- INDOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
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The present invention relates to new indole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole compounds as an active ingredient.
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Page/Page column 18
(2010/08/22)
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- INDOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
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The present invention relates to new indole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole compounds as an active ingredient.
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Page/Page column 60
(2009/04/25)
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- Practical, highly convergent, asymmetric synthesis of a selective PPARγ modulator
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A practical, highly convergent, asymmetric synthesis of a selective PPARγ modulator 1 is described. The inhibitor contains two key components, a 6-trifluoromethoxy-3-acylindole (6) and (R)-raryloxybutanoic acid derivative (10). Twomethods were developed to overcome the regioselectivity issues encountered in the preparation of the 6-substituted indole. The first involved an intramolecular Heck reaction of an iodoaryl enamine. The second involved application of a catalytic Meerwein arylation reaction between 2-nitro-4-trifluoromethoxyaniline and isopropenyl acetate and subsequent reductive cyclization. The α-aryloxybutanoic acid was prepared via an asymmetric hydrogenation of the corresponding α-aryloxy-α,β- unsaturated acid. Tetrabutylammonium iodidecatalyzed coupling of the two fragments and ester hydrolysis completed the convergent synthesis. The described convergent synthesis was used to prepare >3 kg of drug substance 1 in 50% overall yield and with >99.5% ee.
- Maligres, Peter E.,Humphrey, Guy R.,Marcoux, Jean-Francois,Hillier, Michael C.,Zhao, Dalian,Krska, Shane,Grabowski, Edward J.J.
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experimental part
p. 525 - 534
(2010/04/22)
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- BENZOUREAS HAVING ANTI-DIABETIC ACTIVITY
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Benzourea compounds of Formula I having aryl-(CH2)x-oxazolidinedione or aryl-(CH2)x-thiazolidinedione substituents on one of the N atoms of the benzourea ring, wherein x is 0 or 1, are PPAR gamma agonists or partial agonists and are useful in the treatment and control of type II diabetes, including hyperglycemia and other symptoms such as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity, that are often associated with type 2 diabetes. I
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Page/Page column 23
(2008/06/13)
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- NOVEL CRYSTALLINE FORMS OF ANTIDIABETIC COMPOUNDS
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Novel crystalline forms of two indole compounds connected to phenoxyalkylcarboxylic acid groups are selective PPAR gamma partial agonists that are useful in the treatment of type 2 diabetes, hyperglycemia, obesity, dyslipidemia, and the metabolic syndrome. The novel crystal forms include a crystalline free acid dihydrate and crystalline free acid anhydrate of one compound and several crystalline forms of the free acid and the sodium salt of the second compound. The invention also relates to pharmaceutical compositions comprising these novel crystal forms, processes to prepare the crystal forms and their pharmaceutical compositions, and uses of the crystal forms in the treatment of type 2 diabetes and other PPAR gamma modulated diseases.
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Page/Page column 7
(2010/11/23)
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- Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides
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Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy.Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy.The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells.Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substituents in the 6- and /or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells.Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced.Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxide have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V).The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine.The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity.Four of the compounds, 6e, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro.In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine.This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.
- Monge, Antonio,Palop, Juan A.,Cerain, Adela Lopez de,Senador, Virginia,Martinez-Crespo, Francisko J.,et al.
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p. 1786 - 1792
(2007/10/02)
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