Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-06-13
1997-12-09
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
549 63, C07D33336, C07D33342, C07H 1900
Patent
active
056962541
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to diastereoselective processes for preparing optically active cis-nucleosides and nucleoside analogues and derivatives. The novel processes of this invention allow the stereo-controlled synthesis of a given enantiomer of a desired cis-nucleoside or nucleoside analogue or derivative in high optical purity. This invention also relates to novel intermediates useful in the processes of this invention.
BACKGROUND OF THE INVENTION
Nucleosides and their analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleosides have shown antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV) (PCT publication WO 89/04662 and European Patent publication 0349242 A2). Among the nucleosides shown to have antiviral activity are 3'-azido-3'-deoxythymidine (AZT), 2'3'-dideoxy-cytidine (DDC), 2-hydroxymethyl-5-(cytosin-1'-yl)-1,3-oxathiolane and 2-hydroxymethyl-4-(guanin-9'-yl)-1,3-dioxolane (European Patent publication 0382526 A2 and European Patent publication 0377713 A2).
Most nucleosides and nucleoside analogues and derivatives contain at least two chiral centers (shown as * in formula (A)), and exist in the form of two pairs of optical isomers (i.e., two in the cis-configuration and two in the trans-configuration). However, generally only the cis-isomers exhibit useful biological activity. ##STR1## Different enantiomeric forms of the same cis-nucleoside may, however, have very different antiviral activities. M. M. Mansuri et al., "Preparation Of The Geometric Isomers Of DDC, DDA, D4C and D4T As Potential Anti-HIV Agents", Bioorg.Med.Chem. Lett., 1 (1), pp. 65-68 (1991). Therefore, a general and economically attractive stereoselective synthesis of the enantiomers of the biologically active cis-nucleosides is an important goal.
Many of the known processes for producing optically active nucleosides and their analogues and derivatives modify naturally occurring (i.e., optically active) nucleosides by altering the base or by altering the sugar via reductive procedures such as deoxygenation or radical initiated reductions. C. K. Chu et al., "General Synthesis Of 2',3'-Dideoxynucleosides And 2',3'-Didehydro-2',3'-Dideoxynucleosides," J.Org.Chem., 54, pp. 2217-2225 (1989). These transformations involve multiple steps, including protection and deprotection and usually result in low yields. Moreover, they begin with and maintain the optical activity of the starting nucleoside. Thus, the nucleosides produced by these processes are limited to specific analogues of the enantiomeric form of the naturally occurring nucleoside. In addition, these procedures require the availability of the naturally occurring nucleoside, often an expensive starting material.
Other known processes for producing optically active nucleosides rely on conventional glycosylation procedures to add the sugar to the base. These procedures invariably give anomeric mixtures of cis- and trans-isomers which require tedious separation and result in lower yields of the desired biologically active cis-nucleoside. Improved glycosylation methods designed to yield only the cis-nucleoside require addition of a 2'- or 3'-substituent to the sugar. Because the 2'- or 3'-substituent is only useful in controlling cis-nucleoside synthesis in one configuration (when the 2' or 3' substituent is trans- to the 4' substituent), multiple steps are required to introduce this substituent in the proper configuration. The 2'- or 3'-substituent must then be removed after glycosylation, requiring additional steps. L. Wilson and D. Liotta, "A General Method For Controlling Stereochemistry In The Synthesis Of 2'-Deoxyribose Nucleosides", Tetrahedron Lett., 31, pp. 1815-1818 (1990). Furthermore, to obtain an optically pure nucleoside product, the starting sugar must be optically pure. This also requires a series of time-consuming syntheses and purification steps.
SUMMARY OF THE INVENTION
The present inventio
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Jin Haolun
Mansour Tarek
Siddiqui M. Arshad
Tse Allan H. L.
Biochem Pharma Inc.
Crane L. Eric
Haley, Jr. James F.
Kight John
McDonell Leslie A.
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