365541-74-8Relevant academic research and scientific papers
6-(AMINOALKYL)INDAZOLES
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Page/Page column 46-47, (2010/11/28)
6-(Aminoalkyl) indazoles of formula (I) and the salts thereof have renin-inhibiting properties and can be used as antihypertensive, and renal, cardiac and vascular protecting medicinally active ingredients.
Quinolizinone compound and use thereof as HIV integrase inhibitor
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Page/Page column 47, (2010/10/20)
A pharmaceutical agent having an anti-HIV action, particularly, a pharmaceutical agent having an integrase inhibitory action, is provided. The present invention relates to a quinolizinone compound represented by the following formula [I] wherein each symbol is as defined in the specification, a pharmaceutically acceptable salt thereof, and an anti-HIV agent containing same as an active ingredient. The compound of the present invention has an HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compounds can become a more effective anti-HIV agent. Since the compound has a high inhibitory activity specific for integrases, the compound can provide a safe pharmaceutical agent for human with a fewer side effects.
Practical synthesis of an orally active renin inhibitor aliskiren
Dong, Hua,Zhang, Zhi-Liu,Huang, Jia-Hui,Ma, Rujian,Chen, Shu-Hui,Li, Ge
, p. 6337 - 6340 (2007/10/03)
A convergent synthesis of aliskiren was accomplished via the use of Segment AB as the key intermediate, which was prepared via the coupling of the Grignard reagent derived from Segment B with Segment A, followed by subsequent oxidative lactonization.
The nonchiral bislactim diethoxy ether as a highly stereo-inducing synthon for sterically hindered, γ-branched α-amino acids: A practical, large-scale route to an intermediate of the novel renin inhibitor aliskiren
Goeschke, Richard,Stutz, Stefan,Heinzelmann, Walter,Maibaum, Juergen
, p. 2848 - 2870 (2007/10/03)
The diastereoselective synthesis of the sterically hindered, γ-branched α-amino acid derivative (2S,4S)-24a and its N-[(tert-butoxy)carbonyl](Boc)-protected alcohol (2S,4S)-19, both key intermediates of a novel class of nonpeptide renin inhibitors such as aliskiren (1), is described. Initially, the analogous methyl ester (2S,4S)-17 was obtained by alkylation of the chiral Schoellkopf dihydropyrazine (R)-12a with the dialkoxy-substituted alkyl bromide (R)-11a, which proceeded with explicitly high diastereofacial selectivity (ds > 98%) to give (2S,SR,2′S)-13a (Scheme 4), followed by mild acid hydrolysis and N-Boc protection (Scheme 5). Conversely, the complete lack of stereocontrol and poor yields for the reaction of (R)-11a with the enantiomeric (S)-12b suggested, in addition to the anticipated shielding effect by the iPr group at C(2) of the auxiliary, steric repulsion between the MeO-C(6) and the bulky residues of (R)-11a in the proposed transition state, which would strongly disfavor both the Si and Re attack of the electrophile (see Fig.). Based on this rationale, alkylation of the readily accessible achiral diethoxy-dihydropyrazine 21 with (R)-11a was found to provide a 95:5 mixture of diastereoisomers (2S,2′S)-22a and (2R,2′S)-23a in high yield (Scheme 6), which afforded in two steps and after recrystallization enantiomerically pure (2S,4S)-24a. Similarly, the stereochemical course for the alkylation reactions of the related alkyl bromides (S)-28a and (R)-28b with both (R)-12a and (S)-12b as well as with the achiral 21 was investigated (Schemes 7-9). The precursor bromides (R)-11a, (S)-11b, (R)-28a, and (S)-28b were efficiently synthesized via the diastereoselective alkylation of the Evans 3-isovaleroyloxazolidin-2-ones (R)-7a and (S)-7b either with bromide 6 or with benzyl chloromethyl ether, and subsequent standard transformations (Schemes 3 and 7). A practical and economical protocol of the preparation of (2S,4S)-24a on a multi-100-g scale is given. This is the first report of the application of an achiral dihydropyrazine, i.e., in form of 21, as a highly stereo-inducing synthon providing rapid access to a N-protected γ-branched α-amino acid with (2S) absolute configuration.
Asymmetric total synthesis of ent-(-)-roseophilin: Assignment of absolute configuration
Boger,Hong
, p. 8515 - 8519 (2007/10/03)
An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine → 1,2-diazine → pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([α]25D, CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing ah unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.
