Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-06-03
1998-11-03
Wilson, James O.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 278, 536 2781, 536 282, 536 285, 536 2853, 536 2854, 536124, 536125, C07H 100
Patent
active
058310754
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to an improved new process for the preparation of amino acid esters of nucleoside analogues.
Nucleoside analogues constitute an important class of drugs useful predominantly for their anti-viral activity. Their major therapeutic effect thus stems from their ability to interfere with viral nucleic acid metabolism, notably DNA or RNA replication. A great number of nucleoside analogues have been described and many have found clinical application in treating a variety of viral infections. Thus acyclovir (9-(2-hydroxyethoxymethyl)guanine) and BW 882C are particularly useful against Herpes virus (see e.g. Schaeffer et al., Nature 272 583-585, 1978) whereas AZT (azidothymidine, zidovudine, retrovir) and more recently ddI (dideoxyinosine) have been proposed, and indeed are used, for the treatment of AIDS and HIV infection.
Efforts continue to develop new and improved nucleoside analogues and in recent years such efforts have included derivatisation of existing nucleoside analogues to improve their properties, for example in terms of bioactivity, bioavailability, or to facilitate their formulation, eg. by enhancing water solubility.
Thus for example amino acid esters of nucleoside analogues have been synthesised. EP-A-308065 and EP-A-99493 of Wellcome describe, respectively, the valine and isoleucine, and glycine and alanine, esters of acyclovir.
Such amino acid esters are typically synthesized, as described for example in EP-A-303065, through a direct esterification reaction between the free hydroxy group of the nucleoside analogue and the carboxy group of the amino acid. Certain alternative reaction routes however have been described in EP-A-308065.
The prior art processes described and used are however generally multi-step processes involving for example protection and deprotection stages, and requiring costly reagents. Thus activating and/or coupling reagents (such as DCC and DMAP) are frequently required to achieve the desired reaction, adding both to costs and reaction complexity. A need therefore exists for improved processes for the preparation of amino acid nucleoside analogue esters, which are more economical, quicker and above all simpler to perform. The present invention provides just such a process.
In one aspect the present invention thus provides a process for the preparation of an amino acid ester (i.e. a mono, di, tri or polyester) of a nucleoside analogue, said process comprising reacting a nucleoside analogue having an esterifiable hydroxy group in its linear or cyclic ether moiety, with an optionally ring-carbon substituted 2-oxa-4-aza-cycloalkane-l,3-dione.
Naturally occurring nucleosides have two components, a nitrogen-containing purine or pyrimidine ring structure, linked to a sugar ring of ribose or deoxyribose. Such nucleosides form the building blocks of DNA and RNA and are thus recognised by and interact with DNA/RNA synthesising enzymes, including the enzymes of infecting viruses. Either or both of the purine/pyrimidine or sugar components of naturally occurring nucleosides may be altered to create an analogue which is still recognised by the viral machinery but which cannot function as a normal substrate. The nucleoside analogue can thus inhibit enzyme function and/or impair the resulting nucleic acid structure (e.g. by chain termination or base pair mismatching). The term "nucleoside analogue" as used herein covers such analogues.
In many nucleoside analogues, modification of the "sugar" moiety results in an alteration of the chemical nature of the group such that it can no longer correctly be referred to as a sugar; as used herein "ether moiety" describes the group in the analogue resulting from the sugar group modification, and it may be cyclic (as in AZT, ddI and related analogues), or linear, (as in acyclovir or 9-(1,3-dihydroxy-2-propoxymethyl)guanine, DHPG). Nucleoside analogues are described extensively in the literature, and many are listed for example in Nasr et al., Antiviral Research 14, 125-148 (1990) or McGowan et al., Antiviral Chemotherapy,
REFERENCES:
patent: 5318974 (1994-06-01), Beauchamp
Rolabo SL
Wilson James O.
LandOfFree
Amino acid ester of nucleoside analogues does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Amino acid ester of nucleoside analogues, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amino acid ester of nucleoside analogues will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-690810