- Inhibition of c-KIT, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930
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The quinoline domain of OSI-930, a dual inhibitor of receptor tyrosine kinases (RTKs) c-Kit and KDR, was modified in an effort to further understand the SAR of OSI-930, and the binding site characteristics of c-Kit and KDR. A series of 16 compounds with h
- Patel, Jay P.,Kuang, Ye-Hong,Chen, Zhe-Sheng,Korlipara, Vijaya L.
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p. 6495 - 6499
(2011/12/21)
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- TETRAHYDROQUINOLONES AND AZA-ANALOGUES THEREOF FOR USE AS DPP-IV INHIBITORS IN THE TREATEMENT OF DIABETES
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Compound of formula (I) or a pharmaceutically-acceptable salt thereof, formula (I) wherein Ar is optionally substituted phenyl; R1 is selected from: formula a) or b) (wherein is a single or double bond); R5, R6, R7/s
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- HETEROCYCLIC AMIDE DERIVATIVES WHICH POSSES GLYCOGEN PHOSPHORYLASE INHIBITORY ACTIVITY
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Heterocyclic amides of formula (1) wherein: B is selected from R4 and R 5 together are either -S-C(R 6)=C(R 7)_ or _C(R7)=C(R6)_SA is a pyridylene ring; m is 0, 1 or 2; n is 0 or 1; R 2 is for example selected from (I -4C)alkyl, hydroxy(l -4C)alkyl, dihydroxy(2-4C)alkyl and (1 -4C)aIkoxy(1 -4C)alkyl. or a pharmaceutically acceptable salt possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity. Processes for the manufacture of said heterocyclic amide derivatives, intermediates in said processes and pharmaceutical compositions containing the heterocyclic amide derivatives are described.
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Page/Page column 58
(2010/02/11)
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- HETEROCYCLIC AMIDE DERIVATIVES AS INHIBITORS OF GLYCOGEN PHOSPHORYLASE
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Heterocyclic amides of formula (1) wherein: X is N or CH; R4 and R5together are either -S-C(R6)=C(R7)- or -C(R7)=C(R6)-S-; R6 and R7 are independently selected from, f
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Page/Page column 112
(2010/02/07)
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- The synthesis of β-nitropyridine compounds
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Pyridine and a number of substituted pyridines have been nitrated by reaction with N2O5 followed by reaction with an aqueous solution of SO2xH2O or NaHSO3. The dependence of the yields on the pH of the aqueous reaction medium, on the concentration of SO2xH2O-HSO3-, on addition of methanol to the aqueous phase, and on the reaction temperature were investigated. The yields obtained with NaHSO3 were: 3-nitropyridine 77%, 2-methyl-5-nitro-pyridine 36%, 3-methyl-5-nitropyridinc 24%, 3-acetyl-5-nitropyridine 18%, 5-nitropyridine-3-carboxylic acid 15%, 3-chloro-5-nitropyridine 11%, 4-methyl-3-nitropyridine 39%, 4-acetyl-3-nitropyridine 67%, 4-cyano-3-nitropyridine 45%, 4-phenyl-3-nitropyridine 68%, 4-formyl-3-nitropyridine 62% (from reaction in liquid SO2), 3-nitropyridine-4-carboxylic acid 48%, methyl 3-nitropyridine-4-carboxylate 75%, 2,3-dimethyl-5-nitropyridine 37%, 2,4-dimethyl-5-nitropyridine 64%, 3-nitroquinoline 10% and 4-nitroisoquinoline 42%.
- Bakke, Jan M.,Ranes, Eli,Riha, Jaroslav,Svensen, Harald
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p. 141 - 144
(2007/10/03)
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- Synthesis, Topoisomerase I Inhibitory Activity, and in Vivo Evaluation of 11-Azacamptothecin Analogs
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A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay.The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidyne and optically active tricyclic ketone 7.Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay.Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide.Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable complex assay.These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts.The analog 11-aza-(20S)-camptothecin 11-N-oxide was found to significantly retard tumor growth when compared to untreated controls.Finally 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7.Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility.A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts.The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoroacetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays.A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.
- Uehling, David E.,Nanthakumar, Suganthini S.,Croom, Dallas,Emerson, David L.,Leitner, Peter P.,et al.
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p. 1106 - 1118
(2007/10/02)
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- A MILD METHOD FOR THE CONVERSION OF ACTIVATED ARYL METHYL GROUPS TO CARBOXALDEHYDES VIA THE UNCATALYZED PERIODATE CLEAVAGE OF ANAMINES
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A mild procedure for the oxidative cleavage of aryl enamines to aryl aldehydes by periodate without the need for transition metal catalysis is presented.
- Vetelino, Michael G.,Coe, Jotham W.
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p. 219 - 222
(2007/10/02)
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