive commercial materials. The synthesis of the four tetroses is included referring old and modern methodologies.
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Synthesis of Iminosugars from Tetroses
Article
Full-text available
  • May 2014
  • CURR ORG SYNTH
Iminosugars continue receiving a great deal of attention from chemists and biochemists for their potential as pharmaceutics. This is a comprehensive review of the methods found in the literature for the synthesis of piperidine, pyrrolidine, indolizidine, and pirrolizidine iminosugars, starting from D/L-erythrose and D/L-threose carbon chains (tetroses). This review shows the crescent popularity of small molecules to build up iminosugar molecules. Methodologies described herein utilize inexpensive commercial materials. The synthesis of the four tetroses is included referring old and modern methodologies.
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Three trihydroxypiperidines, glycosidase inhibitors, from Eupatorium fortunei TURZ
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  • Jan 1995
A new stereoisomer, mesotrihydroxypiperidine (I) was isolated along with its two known stereoisomers, 3α, 4β, 5α-trihydroxypiperidine (II) and 3β, 4β, 5α-trihydroxypiperidine (III) from Eupalorium fortionei TURZ. The inhibitory activities (IC50) on α-glucosidase were 3.70 μM for, 1.54 μM for II and 1.88 μM for III. The inhibitory activity of II on β-glucosidase was 0.51 μM, that of I on α-mannosidase was 1.88 μM and that of III on β- galactosidase was 3.76 μM.
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Miglitol
Article
  • Mar 2000
Miglitol, the first pseudomonosaccharide α-glucosidase inhibitor, smooths postprandial peak plasma glucose levels and thus improves glycaemic control, which is reflected in a reduced glycosylated haemoglobin (HbA1c) level. This oral antihyperglycaemic agent is indicated for the treatment of patients with type 2 diabetes mellitus. Miglitol is generally well tolerated and, unlike the sulphonylurea agents, is not associated with bodyweight gain or hypoglycaemia when administered as monotherapy. The drug is systemically absorbed but is not metabolised and is rapidly excreted via the kidneys. Clinical trials with miglitol (usually 50 or 100mg 3 times daily) in patients with type 2 diabetes mellitus consistently demonstrated a significant improvement in glycaemic control for periods of 6 to 12 months. There were also marked reductions in postprandial serum insulin levels, although miglitol generally had no effect on fasting insulin levels. In comparative studies miglitol had similar efficacy to acarbose, but at lower therapeutic doses (50 and 100mg 3 times daily, respectively). In addition, although sulphonylurea agents provided superior reductions in HbA1c levels, miglitol provided similar or superior reductions in fasting and postprandial plasma glucose levels. In combination with other oral antidiabetic agents or insulin, miglitol improved glycaemic control in patients in whom metabolic control was suboptimal despite dietary and pharmacological intervention. Most adverse events associated with miglitol treatment involve disturbances of the gastrointestinal tract (most common effects are flatulence, abdominal pain and diarrhoea). These symptoms are usually dose dependent, mild to moderate in severity, occur at the onset of treatment, decline with time and resolve promptly on discontinuation of the drug or with dosage adjustment. As monotherapy, miglitol is not associated with hypoglycaemia, but concomitant use with other oral antidiabetic agents may necessitate dosage adjustment of the other agents. Miglitol had no significant effects on renal, cardiovascular, respiratory or haematological parameters in long term studies. No dosage adjustments are required in elderly patients, in those with hepatic impairment or in those with mild to moderate renal insufficiency. Conclusions: In long term, well designed trials miglitol reduces fasting and postprandial plasma glucose levels, thus improving glycaemic control, which is reflected in a reduced HbA1c level in patients with type 2 diabetes mellitus. Most adverse events associated with miglitol involve disturbances of the gastrointestinal tract. This agent is a useful first-line therapy in patients with type 2 diabetes mellitus insufficiently controlled by diet alone and as second-line or as adjuvant therapy in those insufficiently controlled with diet and sulphonylurea agents. Miglitol may prove particularly beneficial in elderly patients and those with hepatic impairment or mild to moderate renal impairment, in whom other oral antidiabetic agents are contraindicated or need to be used with caution. Pharmacodynamic Properties Miglitol is a 1-deoxynojirimycin derivative which reversibly inhibits intestinal α-glucosidase enzymes responsible for the digestion of carbohydrates to absorbable monosaccharides. Its structure resembles that of glucose, and unlike acarbose (a pseudotetrasaccharide α-glucosidase inhibitor), it is almost completely absorbed in the upper section of the small intestine. The rank order of its inhibitory activity is sucrase > glucoamylase > isomaltase > lactase > trehalase. Although miglitol delayed carbohydrate absorption in healthy volunteers, there were no significant losses of carbohydrates, protein or fat in the faeces and no significant caloric losses. Miglitol smooths postprandial glycaemic peaks thereby reducing postprandial peak plasma glucose levels in patients with type 2 diabetes mellitus (average decrease with multiple 50mg doses was 1.8 to 3.0 mmol/L). Short term studies indicated that miglitol had no effect on postprandial serum insulin levels or C-peptide concentrations; however, after 8 weeks’ treatment with miglitol there was a significant reduction in both of these parameters, which was confirmed in long term clinical trials. A few studies also indicate that miglitol reduces fasting triglyceride levels in patients with type 2 diabetes mellitus following 8 weeks of treatment. Since miglitol is almost completely absorbed, it has been suggested that it may exert extraintestinal effects on glucose homeostasis. Its effect on enhanced glucose uptake following an oral glucose load is unclear and requires confirmation. Miglitol significantly reduced the postprandial increase in gastric inhibitory polypeptide in healthy volunteers and patients with type 2 diabetes mellitus. It also increased peptide tyrosine-tyrosine (PYY) and motilin levels compared with placebo in patients with type 2 diabetes. Animal studies have shown that miglitol (at recommended therapeutic doses) has no effect on lysosomal α-glucosidases and there was no evidence of glycogen storage or changes in liver weight. Miglitol, unlike several other compounds with cationic polarity, e.g. biguanides, had no effect on sodium-dependent small intestine transport of organic solutes, such as, hexoses. Pharmacokinetic Properties Miglitol 25 to 200mg exhibits nonlinear absorption kinetics. The mean peak plasma concentrations (Cmax) following single oral doses of miglitol 25, 50, 100 and 200mg were 0.78, 1.22, 1.86 and 2.61 mg/L, respectively, and were attained within 2 to 4 hours. Miglitol was rapidly and almost completely absorbed after an oral dose of 25mg, but with doses ≥50mg (therapeutic dose range) a saturation of absorption became evident. The maximum absorbable dose was 2.4 mg/kg (i.e. 200mg). In animal studies, absorption of miglitol occurred predominantly in the upper small intestine. The volume of distribution at steady state (Vss) was low (0.28 L/kg) in healthy volunteers. Furthermore, there was virtually no binding of miglitol to plasma proteins over a range of 10 μg/L to 10 mg/L as determined in in vitro assays. Excretion of miglitol occurred very rapidly after both oral and intravenous administration and no metabolism of miglitol was detected. In healthy volunteers, ≈59% of oral miglitol was excreted via the kidneys, with 29% being excreted in the faeces. Miglitol showed a biphasic pattern of elimination; a first phase of 1.8 hours during which >90% of drug was eliminated and a second phase of 2 to 4 hours. The total plasma clearance of radiolabelled drug was 0.103 kg/L · h, which is similar to the glomerular filtration rate. In healthy volunteers, dose-dependent increases in the terminal half-life of the drug indicate that it may accumulate following multiple doses. Studies in healthy volunteers indicate that miglitol 100mg significantly decreases the bioavailability of glibenclamide, but has no clinically relevant effects on the pharmacokinetics of either (R)- or (S)-warfarin or phenytoin. According to the manufacturer’s prescribing information, miglitol reduces the bioavailability of metformin during concomitant administration but the clinical effects of these agents are synergistic. However, the clinical relevance of this is still to be investigated. Further, concomitant administration of miglitol with propranolol or ranitidine reduced the absorption of these agents, and therefore the dose adjustment of propranolol or ranitidine may be necessary. Clinical Efficacy Large, well designed trials of 6 to 12 months’ duration in a total of 1783 patients with type 2 diabetes mellitus insufficiently controlled by diet alone or diet plus sulphonylurea agents have demonstrated that miglitol monotherapy 50 to 100mg 3 times daily (therapeutic range) significantly improves glycaemic control and decreases postprandial serum insulin levels. With miglitol 150 to 300 mg/day, the mean absolute reduction in glycosylated haemoglobin (HbA1c) level was 0.18 to 0.75%, which was associated with a 7.3 to 21.1% reduction in postprandial plasma glucose (PPG) levels (i.e. a mean decrease of 0.86 to 3.21 mmol/L) and a 6.8 to 12.5% reduction in fasting plasma glucose (FPG) levels (i.e. a mean decrease of 0.56 to 1.08 mmol/L). Miglitol had similar efficacy in both younger adults (30 to <70 years of age) and older adults (>60 years) and in different ethnic groups. Efficacy was maintained for the duration of these studies (up to 1 year). Most of these studies reported a group of patients who withdrew because of a lack of efficacy (poor glycaemic control); nonresponder rates between each treatment group of individual studies were generally similar. Miglitol provided similar improvements in glycaemic control to those observed with other oral antihyperglycaemic agents. Thus, miglitol 50 or 100mg 3 times daily was at least as effective as acarbose 100mg 3 times daily in improving glycaemic control. In elderly patients (aged >60 years), although there was a more marked reduction in HbA1c with glibenclamide (p < 0.05 vs miglitol), miglitol 50mg 3 times daily provided a superior reduction in PPG level (p < 0.05). Furthermore, there was a significantly higher incidence of hypoglycaemic episodes with glibenclamide treatment (46%) than with miglitol (9%) or placebo (8%). Approximately 30% of patients responded to treatment (based on changes in HbA1c levels) with miglitol 50mg 3 times daily compared with ≈50% of those in the glibenclamide group and 18% in the placebo group. In addition, after 6 months’ treatment, fewer than 15% of patients receiving miglitol 100mg 3 times daily were in poor control (HbA1c >8%) compared with 14 and 48% in the glibenclamide and placebo groups, respectively. Miglitol significantly reduced postprandial serum insulin levels. The reduction in postprandial serum insulin levels was superior to that of glibenclamide (p < 0.05). However, miglitol generally had no effect on fasting serum insulin levels. There was also a trend to a decrease in body weight with miglitol treatment during the trial period, although this decrease never reached statistically significant levels. In general, unlike acarbose, miglitol had no significant effects on either fasting or postprandial lipid parameters in monotherapy studies of 6 months’ to 1 year’s duration. The concomitant use of miglitol with other oral antihyperglycaemic agents or insulin has been investigated in several large, well designed trials in patients with type 2 diabetes mellitus in whom glycaemic control was suboptimal despite dietary and pharmacological intervention. Miglitol provided significant improvements in HbA1c, FPG and PPG levels, irrespective of the concomitant antidiabetic agent used. With 150 and 300 mg/day dosages, there was a significant reduction in HbA1c (mean absolute reduction in HbA1c level 0.20 to 1.6%), PPG levels (mean reduction 10.1 to 26.1%) and FPG levels (0 to 14% reduction), although the reduction in FPG levels failed to reach statistical significance in some studies. Responder rates in patients receiving concomitant miglitol and sulphonylurea therapy were 27 to 39% compared with 5 to 10% in placebo groups. Improved glycaemic control also appeared more marked during the first 6 months of a 1-year study than during the second 6 months; the placebo-subtracted mean change from baseline in HbA1c levels for these 2 periods was −1.19 and −0.74%, respectively. Similar effects have been reported previously with sulphonylurea and biguanide agents in the United Kingdom Prospective Diabetes Study (UKPDS) and may be a reflection of a progressive loss of pancreatic β cell function associated with the natural progression of this disease. Concomitant use of miglitol in patients using insulin therapy may also reduce the insulin dosage required, although further studies are warranted to confirm this finding. When used concomitantly with sulphonylurea agents, effects of miglitol on fasting and postprandial serum insulin levels were similar to those observed with miglitol in monotherapy studies, with a significant reduction in postprandial levels (10.1 to 20.5% reduction) but no effect on fasting levels. However, there was no effect on postprandial serum insulin level when used concomitantly with exogenous insulin. Concomitant therapy with miglitol and sulphonylurea agents also reduced fasting serum triglyceride levels significantly compared with placebo. As with monotherapy trials, adjuvant treatment with miglitol had no significant effects on fasting high density lipoprotein, low density lipoprotein or total cholesterol levels. Tolerability The most common adverse events in miglitol-treated patients involve the gastrointestinal system and include flatulence, abdominal pain and diarrhoea. Symptoms were usually mild to moderate in intensity, dose dependent, occurred at the onset of treatment, declined with time and resolved promptly on discontinuation of the drug or with dosage adjustment. Compared with placebo, miglitol showed no significant effects on renal, cardiovascular, respiratory or haematological functions in long term clinical studies (6 months to 1 year). There were no significant differences in the withdrawal rate judged by investigators to be attributable to adverse events between individual treatment groups in clinical studies. Dosage and Administration In Europe, the recommended initial dosage of miglitol is 50mg 3 times daily, to be taken orally immediately before each main meal. This should be increased to the recommended maintenance dosage of 100mg 3 times daily after 4 to 12 weeks’ treatment. In the US, the maximum recommended daily dosage is 100mg 3 times daily, with treatment initiated at a dosage of 25mg 3 times daily and gradually increased. The recommended maintenance dose in the US is 50mg 3 times daily. No dosage adjustments are required in elderly patients, in those with hepatic impairment or those with mild to moderate renal insufficiency (creatinine clearance >1.5 L/h). Miglitol is not indicated for use in patients with diabetic ketoacidosis and is contraindicated in patients with inflammatory bowel disease, colonic ulceration or partial intestinal obstruction, in patients predisposed to intestinal obstruction, in individuals under the age of 18 years and in pregnant or lactating women. Miglitol monotherapy does not induce hypoglycaemia, but may potentiate the hypoglycaemic effects of other antidiabetic drugs, and thus the dosage of these agents may need to be adjusted accordingly. Episodes of hypoglycaemia should be treated with glucose. Miglitol should not be used concomitantly with laxatives, intestinal absorbants or digestive enzyme preparations containing carbohydrate-splitting enzymes. Coadministration of miglitol with propranolol and ranitidine reduces their absorption and therefore dose adjustment of these agents may be necessary.
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First Total Synthesis of the Pyrrolizidine Alkaloid Amphorogynine C through Intramolecular Azide–Olefin Cycloaddition
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The first total synthesis of the natural alkaloid amphorogynine C is reported (2.9 % overall yield in 20 steps). The key steps include a Claisen–Johnson rearrangement and an intramolecular azide–olefin cycloaddition, followed by a reduction of the resulting imine. The construction of the pyrrolizidine skeleton was achieved by an alkoxide-mediatedlactone ring opening and subsequent cyclization of a conveniently functionalized bicyclic amine. Finally, the proposed structure of amphorogynine C was confirmed by single-crystal X-ray diffraction analysis.
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