3′-substituted nucleoside derivative

Details 3′-substituted nucleoside derivative 3′-substituted nucleoside derivative

2000-05-26

2003-04-22

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S051000, C536S026230, C536S026260, C536S026700, C536S026710, C536S026740, C536S026800, C536S027110, C536S027600, C536S027620, C536S027630, C536S027800, C536S027810, C536S028500, C536S028510, C536S028520, C536S028530, C536S028540, C536S028550

Reissue Patent

active

RE038090

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a new nucleic acid derivative, and more particularly to a 3′-substituted nucleoside derivative or a pharmaceutically acceptable salt thereof, which has excellent antitumor activities and is useful as a medicine such as an antitumor agent, and use of such a compound for a medicine.
BACKGROUND ART
Pyrimidine compounds such as 5-fluorouracil, tegafur, UFT, doxifluridine, carmofur, cytarabine and enocitabine have heretofore been known as antitumor agents which are nucleic acid antimetabolites.
On the other hand, 1-(2-O-(tert-butyldimethylsilyl)-3-C-ethynyl-&bgr;-D-ribofuranosyl)thymine has been known as a pyrimidine or purine nucleoside having an alkynyl group at a 3-position of a sugar moiety from Tetrahedron, 47, 1727-1736 (1991). There is however no description as to the medicinal utility of this compound, in particular, antitumor action. 1-(3-C-Ethynyl-&bgr;-D-xylofuranosyl)thymine and 1-(2-O-(tert-butyldimethylsilyl)-3-C-ethynyl-&bgr;-D-xylofuranosyl)thymine are also described ibid. The sugar moieties of these two compounds are both composed of xylose and differ in the configuration at a 3-position from the ribose in the compounds according to the present invention. Besides, the literature does not describe anything about antitumor action. compounds having an alkyl group at a 3-position of a sugar moiety are described in Japanese Patent Publication Nos. 11908/1970 and 4376/1971. However, their antitumor effects are extremely little, and they are hence of no utility value as anticancer agents under circumstances.
Accordingly, it is an object of the present invention to provide a new nucleic acid derivative which has excellent antitumor activities and is useful as a medicine, and a medicine comprising such a compound.
In view of the foregoing circumstances, the present inventor has carried out an extensive investigation. As a result, it has been found that a nucleic acid derivative at a 3-position of the sugar moiety of which a substituent has been introduced has excellent antitumor activities and is useful as an antitumor agent, thus leading to completion of the present invention.
DISCLOSURE OF THE INVENTION
The present invention provides 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 general formula (2):
in which R
a
, R
b
and R
c
may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or an oxiranyl group which may be substituted by at least one lower alkyl group, R
1
and R
2
individually represent a hydrogen atom or an ester-forming residue capable of easily leaving in a living body, and R
3
is a hydrogen atom, 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 compound of the present invention represented by the general formula (1) has excellent antitumor activities and is useful as a medicine such as a remedy for various tumors.
Accordingly, the present invention also provides a medicinal composition comprising the compound of the general formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
The present invention further provides a medicine, in particular, an antitumor agent, comprising the compound of the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention further provides use of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof for a medicine.
The present invention still further provides a method of treating or preventing a cancer of a mammal, which comprises administering an effective amount of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof to the mammal.
The present invention yet still further provides a process for the preparation of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
Examples of the nucleic acid residue represented by B in the general formula (1) include pyrimidine bases such as cytosine, thymine and uracil, and purine bases such as adenine and guanine.
Examples of the substituent, by which the nucleic acid base may be substituted, include halogen atoms, lower alkyl groups, acyl groups such as aliphatic acyl groups or aromatic acyl groups, and substituted oxycarbonyl groups such as lower alkoxycarbonyl groups, lower alkenyloxycarbonyl groups or aralkyloxycarbonyl groups.
Examples of the halogen atoms include fluorine, chlorine, bromine and iodine atoms.
Examples of the lower alkyl groups include linear or branched alkyl groups having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl groups.
Examples of the aliphatic acyl groups include linear or branched acyl groups having 1-6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl groups. Examples of the aromatic acyl groups include benzoyl, &agr;-naphthoyl and &bgr;-naphthoyl. These groups may also have a lower alkyl group, lower alkoxy group, halogen atom, nitro group or the like as a substituent.
As examples of the lower alkyl group and halogen atom, may be mentioned the same groups and atoms as those mentioned above.
Examples of the lower alkoxy group include linear or branched alkoxy groups having 1-6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
Examples of the lower alkoxycarbonyl groups include linear or branched alkoxycarbonyl groups having 2-7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups.
Examples of the lower alkenyloxycarbonyl groups include linear or branched alkenyloxycarbonyl groups having 3-7 carbon atoms, such as vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, 1-butenyloxycarbonyl and 2-butenyloxycarbonyl groups.
Examples of the aralkyloxycarbonyl groups include aralkyloxycarbonyl groups having 8-12 carbon atoms, such as benzyloxycarbonyl, phenethyloxycarbonyl, &agr;-naphthylmethyloxycarbonyl and &bgr;-naphthylmethyloxycarbonyl groups. These groups may have a lower alkyl group, lower alkoxy group, halogen atom, nitro group or the like as a substituent.
Examples of the lower alkynyl group represented by Z include alkynyl groups having 2-6 carbon atoms, such as ethynyl, propynyl (1-propynyl, 2-propynyl), butynyl (1-butynyl, 2-butynyl, etc.), pentynyl (1-pentynyl, etc.) and hexynyl (1-hexynyl, etc.) groups, while examples of the lower alkenyl group include alkenyl groups having 2-6 carbon atoms, such as ethenyl, propenyl (1-propenyl, 2-propenyl, isopropenyl), butenyl (1-butenyl, 2-butenyl, 3-butenyl, etc.), pentenyl (1-pentenyl, etc.) and hexenyl (1-hexenyl, etc.) groups. Examples of the oxiranyl group having at least one lower alkyl group include oxiranyl groups substituted by one or two lower alkyl groups, such as 3-methyloxiranyl, 3-ethyloxiranyl, 3-propyloxiranyl, 3-isopropyloxiranyl, 3-butyloxiranyl, 3-tert-butyloxiranyl, 3,3-dimethyloxiranyl and 3,3-diethyloxiranyl groups.
Examples of the group represented by the general formula (2) include silyl groups substituted by three linear or branched alkyl groups having 1-6 carbon atoms, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tri-tert-butylsilyl, trihexylsilyl, dimethylethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, diisopropylmethylsilyl, di-tert-butylmethylsilyl and tert-butyldimethylsilyl groups, and diphenylmethylsilyl, dimethylphenylsilyl, tert-butyldiphenylsilyl and triphen

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