Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-05-10
2002-12-31
Richter, Johann (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S027140, C536S027210, C536S027400, C536S027620, C536S027800
Reexamination Certificate
active
06500946
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel method for producing nucleoside derivatives, more precisely to a novel method for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-&bgr;-D-threo-pentofuranosyl)adenine (hereinafter referred to as “FddA”) and its related compounds which are useful as anti-viral agents, to novel intermediates in the method, and to a novel method for producing the intermediates.
2. Description of the Related Art
It is reported that 9-(2,3-dideoxy-2-fluoro-&bgr;-D-threo-pentofuranosyl)adenine (FddA) has a strong anti-viral activity against human immunodeficiency virus (HIV) and is greatly effective for treatment of acquired immune deficiency syndrome (AIDS) (see V. E. Marquetz, et al., Biochem. Pharmacol., (36) page 2719, 1987; P. Herdewijn, et al., J. Med. Chem., (30), page 2131, 1987), and many clinical tests using it for the treatment of AIDS and AIDS-related complications (ARC) are being made at present. Recently, in addition, reported are FddA derivatives as modified at the nucleic acid base site to improve their potency (see C. K. Chu, et al., J.Med. Chem., (37), page 821, 1994; J. S. Driscoll, et al., J. Med. Chem., (39), page 1619, 1996; C. K. Chu, et al., J. Med. Chem., (39), page 4676, 1996).
The most direct method for producing FddA and its related compounds comprises substituting a substrate, of which the 3′-position in the saccharide moiety is deoxylated, at its 2′-position (see P. Herdewijn, et al., J. Med. Chem., (30), page 2131, 1987; V. E. Marquez, et al., J. Med. Chem., (33), page 978, 1990; H. Shiragami, et al., Nucleosides & Nucleotides, (11), page 391, 1992). However, the yield in the conventional methods is extremely low or is not higher than 10% and the reagent, diethylaminosulfer trifuluoride (DAST), is not available in industrial amount, and therefore the methods could not be used for industrial production of FddA and its related compounds.
1. Problems to be Solved by the Invention
In the course of the completion to the present invention, the above and following problems in the related art have been also found by the present inventors.
Given the situation as above, it is desired to develop an inexpensive method for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-&bgr;-D-threo-pentofuranosyl)adenine (FddA) and its related compounds, in a simplified manner and at a high yield, in particular, an economical and industrial method for producing those nucleoside derivatives that comprises substituting a substrate, of which the 3′-position of the saccharide moiety is deoxylated, at its 2′-position at a high yield. Accordingly, the subject matter in the art is to provide such an excellent production method.
The object of the present invention is to develop an advantageous method for producing the nucleoside derivatives noted above, especially those having anti-viral activity, and to provide intermediates in the method and also a simple method for producing the intermediates.
SUMMARY OF THE INVENTION
We, the present inventors have assiduously studied in order to solve the problems noted above, and, as a result, have found, in a process for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-&bgr;-D-threo-pentofuranosyl)adenine (FddA) and its related compounds, by subjecting a 3′-deoxy derivative of adenine to 2′-deoxylation/substitution with a flurine atom or the like (see P. herdewijn, et al., J. Med. Chem., (30), page 2131, 1987; V. E. Marquez, et al., J. Med. Chem., (33), page 978, 1990; H. Shiragami, et al., Nucleosides & Nucleotides, (11), page 391, 1992 ), the yield thereof is extremely low mainly due to a rearrangement of adenine base.
It is reported that, by subjecting a derivative of adenine, of which the 3′-position is not deoxylated, to 2′-deoxylation/substitution with a fluorine atom or the like, the same kind of rearrangement has occurred as side reaction and lowered the yield (see K. A. Watanabe, et al., J. Org. Chem., (57), page 553, 1992 ). Furthermore, it is reported that, by chlorination at the 6-position of the nucleic acid, this kind of rearrangement can be suppressed (see T. Maruyama, et al., Chem. Pharm. Bull., (44), page 2331, 1996). However, it is not known the case of 3′-deoxy derivatives.
Therefore, we, the present inventors have produced novel intermediates of a general formula (1) mentioned below, which are derivatives as deoxylated at the 3′-position and substituted by a halogen atom at the 6-position of the nucleic acid. Using those novel intermediates, we have found that even substrates, of which the 3′-position of the nucleic acid is deoxylated, can suppress the troblesome rearrangement completely and can be substituted at the 2′-position at an extremely high yield. On the basis of these findings, we have completed the present invention.
Specifically, by subjecting a 3′-deoxy derivative of inosine to 6-halogenation step for halogenating it at the 6-position thereof to give a 6-halide of the derivative, and then subjecting it to 2′-deoxylation/substitution with a fluorine atom or the like, followed by further subjecting it to substitution with an amino group, a hydroxyl group or any other intended substituent at the 6-positioned halogen atom, we have made it possible to produce the intended nucleoside derivatives.
On the basis of our findings noted above, hereinunder illustrated is one embodiment of the production route to give nucleoside derivatives, which covers all the steps in series as concretely demonstrated in Examples to be mentioned hereinafter. All those steps and the compounds as produced therein are usable in the process of producing nucleoside derivatives of the present invention. Naturally, the invention encompasses not only all the steps constituting this production route but also any and every method comprising any one of those steps, novel intermediates as produced in those steps and even the use of those novel intermediates, especially the use thereof for producing various nucleoside derivatives. Production Route:
In those formulae, W represents a halogen atom, X represents a halogen atom, Y represents a substituent of any of a fluorine atom, an azido group or a cyano group, Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a substituent of a formula OR
4
, a substituent of a formula SR
4
and a substituent of a formula NHR
4
, R
1
represents a protective group for the hydroxyl group, SO
2
R
2
represents a sulfonic acid-type leaving group, R
3
represents a protective group for the hydroxyl group, and R
4
represents an optionally. phenyl-substituted, lower (e.g., C1-5) alkyl group.
Preferably, R
2
represents a halogen atom, an optionally-substituted aryl, alkyl or aralkyl group, or an optionally-substituted alkylamino group.
Regarding the definitions and the meanings of the compounds of general formula (1) to (9) as referred to herein, it shall be understood that the compounds designated by the same formula number are the same ones even though they are not individually described herein.
The invention encompasses a novel method for producing the nucleoside derivatives mentioned herein from the novel intermediates (1) and also from various raw compounds, novel intermediates including the intermediates (1) which are for producing the nucleotide derivatives, a novel method for producing those intermediates, and the use of the intermediates. More precisely, the present invention encompasses the following matters.
(i) A method for producing a nucleoside derivative represented by the following general formula (8) or (9), comprising subjecting a 3′-deoxy derivative of inosine, of which a part or all of the two hydroxyl groups may or may not be optionally protected, to 6-halogenation step for halogenating the compound at the 6-position thereof to give a 6-halide of the derivative, and then subjecting it, optionally after protecting its 5′-position, to 2′-
Hirose Naoko
Izawa Kunisuke
Katayama Satoshi
Maruyama Tokumi
Takamatsu Satoshi
Ajinomoto Co. Inc.
Crane Lawrence E.
Richter Johann
LandOfFree
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