Process for the synthesis of oligomeric compounds

Details Process for the synthesis of oligomeric compounds Process for the synthesis of oligomeric compounds

1998-05-06

2000-04-18

Wilson, James O.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 2531, 536 2533, 536 2534, 536 231, 536 2614, 536 267, 536 268, C07H 100, C07H 2100, C07F 902

Patent

active

060516992

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to methods for the preparation of oligomeric compounds having phosphite, phosphodiester, phosphorothioate, or phosphorodithioate linkages, and to intermediates useful in their preparation.


BACKGROUND OF THE INVENTION

Oligonucleotides and their analogs have been developed and used in molecular biology in certain procedures as probes, primers, linkers, adapters, and gene fragments. Modifications to oligonucleotides used in these procedures include labeling with nonisotopic labels, e.g. fluorescein, biotin, digoxigenin, alkaline phosphatase, or other reporter molecules. Other modifications have been made to the ribose phosphate backbone to increase the nuclease stability of the resulting analog. These modifications include use of methyl phosphonate, phosphorothioate, and phosphorodithioate linkages, and 2'-O-methyl ribose sugar units. Further modifications include those made to modulate uptake and cellular distribution. With the success of these compounds for both diagnostic and therapeutic uses, there exists an ongoing demand for improved oligonucleotides and their analogs.
It is well known that most of the bodily states in multicellular organisms, including most disease states, are effected by proteins. Such proteins, either acting directly or through their enzymatic or other functions, contribute in major proportion to many diseases and regulatory functions in animals and man. For disease states, classical therapeutics has generally focused upon interactions with such proteins in efforts to moderate their disease-causing or disease-potentiating functions. In newer therapeutic approaches, modulation of the actual production of such proteins is desired. By interfering with the production of proteins, the maximum therapeutic effect may be obtained with minimal side effects. It is a general object of such therapeutic approaches to interfere with or otherwise modulate gene expression, which would lead to undesired protein formation.
One method for inhibiting specific gene expression is with the use of oligonucleotides, especially oligonucleotides which are complementary to a specific target messenger RNA (mRNA) sequence. Several oligonucleotides are currently undergoing clinical trials for such use. Phosphorothioate oligonucleotides are presently being used as antisense agents in human clinical trials for various disease states, including use as antiviral agents.
Transcription factors interact with double-stranded DNA during regulation of transcription. Oligonucleotides can serve as competitive inhibitors of transcription factors to modulate their action. Several recent reports describe such interactions (see Bielinska, A., et. al., Science, 1990, 250, 997-1000; and Wu, H., et. al., Gene, 1990, 89, 203-209).
In addition to such use as both indirect and direct regulators of proteins, oligonucleotides and their analogs also have found use in diagnostic tests. Such diagnostic tests can be performed using biological fluids, tissues, intact cells or isolated cellular components. As with gene expression inhibition, diagnostic applications utilize the ability of oligonucleotides and their analogs to hybridize with a complementary strand of nucleic acid. Hybridization is the sequence specific hydrogen bonding of oligomeric compounds via Watson-Crick and/or Hoogsteen base pairs to RNA or DNA. The bases of such base pairs are said to be complementary to one another.
Oligonucleotides and their analogs are also widely used as research reagents. They are useful for understanding the function of many other biological molecules as well as in the preparation of other biological molecules. For example, the use of oligonucleotides and their analogs as primers in PCR reactions has given rise to an expanding commercial industry. PCR has become a mainstay of commercial and research laboratories, and applications of PCR have multiplied. For example, PCR technology now finds use in the fields of forensics, paleontology, evolutionary studies and genetic counseling. Commercialization ha

REFERENCES:
patent: 34069 (1862-09-01), Koster et al.
patent: 3687808 (1972-08-01), Merigan et al.
patent: 4415732 (1983-11-01), Caruthers et al.
patent: 4458066 (1984-07-01), Caruthers et al.
patent: 4500707 (1985-02-01), Caruthers et al.
patent: 4668777 (1987-05-01), Caruthers et al.
patent: 4725677 (1988-02-01), Koster et al.
patent: 4816571 (1989-03-01), Andrus et al.
patent: 4973679 (1990-11-01), Caruthers et al.
patent: 5026838 (1991-06-01), Nojiri et al.
patent: 5132418 (1992-07-01), Caruthers et al.
patent: 5210264 (1993-05-01), Yau
patent: 5212295 (1993-05-01), Cook
patent: 5705621 (1998-01-01), Ravikumar
patent: 5859232 (1999-01-01), Ravikumar
Aldrich Chemical Company Catalog, 1994-1995, p. 32.
Alul, R.H. et al., "Oxalyl-CPG: a labile support for synthesis of sensitive oligonucleotide derivatives", Nuc. Acid Res., 1991, 19, 1527-1532.
Bannwarth, W., "Synthesis of Oligodeoxynucleotides by the Phosphite-Triester Method Using Dimer Units and Different Phosphorous-Protecting Groups", Helvetica Chim. Acta, 1985, 68, 1907-1913.
Beaucage, S.L. et al., "The Synthesis of Modified Oligonucleotides by the Phosphoramidite Approach and their Applications", Tetrahedron, 1993, 49, 6123-6194.
Beaucage, S.L. et al., "Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach", Tetrahedron, 1992, 48, 2223-2311.
Bielinska, A. et al., "Regulation of Gene Expression with Double-Stranded Phosphorothioate Oligonucleotides", Science, 1990, 250, 997-1000.
Brown, T. et al., "Modern machine-aided methods of oligodeoxyribonucleotide synthesis", Oligonucleotides and Analogs, Ekstein, F., ed., IRL Press, 1991, Chapter 1, 1-24.
Cook, P.D., "Medicinal chemistry of antisense oligonucleotides--future opportunities", Anti-Cancer Drug Design, 1991, 6, 585-607.
Delgado, C. et al., "The Uses and Properties of PEG-Linked Proteins", Crit. Rev. in Therapeutic Drug Carrier Sys., 1992, 9, 249-304.
Englisch, U. et al., "Chemically Modified Oligonucleotides as Probes and Inhibitors", Angew. Chem. Int. Ed. Eng., 1991, 30, 613-629.
Iyers, R.P. et al., "3H-1,2-Benzodithiole-3-one 1,1-Dioxide as an Improved Sulfurizing Reagent in the Solid-Phase Synthesis of Oligodeoxyribonucleoside Phophorothioates", J. Am. Chem. Soc., 1990, 112, 1253-1254.
Iyer, R.P. et al., "The Automated Synthesis of Sulfur-Containing Oligodeoxyribonucleotides Using 3H-1,2-Benzodithiol-3-one 1,1-Dioxide as a Sulfur-Transfer Reagent", J. Org. Chem., 1990, 55, 4693-4699.
Kamer, P.C.J. et al., "An Efficient Approach Toward the Synthesis of Phosphorothioate Diesters via the Schonberg Reaction", Tetrahedron Letts., 1989, 30, 7657-6760.
Kroschwitz, J.I. (ed.), "Polynucleotides", Concise Encyclopedia of Polymer Science and Engineering, John Wiley & Sons, New York, 1990, 858-859.
Kumar, G. et al., "Improvements in Oligodeoxyribonucleotide Synthesis: Methyl N,N-Dialkylphosphoramidite Dimer Units for Solid Support Phosphite Methodology", J. Org. Chem., 1984, 49, 4905-4912.
Miura, K. et al., "Blockwise Mechanical Synthesis of Oligonucleotides by the Phosphoramidite Method", Chem Parm. Bull., 1987, 35, 833-836.
Ogilvie, "The chemical synthesis of oligoribonucleotides. IX. A comparison of protecting groups in the dichloridite procedure", Can. J. Chem., 1980, 58, 2686-2693.
Ouchi, T. et al., "Synthesis and Antitumor Activity of Poly(Ethylene Glycol)s Linked to 5'-Fluorouracil via a Urethane or Urea Bond", Drug Des. & Disc., 1992, 9, 93-105.
Rao, M.V. et al., "Dibenzoyl Tetrasulphide-A Rapid Sulphur Transfer Agent in the Synthesis of Phosphorothioate Analogues of Oligonucleotides", Tetrahedron Letts., 1992, 33, 4839-4842.
Ravasio, N. et al., "Selective Hydrogenations Promoted by Copper Catalysts. 1. Chemoselectivity, Regioselectivity, and Strereoselectivity in the Hydrogenation of 3-Substituted Steroids", J. Org. Chem., 1991, 56, 4329-4333.
Secrist, J.A. et al., "Synthesis and Biological Activity of 4'-Thionucleosides", 10th International Rountable: Nucleosides, Nucleotides and their Biological Applications, Sept. 16-20

Affiliated with

Also associated with

Rating

Process for the synthesis of oligomeric compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the synthesis of oligomeric compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the synthesis of oligomeric compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2337149