US RE38,090 E1 · 3′-substituted nucleoside derivative

Abstract

The invention relates to a 3′-substituted nucleoside derivative represented by the following general formula (1): wherein B means a nucleic acid base which may have a substituent, Z represents a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the formula: in which Ra, Rb and Rc are individually a lower alkyl group or a phenyl group, or an oxiranyl group which may have at least one lower alkyl group, R1 and R2 individually represent H or an ester-forming residue capable of easily leaving in a living body, and R3 is H, a mono- or polyphosphoric acid residue, or an ester-forming residue capable of easily leaving in a living body, with the proviso that the sugar moiety is ribose, or a pharmaceutically acceptable salt thereof. The 3′-substituted nucleoside derivative according to the invention has an excellent antitumor activity and is hence useful for treatment for and prevention of cancers.

Claims22

Dependent claims

A 3′-substituted nucleoside derivative represented by general formula (1), or a pharmaceutically acceptable salt thereof:

wherein B represents a nucleic acid base which may have a substituent,
wherein Z represents:
(i) a lower alkynyl or lower alkenyl group which may be substituted by a group represented by general formula (2):
in which Ra, Rb and Rc may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or
(ii) an oxiranyl group which may be substituted by at least one lower alkyl group,
wherein R1 and R2 individually represent a hydrogen atom or an ester-forming residue capable of easily being removed in a living body aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, and R3 is a hydrogen atom, a mono- or polyphosphoric mono-, di- or tri-phosphoric acid residue, or an ester-forming residue capable of easily being removed in a living body aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, with the proviso that Z is in a cis configuration with respect to B.

3 more elements

A process for the preparation of a 3′-substituted nucleoside derivative represented by general formula (1), or a pharmaceutically acceptable salt thereof:

wherein B represents a nucleic acid base which may have a substituent,
wherein Z represents:
(i) a lower alkynyl or lower alkenyl group which may be substituted by a group represented by general formula (2):
in which Ra, Rb and Rc may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or
(ii) an oxiranyl group which may be substituted by at least one lower alkyl group,
wherein R1 and R2 individually represent a hydrogen atom or an ester-forming residue capable of easily being removed in a living body aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, and R3 is a hydrogen atom, a mono- or polyphosphoric mono-, di- or tri-phosphoric acid residue, or an ester-forming residue capable of easily being removed in a living body aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, with the proviso that Z is in a cis configuration with respect to B, which comprises the step of:
reacting a sugar derivative represented by general formula (3):
wherein R1′, R2′ and R3′ mean individually a protecting group for a hydroxyl group, Ac represents an acetyl group, and Z has the same meaning as defined above, with a nucleic acid derivative represented by general formula (4):
B—Y (4)
wherein B has the same meaning as defined above, and Y is a silyl protecting group, wherein said reacting occurs in the presence of a Lewis acid in a nonpolar solvent.

7 more elements

A process for the preparation of a 3′-substituted nucleoside derivative represented by general formula (1), or a pharmaceutically acceptable salt thereof:

wherein B represents a nucleic acid base which may have a substituent,
wherein Z represents:
(i) a lower alkynyl or lower alkenyl group which may be substituted by a group represented by general formula (2):
in which Ra, Rb and Rc may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or
(ii) an oxiranyl group which may be substituted by at least one lower alkyl group,
wherein R1 and R2 individually represent a hydrogen atom or an ester-forming residue capable of easily being removed in a living body aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, and R3 is a hydrogen atom, a mono- or polyphosphoric mono-, di- or tri-phosphoric acid residue, or an ester-forming residue capable of easily being removed in a living body aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, with the proviso that Z is in a cis configuration with respect to B, which comprises the steps of:
(A) partially hydrolyzing a compound represented by general formula (5):
wherein B has the same meaning as defined above, to form a compound represented by general formula (6):
wherein B has the same meaning as defined above,
(B) reacting the resulting compound represented by general formula (6) with a compound represented by formula:
z—x
wherein Z has the same meaning as defined above, and X represents a hydrogen or halogen atom, or MgBr,
wherein when X represents a hydrogen or halogen atom, said reacting occurs in the presence of n-butyllithium in tetrahydrofuran;
and wherein when X represents MgBr, said reacting occurs in tetrahydrofuran, to form a compound represented by general formula (7):
wherein B and Z have the same meaning as defined above, and
(C) hydrolyzing the resulting compound represented by general formula (7) to give rise to a compound represented by general formula (1).

13 more elements

Dependencies are inferred from the claim text.

3′-substituted nucleoside derivative

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3′-substituted nucleoside derivative

Life of this patent

Abstract

Claims22