109583-02-0Relevant academic research and scientific papers
Synthesis of artificial HMG-CoA reductase inhibitors based on the olefination strategy
Hiyama,Minami,Takahashi
, p. 364 - 372 (2007/10/02)
Synthetic methods were studied for optically active 6-oxo-3,5-isopropylidenedioxyhexanoate esters (4), which could be used as a key precursor of various kinds of artificial analogs of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. An enantiomer (+)-4 was prepared by asymmetric reduction of β,δ-diketo esters derived from the Taber's alcohol or L-tartrate followed by a series of chemical transformations, and the desired enantiomer (-)-4 was prepared by the same asymmetric reduction starting from D-tartrate. The key intermediate (-)-4 was finally converted into a highly potent HMG-CoA reductase inhibitor, NK-104.
Stereoselective reduction of β,δ-diketo esters. A novel strategy for the synthesis of artificial HMG-CoA reductase inhibitors
Hiyama,Reddy,Minami,Hanamoto
, p. 350 - 363 (2007/10/02)
Condensation of N-methoxy-N-methyl amides with the dianions of acetoacetates gives in good yields β,δ-diketo esters, which are reduced with Et2BOMe-NaBH4 in tetrahydrofuran-methanol highly selectively to give syn-β,δ-dihydroxy esters in one step. Similarly, the β,δ-diketo esters of the Taber's chiral alcohol or its enantiomer respectively are reduced to give syn-β,δ-dihydroxy esters of moderate enantiomeric excess. Higher diastereo- and enantioselectivity were achieved by reduction of the β,δ-diketo esters of the Taber's chiral alcohol or its enantiomer successively with diisobutylalane and with Et2BOMe-NaBH4. The resulting syn-diol esters were hydrolyzed and lactonized to give various types of β-hydroxy-δ-lactones commonly found in artificial HMG-CoA reductase inhibitors.
A novel enantioselective synthesis of HMG Co-A reductase inhibitor NK-104 and a related compound
Minami, Tatsuya,Hiyama, Tamejiro
, p. 7525 - 7526 (2007/10/02)
Optically active methyl 6-oxo-3,5-syn-isopropylidenedioxyhexanoate (5) was prepared by enantioselective syn-reduction of β,δ-diketo ester 2, followed by hydrolysis, protection of the diol moiety and ozonolysis, and was converted into a highly potent HMG Co-A reductase inhibitor NK-104 and an analogue.
Antihypercholesterolemic tetrazole compounds
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, (2008/06/13)
Compounds of the formula STR1 wherein R1 and R4 each are independently hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, or trifluoromethyl; R2, R3, R5 and R6 each are independently hydrogen, halogen C1-4 alkyl or C1-4 alkoxy; tet is STR2 n is an integer of from 0 to 2, inclusive; A is STR3 R7 is hydrogen, C1-4 alkyl, C1-4 alkoxy(lower) alkyl or (2-methoxyethoxy)methyl; X is --OH or =O; and R8 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt, are novel antihypercholesterolemic agents which inhibit cholesterol biosynthesis. Intermediates and processes for their preparation are disclosed.
Synthesis, biological profile, and quantitative structure - Activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
Sit,Parker,Motoc,Han,Balasubramanian,Catt,Brown,Harte,Thompson,Wright
, p. 2982 - 2999 (2007/10/02)
A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)-6,8-nonad ienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, K(i) = 4.3 x 10-9 M when K(m) for HMG-CoA is 28 x 10-6 M; the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal hepatocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.
Intermediates for antihypercholesterolemic tetrazole compounds
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, (2008/06/13)
This invention provides novel intermediates of the formula STR1 in substantially the cis or cis-(4R,6S) form wherein R9 and R10 each are C1-4 alkyl or R9 and R10, taken together with the carbon atom to which they are attached, is cyclopentyl, cyclohexyl or cycloheptyl; and R12 is hydrogen, C1-4 alkyl or a metal cation and processes thereof which are useful for the preparation of antihypercholesterolemic agents.
Antihypercholesterolemic tetrazol-1-yl compounds
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, (2008/06/13)
Compounds of the formula STR1 wherein R1, R2, R3, and R4 each are independently hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or trifluoromethyl; R is hydrogen, C1-4 alkyl or phenyl; A is STR2 R5 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt, are novel antihypercholesterolemic agents which inhibit cholesterol biosynethesis. Intermediates and processes for their preparation are disclosed.
SYNTHESES OF ARGENTILACTONE 11 AND GONIOTHALAMIN 15
O'Connor, Brian,Just, George
, p. 5201 - 5202 (2007/10/02)
Syntheses of (-)-(5R)-argentilactone 11 and (+)-(5R)-goniothalamin 15 are described starting from olefin 4.
