- Development of novel quinone phosphorodiamidate prodrugs targeted to DT-diaphorase
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A series of naphthoquinone and benzimidazolequinone phosphorodiamidates has been synthesized and studied as potential cytotoxic prodrugs activated by DT-diaphorase. Reduction of the quinone moiety in the target compounds was expected to provide a pathway for expulsion of the phosphoramide mustard alkylating agent. All of the compounds synthesized were excellent substrates for purified human DT-diaphorase (k(cat)/K(m) = 3 x 107 - 3 x 108 M-1 s-1). The naphthoquinones were toxic to both HT-29 and BE human colon cancer cell lines in a clonogenic assay; however, cytotoxicity did not correlate with DT-diaphorase activity in these cell lines. The benzimidazolequinone analogues were 1-2 orders of magnitude less cytotoxic than the naphthoquinone analogues. Chemical reduction of the naphthoquinone led to rapid expulsion of the phosphorodiamidate anion; in contrast, the benzimidazole reduction product was stable. Michael addition of glutathione and other sulfur nucleophiles provides an alternate mechanism for activation of the naphthoquinone phosphorodiamidates, and this mechanism may contribute to the cytotoxicity of these compounds.
- Flader,Liu,Borch
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- Substitued A-Piperazingly Phenylpropionic Acid Derivatives As Hppar Alpha And/Or Hppar Gamma Agonists
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The present invention relates to a compound of formula I, racemates, optically active isomers, or pharmaceutically acceptable salts or solvates thereof, and a pharmaceutical composition comprising the compound, the various radicals in the formula I are the same as defined in the claims. The present invention also relates to a process for preparing the compound of formula I and use of said compound in the preparation of a medicament for the treatment of hyperglycemia, dyslipidemia, type II diabetes mellitus including associated diabetic dyslipidemia
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(2008/06/13)
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- Tricyclic analgesics
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A tricyclic compound of Formula (I): wherein: R1 is hydrogen or hydroxy; R2 is hydrogen or hydroxy; or R1 and R2 together are oxygen; A is a bond, CH2, CH CH3, CH2 CH2 or C(CH3)2; R3 and R4 are the same or different and are hydrogen, halo, C1-C6 alkyl, C1-C4 alkoxy, trifluoromethyl NO2, COR6, COOR6 or NR6R7, wherein R6 and R7 are the same or different and are hydrogen, C1-C6 alkyl or benzyl; R5 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, (O═C)—C1-6 alkyl, (O═C)—C2-6 alkenyl, (O═C)—C3-6 cycloalkyl wherein said alkyl, alkenyl and cycloalkyl groups can be substituted by 1, 2 or 3 groups selected from halo, C3-C6 cycloalkyl, phenyl or substituted phenyl, and salts thereof, are particularly useful for treating, among other indications, neuropathic pain and other CNS disorders.
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- Phosphoramidate analogs of 2'-deoxyuridine
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The present invention provides a series of cytotoxic phosphoramidate analogs of 5-fluoro-2'-deoxyuridine of the general formula (I): STR1 wherein R1 is H, F or (C1 -C4)alkyl; R2 is CH2 CH2 X wherein X is Cl, Br, I or p-toluenesulfonyl; R3 is (C1 -C4)alkyl or CH2 CH2 X wherein X is Cl, Br, I or p-toluenesulfonyl; or wherein R2 and R3, taken together with the N atom, can be a 5- or 6-membered heterocyclic ring which is aliphatic or aliphatic interrupted by a ring oxygen or a second ring nitrogen; R4 is H, one equivalent of a pharmaceutically-acceptable cation or (4,4,6-trimethyltetrahydro-1,3-oxazin-2-yl)ethyl, and the pharmaceutically-acceptable salts thereof.
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