- Self-Condensation of Benzothiazolylchloromethyllithiums.
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Benzothiazolylchloromethyllithium 1c and benzothiazolyldichloromethyllithium 1e, easily available by lithiation of 1b and 1d (or 1f) respectively, undergo a different type of self-condensation reaction giving 5 and 7a respectively.The possibility that 1c and 1e behave as halocarbenoids is discussed.
- Florio, Saverio,Capriati, Vito,Solimini, Maria Cristina,Troisi, Luigino
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- HETEROCYCLIC COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER
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The present invention provides MDM2 inhibitor compounds of Formula I or II, or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.
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Page/Page column 140; 141
(2013/04/13)
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- Functionalized orthoesters as powerful building blocks for the efficient preparation of heteroaromatic bicycles
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By combining substituted anilines with functionalized orthoesters, an efficient and connective methodology for the preparation of benzoxazole, benzothiazole, and benzimidazole derivatives has been established. The versatility of this approach enables the development of new libraries of heterocycles containing multifunctional sites.
- Bastug, Gulluzar,Eviolitte, Christophe,Markó, István E.
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supporting information; experimental part
p. 3502 - 3505
(2012/08/08)
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- Highly selective aldose reductase inhibitors. II. Optimization of the aryl part of 3-(arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic acids
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Accumulation of intracellular sorbitol, the product of glucose reduction catalyzed by aldose reductase (AR) [EC 1.1.1.21], is thought to be the main culprit in the development of diabetic complications. A series of 3- arylalkyl-2,4,5-trioxoimidazolidine-1-acetic acids was prepared and tested for inhibitory activities towards AR and aldehyde reductase (ALR) [EC 1.1.1.2]. These derivatives showed strong inhibitory activity against AR without markedly inhibiting ALR. In particular, the compounds with 3- nitrophenyl, 4-chloro-3-nitrophenyl, and chloro-substituted benzothiazolyl groups as the aryl part showed powerful AR-inhibitory activity. The chloro- substituted benzothiazolyl compound showed an AR selectivity of more than 5000 fold.
- Kotani, Takayuki,Ishii, Akira,Nagaki, Yasuhiro,Toyomaki, Yoshio,Yago, Hisashi,Suehiro, Seishi,Okukado, Nobuhisa,Okamoto, Kaoru
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p. 297 - 304
(2007/10/03)
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- Synthesis of ethenylbenzothiazole derivatives
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Ethenylbenzothiazoles were synthesized by the Horner-Emmons reaction of benzothiazolylmethylphosphonate with aldehydes under phase transfer catalytic conditions in 60-71% yields. Not only aromatic but also aliphatic aldehydes gave the desired products und
- Ohba,Kosaka,Wakabayashi
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p. 3421 - 3426
(2007/10/03)
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- Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1- phthalazineacetic acid (zopolrestat) and congeners
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A new working hypothesis that there is a hitherto unrecognized binding site on the aldose reductase (AR) enzyme with strong affinity for benzothiazoles was pursued for the design of novel, potent aldose reductase inhibitors (ARIs). The first application of this hypothesis led to a novel series of 3,4-dihydro-4-oxo-3-(benzothiazolylmethyl)-1-phthalazineacetic acids. The parent of this series (207) was a potent inhibitor of AR from human placenta (IC50 = 1.9 x 10-8 M) and was orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications (ED50 = 18.5 mg/kg). Optimization of this lead through medicinal chemical rationale, including analogy from other drug series, led to more potent congeners of 207 and culminated in the design of 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1- phthalazineacetic acid (216, CP-73,850, zopolrestat). Zopolrestat was found to be more potent than 207, both in vitro and in vivo. Its IC50 against AR and ED50 in the acute test were 3.1 x 10-9 M and 3.6 mg/kg, respectively. Its ED50s in reversing already elevated sorbitol accumulation in rat sciatic nerve, retina, and lens in a chronic test were 1.9, 17.6, and 18.4 mg/kg, respectively. It was well absorbed in diabetic patients, resulting in high blood level, showed a highly favorable plasma half-life (27.5 h), and is undergoing further clinical evaluation. An assortment of synthetic methods used for the construction of benzothiazoles, including an efficient synthesis of zopolrestat, is described. Structure-activity relationships in the new series are discussed.
- Mylari,Larson,Beyer,Zembrowski,Aldinger,Dee,Siegel,Singleton
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p. 108 - 122
(2007/10/02)
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- 2-CHLORO-1,1,1-TRIETHOXYETHANE AND ITS USE IN A VERSATILE SYNTHESIS OF SUBSTITUTED, 2-CHLOROMETHYL HETEROCYCLES INCLUDING BENZOTHIAZOLE AND BENZOXAZOLE
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An efficient procedure suitable for large scale preparation of 2-chloro-1,1,1-triethoxyethane and its use in a versatile synthesis of 2-chloromethyl derivatives of an assortment of heterocycles are described.
- Mylari, Banavara L.,Scott, Pamela J.,Zembrowski, William J.
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p. 2921 - 2924
(2007/10/02)
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