JP2664837B2 - Trifluorothymidine derivative, process for producing the same, and anticancer agent containing the same as active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel trifluorothymidine derivative having an anticancer effect.

[0002] Trifluorothymidine (hereinafter referred to as "F3Th")
d ”), that is, the general formula (5 )

[0003]

Embedded image Is a nucleic acid antimetabolite first synthesized by Heidelberger et al. In 1962 (Journal of the American Chemical Society, vol. 84, p. 3597, 1962), and its pharmacological properties have been studied since then. Have been. As a result of these studies, it is known that the compound inhibits DNA synthesis and is more effective as an antiviral agent than an anticancer agent, for example, for herpes and vaccinia infections. With respect to antitumor activity, the compound is identified as L1210leukemia or aden
It has been reported that it shows an excellent antitumor effect against experimental tumors such as ocarcinoma-755 (Cancer Research, 24, 1979, 1964). However, in clinical practice, it has poor oral absorbability and is not persistent in vivo, so it does not always show the antitumor effect obtained with experimental tumors and has strong side effects such as bone marrow suppression. have. In order to solve these problems, development of a novel F3Thd derivative which improves antitumor activity and reduces side effects has been desired.

[0004] Examples of F3Thd derivatives having antitumor activity include JP-A-58-152898 and JP-A-59-366.
96, JP-A-60-56996, JP-A-62-1874
82, Chemical Pharmaceutical Britain, 3
7, 2287, 1989. However, none of these have yet fully satisfied the above demands. In particular, these known derivatives undergo metabolism and excretion such as conjugation promptly in the living body, without sustained expression of F3Thd, which is the active substance, and provide a clinically useful compound at all. It is not at present.

[0005]

An object of the present invention is to provide an F3
It is easier to absorb orally than Thd and the derivatives known so far, and is less susceptible to metabolism and excretion such as conjugation, so that the kinetics of the drug and the active substance in the blood are improved, and thus the antitumor activity is greatly improved. And further reduced side effects,
An object of the present invention is to provide a novel anticancer agent which is a clinically useful F3Thd derivative.

[0006]

Means for Solving the Problems The present inventors have proposed F3Th.
d and its known derivatives, it is easier to absorb orally,
In order to develop a compound that is less susceptible to metabolism and excretion such as conjugation and has less side effects, the present inventors have focused on improving the blood kinetics of F3Thd while utilizing the antitumor effect of F3Thd itself. In other words, in order to solve this problem by making a derivative capable of reversibly releasing F3Thd in vivo, a so-called prodrug, the introduction of various substituents mainly at the 3′- and 5′-positions of deoxyribose of F3Thd is examined. did. As a result, as will be described in detail in pharmacological test examples and the like later, surprisingly, a series of novel compounds in which a 2-propynyl group is introduced at the 3′-position of F3Thd, particularly a series of novel compounds substituted with a propargyl group, have an oral absorbability. And found to far surpass the effects of known derivatives. This is thought to be because the propargyl group is characteristically gradually eliminated by the enzyme, releases the active substance F3Thd with time, and is less susceptible to inactivation by metabolism or excretion such as conjugation. In addition, the present compound group has been found to release F3Thd gradually, so that side effects such as gastrointestinal tract disorders are also greatly reduced and have a high anticancer effect, thus completing the present invention. That is, the present invention relates to a compound represented by the general formula (1) :

[0007]

Embedded image (Wherein, R ₁ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and R ₂ represents a hydrogen atom, a C ₁ -C ₃₀ saturated or unsaturated alkyl-substituted carbonyl group, an alkyl-substituted benzoyl group, a C ₁ -C ₄ group. alkyloxycarbonyl group C _4, dimethylaminoethyl oxycarbonyl group, alkyloxymethyl group of C ₁ -C _4, butoxyethoxy acetyl group,
Benzyl _group, an alkyl-substituted silyl group of C 1 _{-C 20,} C
Alkyl and phenyl-substituted silyl group having ₁ -C _10, C
₁ -C ₃₀ cyclic or chain alkyl-substituted carbamoyl group, diethylamino propylcarbamoyl group, N- alkyl piperazinyl acetyl, N- alkyl prolyl group, valyl group, a trityl group, an alkyl-substituted phosphoryl group or Buroparugiru group , R ₃ is a hydrogen atom, C _1-
Alkyl C _4, benzyl group, benzoyl _{group, C} 1 ~
Alkyloxy substituted benzoyl group C _4, furoyl group,
A C ₁ -C ₄ alkyloxymethyl group or C ₁ -C ₄
Represents an alkyl-substituted carbonyl group. ), A process for producing the compound, and an anticancer agent containing the compound.

[0008] The trifluorothymidine derivative of the present invention will be described in detail below. R ₁ in the general formula (1) represents a hydrogen atom or a C _{1 to} C ₄ alkyl group;
Examples of the C ₁ -C ₄ alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a t-butyl group.

[0009] R_TwoIs a hydrogen atom, C₁~ C₃₀Saturation or non-saturation
Saturated alkyl-substituted carbonyl group, C ₁~ C_TenThe alkyl of
Substituted benzoyl group, C₁~ C_FourAlkyloxycarboni
Group, dimethylaminoethyloxycarbonyl group, C₁
~ C_FourAlkyloxymethyl group, butoxyethoxy
Cetyl group, benzyl group, C₁~ C₂₀Alkyl-substituted silyl
Group, C₁~ C_TenAlkyl and phenyl substituted silyl of
Group, C₁~ C₃₀Cyclic or linear alkyl-substituted carbamo of
Yl group, diethylaminopropylcarbamoyl group, N-
Alkylpiperazinylacetyl group, N-alkylprolyl
Group, valyl group, trityl group, alkyl-substituted phosphoryl
Group or bromopargyl group;₁~ C₃₀The saturation of
Is an unsaturated alkyl-substituted carbonyl group, for example,
Cetyl, propionyl, pivaloyl, butyryl
Group, valeryl group, hexanoyl group, octanoyl group,
Nanoyl group, decanoyl group, lauroyl group, myristoy
, Palmitoyl, stearoyl, icosanoyl
Group, docosanoyl group, tetracosanoyl group, hexacosa
Noyl group, octacosanoyl group, crotonoyl group, 9-
Hexadecenoyl group, oleoyl group, 11-octadece
A noyl group, a 9,12-octadecadienoyl group, 6,
9,12-octadecatrienoyl group, 9,11,13
-Octadecatrienoyl group, 8,11-icosadieno
Yl group, 5,8,11-icosatrienoyl group, 5,
8,11,14-icosatetraenoyl group, 15-tetra
Lacosenoyl groups and the like are substituted with alkyl-substituted benzoyl groups.
Is, for example, a 4-methylbenzoyl group, 4-ethylbenzo
Yl group, 4-propylbenzoyl group, 4-butylbenzo
Yl group, 4-pentylbenzoyl group, 4-hexylben
Zoyl group, group, 4-heptylbenzoyl group, 4-octyl
Rubenzoyl group, 4-nonylbenzoyl group, 4-decyl
A benzoyl group or the like;₁~ C_FourAlkyloxycarbo
Examples of the enyl group include a methoxycarbonyl group and ethoxy.
Carbonyl group, propoxycarbonyl group, butoxycal
A carbonyl group or the like,₁~ C_FourWith an alkyloxymethyl group of
For example, methoxymethyl group, ethoxymethyl group
What, C₁~ C₂₀The alkyl-substituted silyl group of
Trimethylsilyl group, ethyldimethylsilyl group, trie
Tylsilyl, propyldimethylsilyl, isopropyl
Dimethylsilyl group, tripropylsilyl group, triiso
Propylsilyl group, butyldimethylsilyl group, dibutyl
Methylsilyl group, tributylsilyl group, triisobutyl
Silyl group, isobutyldimethylsilyl group, tert-butyl
Tyldimethylsilyl group, di-tert-butylmethylsilyl group
Ryl group, pentyldimethylsilyl group, (2,3-dimethyl
Propyl) dimethylsilyl group, hexyldimethylsilyl group
Group, cyclohexyldimethylsilyl group, trihexyl
Silyl group, (3,3-dimethylbutyl) dimethylsilyl
Group, (1,1,2-trimethylpropyl) dimethylsilyl
Group, heptyldimethylsilyl group, octyldimethylsilyl group
Ryl, nonyldimethylsilyl, decyldimethylsilyl
Group, dodecyldimethylsilyl group, tetradecyldimethyl
Lucyl group, hexadecyldimethylsilyl group, octade
Sildimethylsilyl group, icosyldimethylsilyl group, etc.
And C₁~ C_TenAnd phenyl-substituted silyl groups of
Is, for example, a diphenylmethylsilyl group,
Tylsilyl group, triphenylsilyl group, tert-butyl
Rudiphenylsilyl group, diphenylbutylsilyl group, etc.
And C₁~ C₃₀Cyclic or linear alkyl-substituted carbamo of
The yl group is, for example, N-cyclopentylcarbamoyl
Group, N-cyclohexylcarbamoyl group, N-cyclo
Butylcarbamoyl group, N-cyclooctylcarbamoy
Group, N-cyclopentyl-N-methylcarbamoyl
Group, N-cyclohexyl-N-methylcarbamoyl group,
N-cycloheptyl-N-methylcarbamoyl group, N-
Cyclooctyl-N-methylcarbamoyl group, N-cycl
Lopentyl-N-ethylcarbamoyl group, N-cyclo
Xyl-N-ethylcarbamoyl group, N-cyclohepti
Ru-N-ethylcarbamoyl group, N-cyclooctyl-
N-ethylcarbamoyl group, N-cyclopentyl-N-
Propylcarbamoyl group, N-cyclohexyl-N-propyl
Ropylcarbamoyl group, N-cycloheptyl-N-pro
Pyrcarbamoyl group, N-cyclooctyl-N-propyl
Rucarbamoyl group, N-cyclopentyl-N-butylcap
Rubamoyl group, N-cyclohexyl-N-butylcarba
Moyl group, N-cycloheptyl-N-butylcarbamoy
Group, N-cyclooctyl-N-butylcarbamoyl
Group, N-methylcarbamoyl group, N-ethylcarbamoy
Group, N-propylcarbamoyl group, N-butylcarba
Moyl group, N-pentylcarbamoyl group, N-hexyl
Carbamoyl group, N-heptylcarbamoyl group, N-O
Octylcarbamoyl group, N-nonylcarbamoyl group, N
-Dodecylcarbamoyl group, N-tetradecylcarbamo
Yl group, N-hexadecylcarbamoyl group, N-octa
Decylcarbamoyl group, N-icosanylcarbamoyl
Group, N-docosanylcarbamoyl group, (N-tetracosa
Nylcarbamoyl group, N-hexacosanylcarbamoyl
Group, N-octacosanylcarbamoyl group, N-triako
Tantanylcarbamoyl group, N, N-dimethylcarbamoy
Group, N-ethyl-N-methylcarbamoyl group, N-
Ropyl-N-methylcarbamoyl group, N-butyl-N-
Methylcarbamoyl group, N-pentyl-N-methylcarb
Bamoyl group, N-hexyl-N-methylcarbamoyl
Group, N-heptyl-N-methylcarbamoyl group, N-O
Octyl-N-methylcarbamoyl group, N-nonyl-N-
Methylcarbamoyl group, N-dodecyl-N-methylcarb
Bamoyl group, N-tetradecyl-N-methylcarbamoy
A N-hexadecyl-N-methylcarbamoyl group;
N-octadecyl-N-methylcarbamoyl group, N, N
-Diethylcarbamoyl group, N-propyl-N-ethyl
Carbamoyl group, N-butyl-N-ethylcarbamoyl
Group, N-pentyl-N-ethylcarbamoyl group, N-
Xyl-N-ethylcarbamoyl group, N-heptyl-N
-Ethylcarbamoyl group, N-octyl-N-ethylca
Rubamoyl group, N-nonyl-N-ethylcarbamoyl
Group, N-dodecyl-N-ethylcarbamoyl group, N-te
Tradecyl-N-ethylcarbamoyl group, N-hexade
Sil-N-ethylcarbamoyl group, N-octadecyl-
N-ethylcarbamoyl group, N, N-dipropylcarba
Moyl group, N-butyl-N-propylcarbamoyl group,
N-pentyl-N-propylcarbamoyl group, N-hex
A sil-N-propylcarbamoyl group, N-heptyl-N
-Propylcarbamoyl group, N-octyl-N-propyl
Rucarbamoyl group, N-nonyl-N-propylcarbamo
An yl group, an N-dodecyl-N-propylcarbamoyl group,
N-tetradecyl-N-propylcarbamoyl group, N-
Hexadecyl-N-propylcarbamoyl group, N-octane
Tadecyl-N-propylcarbamoyl group, N, N-dibu
Tylcarbamoyl group, N-pentyl-N-butylcarba
Moyl group, N-hexyl-N-butylcarbamoyl group,
N-heptyl-N-butylcarbamoyl group, N-octyl
Ru-N-butylcarbamoyl group, N-nonyl-N-butyl
Rucarbamoyl group, N-dodecyl-N-butylcarbamo
Yl group, N-tetradecyl-N-butylcarbamoyl
Group, N-hexadecyl-N-butylcarbamoyl group, N
-Octadecyl-N-butylcarbamoyl group, N- ｛3
-(Diethylamino) propyl} carbamoyl group, etc.
Is an N-alkylpiperazinylacetyl group, for example,
N-methylpiperazinylacetyl group, N-ethylpipera
Dinylacetyl group, N-propylpiperazinylacetyl
Group, N-butylpiperazinylacetyl group, N-pentyl
Piperazinylacetyl group, N-hexylpiperazinyl
Cetyl group, N-heptylpiperazinylacetyl group, N-
Octylpiperazinylacetyl group, N-nonylpiperazi
Nylacetyl group, N-decylpiperazinylacetyl group,
N-dodecylpiperazinylacetyl group, N-tetradeci
Lupiperazinylacetyl group, N-hexadecylpiperazi
Nylacetyl group, N-octadecylpiperazinyl acetyl
And an N-alkylprolyl group, for example, N-alkylprolyl group.
Methyl-L-prolyl group, N-ethyl-L-prolyl
Group, N-propyl-L-prolyl group, N-butyl-L-
Prolyl group, N-pentyl-L-prolyl group, N-hexyl
Sil-L-prolyl group, N-heptyl-L-prolyl
Group, N-octyl-L-prolyl group, N-nonyl-L-
Prolyl group, N-decyl-L-prolyl group, N-dodecyl
Ru-L-prolyl group, N-tetradecyl-L-prolyl
Group, N-hexadecyl-L-prolyl group, N-octade
An alkyl-substituted phosphoryl group such as a sil-L-prolyl group
The group is, for example, ethoxyhydroxyphosphoryl, butoxy,
Cihydroxyphosphoryl, hexyloxyhydroxypho
Suphoryl, octyloxyhydroxyphosphoryl, deci
Ruoxyhydroxyphosphoryl, dodecyloxyhydro
Xyphosphoryl, dibutoxyphosphoryl, 2-oxo-
Examples include a 1,3-dioxaphosphol-2-yl group and the like.
You.

R ₃ is a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a benzoyl group, a C ₁ -C ₄ alkyloxy-substituted benzoyl group, a furoyl group, or a C ₁ -C ₄ alkyl-substituted carbonyl group. And a C ₁ -C ₄ alkyl group means, for example, a methyl group, an ethyl group, a propyl group, or a butyl group; and a C ₁ -C ₄ alkyloxy-substituted benzoyl group means, for example, a 4-methoxybenzoyl group, a 4-methoxybenzoyl group. etc. ethoxy benzoyl group, and a furoyl group and 2-furoyl group, the alkyl group in the substituted carbonyl group of C ₁ -C ₄ can be cited the same example as the alkyl group in R _1. The following are specifically included as these derivatives.

3'-O-propargyl-α, α, α-trifluorothymidine, 5'-O-trimethylsilyl-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-ethyldimethylsilyl-3′-O-
Propargyl-α, α, α-trifluorothymidine;
5′-O-triethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-propyldimethylsilyl-3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O-isopropyldimethylsilyl-3′-O-propargyl-α, α,
α-trifluorothymidine, 5′-O-tripropylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-triisopropylsilyl-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-butyldimethylsilyl-3′-O-
Propargyl-α, α, α-trifluorothymidine;
5′-O-dibutylmethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
Tributylsilyl-3′-O-propargyl-α, α,
α-trifluorothymidine, 5′-O-triisobutylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-isobutyldimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-tert-butyldimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-di-tert-butylmethylsilyl-3 '-O-propargyl-α, α, α-trifluorothymidine, 5'-O-pentyldimethylsilyl-3'
-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (2,3-dimethylpropyl) dimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′ -O-hexyldimethylsilyl-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-trihexylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine,

5'-O- (3,3-dimethylbutyl) dimethylsilyl-3'-O-propargyl-α, α, α-
Trifluorothymidine, 5′-O- (1,1,2-trimethylpropyl) dimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
Heptyldimethylsilyl-3′-O-propargyl-
α, α, α-trifluorothymidine, 5′-O-octyldimethylsilyl-3′-O-propargyl-α, α,
α-trifluorothymidine, 5′-O-nonyldimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-decyldimethylsilyl-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-dodecyldimethylsilyl-3′-O
-Propargyl-α, α, α-trifluorothymidine,
5′-O-tetradecyldimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′
—O-hexadecyldimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O
-Octadecyldimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-icosyldimethylsilyl-3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O-diphenylmethylsilyl-3′-O-propargyl-α, α, α-
Trifluorothymidine, 5′-O-phenyldimethylsilyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-triphenylsilyl-3′-
O-propargyl-α, α, α-trifluorothymidine, 5′-O-tert-butyldiphenylsilyl-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-diphenylbutylsilyl-3′-O
-Propargyl-α, α, α-trifluorothymidine,
5′-O-acetyl-3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O-pivaloyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O-propargyl-α, α , Α-trifluorothymidine, 5'-
O-benzyl-3′-O-propargyl-α, α, α-
Trifluorothymidine,

3'-O-propargyl-5'-O-trityl-α, α, α-trifluorothymidine, 3'-O-
Propargyl-5'-O-butyryl-α, α, α-trifluorothymidine, 3'-O-propargyl-5'-O-
Valeryl-α, α, α-trifluorothymidine, 3′-O
-Propargyl-5'-O-hexanoyl-α, α, α-
Trifluorothymidine, 3'-O-propargyl-5 '
-O-octanoyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-nonanoyl-
α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-decanoyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-lauroyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-myristoyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O
-Palmitoyl-α, α, α-trifluorothymidine,
3'-O-propargyl-5'-O-stearoyl-
α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-icosanoyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-docosanoyl-α, α, α-trifluorothymidine, 3′-O
-Propargyl-5'-O-tetracosanoyl-α, α,
α-trifluorothymidine, 3′-O-propargyl-
5′-O-hexacosanoyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-octacosanoyl-α, α, α-trifluorothymidine, 3′-
O-propargyl-5'-O-crotonoyl-α, α, α
-Trifluorothymidine, 3'-O-propargyl-
5′-O- (9-hexadecenoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O
-Oleoyl-α, α, α-trifluorothymidine,

3'-O-propargyl-5'-O- (1
1-octadecenoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (9,12
-Octadecadienoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (9,1
2,15-octadecatrienoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O
-(6,9,12-octadecatrienoyl) -α, α,
α-trifluorothymidine, 3′-O-propargyl-
5′-O- (9,11,13-octadecatrienoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (8,11-icosadienoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (5,8,11-icosatrienoyl) -α, α, α-trifluorothymidine, 3′-O
-Propargyl-5'-O- (5,8,11,14-icosatetraenoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (15-tetracosenoyl) -Α, α, α-trifluorothymidine,
3′-O-propargyl-5′-O- (4-methylbenzoyl) -α, α, α-trifluorothymidine, 3′-O
-Propargyl-5'-O- (4-ethylbenzoyl)
-Α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (4-propylbenzoyl) -α,
α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (4-butylbenzoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-
O- (4-pentylbenzoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-
(4-hexylbenzoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (4-
Heptylbenzoyl) -α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- (4-octylbenzoyl) -α, α, α-trifluorothymidine;
3′-O-propargyl-5′-O- (4-nonylbenzoyl) -α, α, α-trifluorothymidine, 3′-O
-Propargyl-5'-O- (4-decylbenzoyl)
-Α, α, α-trifluorothymidine,

3'-O-propargyl-5'-O-methoxycarbonyl-α, α, α-trifluorothymidine;
3′-O-propargyl-5′-O-ethoxycarbonyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-propoxycarbonyl-α, α, α
-Trifluorothymidine, 3'-O-propargyl-
5′-O-butoxycarbonyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-pentyloxycarbonyl-α, α, α-trifluorothymidine, 3′-O-propargyl -5'-O-hexyloxycarbonyl-α, α, α-trifluorothymidine, 3 ′
—O-propargyl-5′-O-heptyloxycarbonyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-octyloxycarbonyl-
α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-nonyloxycarbonyl-α, α, α-
Trifluorothymidine, 3'-O-propargyl-5 '
-O-decyloxycarbonyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O- ｛2
-(Dimethylamino) ethyloxy) carbonyl-α,
α, α-trifluorothymidine, 5′-O- ｛2- (2-
Butoxyethoxy) acetyl {-3′-O-propargyl-α, α, α-trifluorothymidine;

5'-O- (N-cyclopentylcarbamoyl) -3'-O-propargyl-α, α, α-trifluorothymidine, 5'-O- (N-cyclohexylcarbamoyl) -3'-O-propargyl -Α, α, α-trifluorothymidine, 5′-O- (N-cycloheptylcarbamoyl) -3′-O-propargyl-α, α, α
-Trifluorothymidine, 5'-O- (N-cyclooctylcarbamoyl) -3'-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-cyclopentyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′
—O- (N-cyclohexyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-cycloheptyl-N-
Methylcarbamoyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-cyclooctyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′
—O- (N-cyclopentyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-cyclohexyl-N-
Ethylcarbamoyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-cycloheptyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′
—O- (N-cyclooctyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-cyclopentyl-N-
Propylcarbamoyl) -3′-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Cyclohexyl-N-propylcarbamoyl) -3′-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-cycloheptyl-N-propylcarbamoyl) -3′-O-propargyl-α, α, α-
Trifluorothymidine, 5′-O- (N-cyclooctyl-N-propylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
(N-cyclopentyl-N-butylcarbamoyl)-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-cyclohexyl-N-butylcarbamoyl) -3′-O-propargyl-α, α, α
-Trifluorothymidine, 5'-O- (N-cycloheptyl-N-butylcarbamoyl) -3'-O-propargyl-α, α, α-trifluorothymidine, 5'-O-
(N-cyclooctyl-N-butylcarbamoyl)-
3′-O-propargyl-α, α, α-trifluorothymidine;

5'-O- (N-methylcarbamoyl)-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-ethylcarbamoyl) -3 ′
-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-propylcarbamoyl) -3′-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-butylcarbamoyl) -3′-O
-Propargyl-α, α, α-trifluorothymidine,
5'-O- (N-pentylcarbamoyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine;
5'-O- (N-hexylcarbamoyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine;
5'-O- (N-heptylcarbamoyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine;
5'-O- (N-octylcarbamoyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine;
5′-O- (N-nonylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′
—O- (N-dodecylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-
O- (N-tetradecylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′
-O- (N-hexadecylcarbamoyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine;
5'-O- (N-octadecylcarbamoyl) -3'-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-icosanylcarbamoyl) -3 ′
-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-docosanylcarbamoyl) -3 ′
-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-tetracosanylcarbamoyl)-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-hexacosanylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′ -O- (N-octacosanylcarbamoyl) -3'-O-propargyl-α, α, α-trifluorothymidine, 5'-O- (N-triacontanylcarbamoyl) -3'-O-propargyl- α, α, α
-Trifluorothymidine,

5'-O- (N, N-dimethylcarbamoyl) -3'-O-propargyl-α, α, α-trifluorothymidine, 5'-O- (N-ethyl-N-methylcarbamoyl)- 3′-O-propargyl-α, α, α-
Trifluorothymidine, 5'-O- (N-propyl-N
-Methylcarbamoyl) -3'-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Butyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O
-(N-pentyl-N-methylcarbamoyl) -3'-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-hexyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′- O- (N-heptyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α
-Trifluorothymidine, 5'-O- (N-octyl-
N-methylcarbamoyl) -3′-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Nonyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O
-(N-dodecyl-N-methylcarbamoyl) -3'-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-tetradecyl-N-methylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′- O- (N-hexadecyl-N
-Methylcarbamoyl) -3'-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Octadecyl-N-methylcarbamoyl) -3′-O—
Propargyl-α, α, α-trifluorothymidine;
5'-O- (N, N-diethylcarbamoyl) -3'-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-propyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′- O- (N-butyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-
Trifluorothymidine, 5'-O- (N-pentyl-N
-Ethylcarbamoyl) -3'-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Hexyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-
O- (N-heptyl-N-ethylcarbamoyl) -3 ′
-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-octyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′ -O- (N-nonyl-N-ethylcarbamoyl) -3'-O-propargyl-α, α, α-
Trifluorothymidine, 5'-O- (N-dodecyl-N
-Ethylcarbamoyl) -3'-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Tetradecyl-N-ethylcarbamoyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine;
5′-O- (N-hexadecyl-N-ethylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-octadecyl-N-ethylcarbamoyl) -3 '-O-propargyl-α,
α, α-trifluorothymidine,

5'-O- (N, N-dipropylcarbamoyl) -3'-O-propargyl-α, α, α-trifluorothymidine, 5'-O- (N-butyl-N-propylcarbamoyl) -3'-O-propargyl-α, α,
α-trifluorothymidine, 5′-O- (N-pentyl-N-propylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
(N-hexyl-N-propylcarbamoyl) -3′-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-heptyl-N-propylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′- O- (N-octyl-N-propylcarbamoyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-nonyl-N-propylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
(N-dodecyl-N-propylcarbamoyl) -3′-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-tetradecyl-N-propylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′- O- (N-hexadecyl-
N-propylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N
-Octadecyl-N-propylcarbamoyl) -3'-
O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N, N-dibutylcarbamoyl)-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-pentyl-N-butylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-hexyl-N-butylcarbamoyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-heptyl-N-butylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
(N-octyl-N-butylcarbamoyl) -3′-O
-Propargyl-α, α, α-trifluorothymidine,
5'-O- (N-nonyl-N-butylcarbamoyl)-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- (N-dodecyl-N-butylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5'-O- (N-tetradecyl-N
-Butylcarbamoyl) -3′-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Hexadecyl-N-butylcarbamoyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine;
5′-O- (N-octadecyl-N-butylcarbamoyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- [N- {3- (diethylamino) propyl} carbamoyl ] -3′-O-propargyl-α, α, α-trifluorothymidine;

5'-O- {2- (4-methylpiperazin-1-yl) acetyl} -3'-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- ｛2-
(4-ethylpiperazin-1-yl) acetyl {-3 ′
-O-propargyl-α, α, α-trifluorothymidine, 5′-O- {2- (4-propylpiperazine-1-
Yl) acetyl {-3'-O-propargyl-α, α,
α-trifluorothymidine, 5′-O- {2- (4-butylpiperazin-1-yl) acetyl} -3′-O-propargyl-α, α, α-trifluorothymidine, 5 ′
-O- {2- (4-pentylpiperazin-1-yl) acetyl} -3'-O-propargyl-α, α, α-trifluorothymidine, 5′-O- {2- (4-hexylpiperazine- 1-yl) acetyl {-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
{2- (4-heptylpiperazin-1-yl) acetyl} -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- {2- (4-octylpiperazin-1-yl) ) Acetyl {-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- {2
-(4-nonylpiperazin-1-yl) acetyl}-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O- {2- (4-decylpiperazine-1)
-Yl) acetyl {-3'-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-methyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-ethyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-propyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-butyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-pentyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-hexyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-heptyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-octyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-nonyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-decyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-dodecyl-L-prolyl) -3′-O-propargyl-α,
α, α-trifluorothymidine, 5′-O- (N-tetradecyl-L-prolyl) -3′-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (N-
Hexadecyl-L-prolyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
(N-octadecyl-L-prolyl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-
O-valyl-3′-O-propargyl-α, α, α-trifluorothymidine;

5'-O- (ethoxyhydroxyphosphoryl) -3'-O-propargyl-α, α, α-trifluorothymidine, 5'-O- (butoxyhydroxyphosphoryl) -3'-O-propargyl-α , Α, α-trifluorothymidine, 5′-O- (hexyloxyhydroxyphosphoryl) -3′-O-propargyl-α, α, α
-Trifluorothymidine, 5'-O- (octyloxyhydroxyphosphoryl) -3'-O-propargyl-
α, α, α-trifluorothymidine, 5′-O- (decyloxyhydroxyphosphoryl) -3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
(Dodecyloxyhydroxyphosphoryl) -3′-O—
Propargyl-α, α, α-trifluorothymidine;
5′-O-dibutoxyphosphoryl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-
(2-oxo-1,3-dioxaphospho-2-yl)-
3′-O-propargyl-α, α, α-trifluorothymidine, 3′-O-propargyl-3-benzoyl-
α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-3′-O-propargyl-3-benzoyl-α, α, α-trifluorothymidine, 5′-
O-acetyl-3′-O-propargyl-3-benzoyl-α, α, α-trifluorothymidine, 5′-O-pivaloyl-3′-O-propargyl-3-benzoyl-
α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O-propargyl-3-benzoyl-
α, α, α-trifluorothymidine, 5′-O-benzyl-3′-O-propargyl-3-benzoyl-α, α,
α-trifluorothymidine, 3′-O-propargyl-
5′-O-trityl-3-benzoyl-α, α, α-trifluorothymidine, 3′-O-propargyl-3-
(4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-
3′-O-propargyl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-O-
Acetyl-3′-O-propargyl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine;
5'-O-pivaloyl-3'-O-propargyl-3-
(4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O-propargyl-3- (4-methoxybenzoyl) -α,
α, α-trifluorothymidine, 5′-O-benzyl-
3′-O-propargyl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O-
Propargyl-5'-O-trityl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine;
3′-O-propargyl-3- (2-furoyl) -α,
α, α-trifluorothymidine,

5'-Ot-butyldimethylsilyl-
3′-O-propargyl-3- (2-furoyl) -α,
α, α-trifluorothymidine, 5′-O-acetyl 3′-O-propargyl-3- (2-furoyl) -α,
α, α-trifluorothymidine, 5′-O-pivaloyl-3′-O-propargyl-3- (2-furoyl)-
α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O-propargyl-3- (2-furoyl) -α, α, α-trifluorothymidine, 5′-O-
Benzyl-3′-O-propargyl-3- (2-furoyl) -α, α, α-trifluorothymidine, 3′-O
-Propargyl-5'-O-trityl-3- (2-furoyl) -α, α, α-trifluorothymidine, 3′-O
-Propargyl-3-acetyl-α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-
3′-O-propargyl-3-acetyl-α, α, α-
Trifluorothymidine, 3-N: 5′-O-diacetyl-3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-pivaloyl-3′-O-propargyl-3-acetyl- α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O-propargyl-3-acetyl-α, α, α-trifluorothymidine, 5′-O-benzyl-3′-O -Propargyl-3
-Acetyl-α, α, α-trifluorothymidine, 3 ′
—O-propargyl-5′-O-trityl-3-acetyl-α, α, α-trifluorothymidine, 3′-O-propargyl-3-pivaloyl-α, α, α-trifluorothymidine, 5′- Ot-butyldimethylsilyl-
3′-O-propargyl-3-pivaloyl-α, α, α
-Trifluorothymidine, 5'-O-acetyl-3'-
O-propargyl-3-pivaloyl-α, α, α-trifluorothymidine, 3-N: 5′-O-dipivaloyl-
3′-O-propargyl-α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O-propargyl-3-pivaloyl-α, α, α-trifluorothymidine, 5′-O -Benzyl-3'-O-propargyl-3-pivaloyl-α, α, α-trifluorothymidine, 3′-O-propargyl-5′-O-trityl-3
-Pivaloyl-α, α, α-trifluorothymidine,

3'-O- (2-butynyl) -α, α, α
-Trifluorothymidine, 5'-O-t-butyldimethylsilyl-3'-O- (2-butynyl) -α, α, α-
Trifluorothymidine, 5'-O-acetyl-3'-O
-(2-butynyl) -α, α, α-trifluorothymidine, 3′-O- (2-butynyl) -5′-O-pivaloyl-α, α, α-trifluorothymidine, 3′-O-
(2-butynyl) -5′-O-methoxymethyl-α,
α, α-trifluorothymidine, 5′-O-benzyl-
3′-O- (2-butynyl) -α, α, α-trifluorothymidine, 3′-O- (2-butynyl) -5′-O-
Trityl-α, α, α-trifluorothymidine, 3′-
O- (2-butynyl) -3-benzoyl-α, α, α-
Trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O- (2-butynyl) -3-benzoyl-α, α, α-trifluorothymidine, 5′-O-acetyl-3′- O- (2-butynyl) -3-benzoyl-
α, α, α-trifluorothymidine, 3′-O- (2-
(Butynyl) -5′-O-pivaloyl-3-benzoyl-
α, α, α-trifluorothymidine, 3′-O- (2-
(Butynyl) -5′-O-methoxymethyl-3-benzoyl-α, α, α-trifluorothymidine, 3′-O-
(2-butynyl) -3- (4-methoxybenzoyl)-
α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-3′-O- (2-butynyl) -3
-(4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (2-
Butynyl) -3- (4-methoxybenzoyl) -α,
α, α-trifluorothymidine, 3′-O- (2-butynyl) -5′-O-pivaloyl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3 ′
-O- (2-butynyl) -5'-O-methoxymethyl-
3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O- (2-butynyl) -3-
(2-furoyl) -α, α, α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O-
(2-butynyl) -3- (2-furoyl) -α, α, α
-Trifluorothymidine, 5'-O-acetyl-3'-
O- (2-butynyl) -3- (2-furoyl) -α,
α, α-trifluorothymidine, 3′-O- (2-butynyl) -5′-O-pivaloyl-3- (2-furoyl)
-Α, α, α-trifluorothymidine, 3′-O- (2
-Butynyl) -5'-O-methoxymethyl-3- (2-
Furyl) -α, α, α-trifluorothymidine, 3 ′
—O- (2-pentynyl) -α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-3 ′
-O- (2-pentynyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (2-pentynyl) -α, α, α-trifluorothymidine, 3′-
O- (2-pentynyl) -5'-O-pivaloyl-3-
α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O- (2-pentynyl) -α, α, α
-Trifluorothymidine, 5'-O-benzyl-3'-
O- (2-pentynyl) -α, α, α-trifluorothymidine, 3′-O- (2-pentynyl) -5′-O-trityl-α, α, α-trifluorothymidine, 3′-O
-(2-pentynyl) -3-benzoyl-α, α, α-
Trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O- (2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine, 5′-O-acetyl-3′- O- (2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine;

3'-O- (2-pentynyl) -5'-O
-Pivaloyl-3-benzoyl-α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O—
(2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine, 3′-O- (2-pentynyl)-
3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O- (2-pentynyl) -3- (4-methoxybenzoyl)- α, α, α-trifluorothymidine,
5'-O-acetyl-3'-O- (2-pentynyl)-
3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O- (2-pentynyl) -5 ′
-O-pivaloyl-3- (4-methoxybenzoyl)-
α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O- (2-pentynyl) -3- (4-
Methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O- (2-pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 5′-O
-T-butyldimethylsilyl-3'-O- (2-pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (2 −
Pentynyl) -3- (2-furoyl) α, α, α-trifluorothymidine, 3′-O- (2-pentynyl)-
5′-O-pivaloyl-3- (2-furoyl) -α,
α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O- (2-pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 3′-O
-(2-hexynyl) -α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-3′-O
-(2-hexynyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (2-hexynyl) -α, α, α-trifluorothymidine, 3′-O-
(2-hexynyl) -5′-O-pivaloyl-α, α,
α-trifluorothymidine, 3′-O- (2-hexynyl) -5′-O-methoxymethyl-α, α, α-trifluorothymidine, 5′-O-benzyl-3′-O- (2
-Hexynyl) -α, α, α-trifluorothymidine,
3'-O- (2-hexynyl) -5'-O-trityl-
α, α, α-trifluorothymidine, 3′-O- (2-
Hexynyl) -3-benzoyl-α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-
3′-O- (2-hexynyl) -3-benzoyl-α,
α, α-trifluorothymidine, 5′-O-acetyl-
3′-O- (2-hexynyl) -3-benzoyl-α,
α, α-trifluorothymidine, 3′-O- (2-hexynyl) -5′-O-pivaloyl-3-benzoyl-
α, α, α-trifluorothymidine, 3′-O- (2-
Hexynyl) -5'-O-methoxymethyl-3-benzoyl-α, α, α-trifluorothymidine, 3'-O-
(2-hexynyl) -3- (4-methoxybenzoyl)
-Α, α, α-trifluorothymidine,

5'-Ot-butyldimethylsilyl 3 '
-O- (2-hexynyl) -3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-O
-Acetyl-3'-O- (2-hexynyl) -3- (4
-Methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O- (2-hexynyl) -5′-O-pivaloyl-3- (4-methoxybenzoyl) -α, α,
α-trifluorothymidine, 3′-O- (2-hexynyl) -5′-O-methoxymethyl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine,
3'-O- (2-hexynyl) -3- (2-furoyl)
-Α, α, α-trifluorothymidine, 5′-Ot-
Butyldimethylsilyl-3'-O- (2-hexynyl)
-3- (2-furoyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (2-hexynyl) -3- (2-furoyl) -α, α, α -Trifluorothymidine, 3'-O- (2-hexynyl) -5'-
O-pivaloyl-3- (2-furoyl) -α, α, α-
Trifluorothymidine, 3'-O- (2-hexynyl)
-5'-O-methoxymethyl-3- (2-furoyl)-
α, α, α-trifluorothymidine, 3′-O- (2-
Heptinyl) -α, α, α-trifluorothymidine,
5′-Ot-butyldimethylsilyl-3′-O- (2
-Heptynyl) -α, α, α-trifluorothymidine;
5'-O-acetyl-3'-O- (2-heptynyl)-
α, α, α-trifluorothymidine, 3′-O- (2-
Heptinyl) -5'-O-pivaloyl-α, α, α-trifluorothymidine, 3′-O- (2-heptynyl)-
5′-O-methoxymethyl-α, α, α-trifluorothymidine, 5′-O-benzyl-3′-O- (2-heptynyl) -α, α, α-trifluorothymidine, 3′-
O- (2-heptynyl) -5′-O-trityl-α,
α, α-trifluorothymidine, 3′-O- (2-heptynyl) -3-benzoyl-α, α, α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3 ′
—O- (2-heptynyl) -3-benzoyl-α, α,
α-trifluorothymidine, 5′-O-acetyl-3 ′
—O- (2-heptynyl) -3-benzoyl-α, α,
α-trifluorothymidine, 3′-O- (2-heptynyl) -5′-O-pivaloyl-3-benzoyl-α,
α, α-trifluorothymidine, 3′-O- (2-heptynyl) -5′-O-methoxymethyl-3-benzoyl-α, α, α-trifluorothymidine, 3′-O- (2
-Heptynyl) -3- (4-methoxybenzoyl)-
α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-3′-O- (2-heptynyl)-
3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (2
-Heptynyl) -3- (4-methoxybenzoyl)-
α, α, α-trifluorothymidine, 3′-O- (2-
Heptinyl) -5'-O-pivaloyl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O- (2-heptynyl) -5′-O-methoxymethyl-3- (4-methoxybenzoyl) -α, α,
α-trifluorothymidine, 3′-O- (2-heptynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine,

5'-Ot-butyldimethylsilyl-
3'-O- (2-heptynyl) -3- (2-furoyl)
-Α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (2-heptynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 5′- O
-Pivaloyl-3'-O- (2-heptynyl) -3-
(2-furoyl) -α, α, α-trifluorothymidine, 3′-O- (2-heptynyl) -5′-O-methoxymethyl-3- (2-furoyl) -α, α, α-trim Fluorothymidine, 3′-O- (4-methyl-2-pentynyl) -α, α, α-trifluorothymidine, 5′-O
-T-butyldimethylsilyl-3'-O- (4-methyl-2-pentynyl) -α, α, α-trifluorothymidine, 5'-O-acetyl-3'-O- (4-methyl-2
-Pentynyl) -α, α, α-trifluorothymidine;
3'-O- (4-methyl-2-pentynyl) -5'-O
-Pivaloyl-3-α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O- (4-methyl-2-pentynyl) -α, α, α-trifluorothymidine, 5 ′ -O-benzyl-3'-O- (4-methyl-
2-pentynyl) -α, α, α-trifluorothymidine, 3′-O- (4-methyl-2-pentynyl) -5 ′
—O-trityl-α, α, α-trifluorothymidine,
3′-O- (4-methyl-2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine, 5′-O
-T-butyldimethylsilyl-3'-O- (4-methyl-2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine, 5'-O-acetyl-3'-O-
(4-methyl-2-pentynyl) -3-benzoyl-
α, α, α-trifluorothymidine, 3′-O- (4-
Methyl-2-pentynyl) -5′-O-pivaloyl-3
-Benzoyl-α, α, α-trifluorothymidine,
5'-O-methoxymethyl-3'-O- (4-methyl-
2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine, 3′-O- (4-methyl-2-pentynyl) -3- (4-methoxybenzoyl) -α, α,
α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O- (4-methyl-2-pentynyl) -3- (4-methoxybenzoyl) -α, α, α-
Trifluorothymidine, 5'-O-acetyl-3'-O
-(4-methyl-2-pentynyl) -3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine;
3'-O- (4-methyl-2-pentynyl) -5'-O
-Pivaloyl-3- (4-methoxybenzoyl) -α,
α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O- (4-methyl-2-pentynyl) -3
-(4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O- (4-methyl-2-pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine 5′-Ot-butyldimethylsilyl-
3'-O- (4-methyl-2-pentynyl) -3- (2
-Furyl) -α, α, α-trifluorothymidine,
5′-O-acetyl-3′-O- (4-methyl-2-pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 3′-O- (4-methyl- 2-pentynyl) -5′-O-pivaloyl-3- (2-furoyl) -α, α, α-trifluorothymidine, 5′-O-
Methoxymethyl-3′-O- (4-methyl-2-pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 3′-O- (4,4-dimethyl-2- Pentynyl) -α, α, α-trifluorothymidine;

5'-Ot-butyldimethylsilyl-
3'-O- (4,4-dimethyl-2-pentynyl)-
α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (4,4-dimethyl-2-pentynyl)
-Α, α, α-trifluorothymidine, 3′-O—
(4,4-dimethyl-2-pentynyl) -5′-O-pivaloyl-α, α, α-trifluorothymidine, 3′-
O- (4,4-dimethyl-2-pentynyl) -5'-O
-Methoxymethyl-α, α, α-trifluorothymidine, 5′-O-benzyl-3′-O- (4,4-dimethyl-2-pentynyl) -α, α, α-trifluorothymidine, 3 ′ —O- (4,4-dimethyl-2-pentynyl) -5′-O-trityl-α, α, α-trifluorothymidine, 3′-O- (4,4-dimethyl-2-pentynyl) -3 -Benzoyl-α, α, α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-
O- (4,4-dimethyl-2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine, 5′-O
-Acetyl-3'-O- (4,4-dimethyl-2-pentynyl) -3-benzoyl-α, α, α-trifluorothymidine, 3′-O- (4,4-dimethyl-2-pentynyl) -5'-O-pivaloyl-3-benzoyl-α,
α, α-trifluorothymidine, 3′-O- (4,4-
Dimethyl-2-pentynyl) -5′-O-methoxymethyl-3-benzoyl-α, α, α-trifluorothymidine, 3′-O- (4,4-dimethyl-2-pentynyl)
-3- (4-Methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O- (4,4-dimethyl-2-pentynyl)
-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine,

5'-O-acetyl-3'-O- (4,4
-Dimethyl-2-pentynyl) -3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3 ′
-O- (4,4-dimethyl-2-pentynyl) -5'-
O-pivaloyl-3- (4-methoxybenzoyl)-
α, α, α-trifluorothymidine, 3′-O- (4,
4-dimethyl-2-pentynyl) -5′-O-methoxymethyl-3- (4-methoxybenzoyl) -α, α, α
-Trifluorothymidine, 3'-O- (4,4-dimethyl-2-pentynyl) -3- (2-furoyl) -α,
α, α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O- (4,4-dimethyl-2-
Pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O-
(4,4-dimethyl-2-pentynyl) -3- (2-furoyl) -α, α, α-trifluorothymidine, 3′-
O- (4,4-dimethyl-2-pentynyl) -5'-O
-Pivaloyl-3- (2-furoyl) -α, α, α-trifluorothymidine, 3′-O- (4,4-dimethyl-
2-pentynyl) -5'-O-methoxymethyl-3-
(2-furoyl) -α, α, α-trifluorothymidine, 3′-O- (5-methyl-2-hexynyl) -α,
α, α-trifluorothymidine, 3′-O- (5-methyl-2-hexynyl) -α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-3′-O
-(5-methyl-2-hexynyl) -α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O-
(5-methyl-2-hexynyl) -α, α, α-trifluorothymidine, 3′-O- (5-methyl-2-hexynyl) -5′-O-pivaloyl-α, α, α-trifluoro Thymidine, 5'-O-methoxymethyl-3'-O-
(5-methyl-2-hexynyl) -α, α, α-trifluorothymidine, 5′-O-benzyl-3′-O- (5
-Methyl-2-hexynyl) -α, α, α-trifluorothymidine, 3′-O- (5-methyl-2-hexynyl) -5′-O-trityl-α, α, α-trifluorothymidine, 3'-O- (5-methyl-2-hexynyl)
-3-benzoyl-α, α, α-trifluorothymidine, 5′-O-t-butyldimethylsilyl-3′-O-
(5-methyl-2-hexynyl) -3-benzoyl-
α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (5-methyl-2-hexynyl) -3-
Benzoyl-α, α, α-trifluorothymidine, 3 ′
—O- (5-methyl-2-hexynyl) -5′-O-pivaloyl-3-benzoyl-α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O- (5
-Methyl-2-hexynyl) -3-benzoyl-α,
α, α-trifluorothymidine, 3′-O- (5-methyl-2-hexynyl) -3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-O-
t-butyldimethylsilyl-3′-O- (5-methyl-
2-hexynyl) -3- (4-methoxybenzoyl)-
α, α, α-trifluorothymidine, 5′-O-acetyl-3′-O- (5-methyl-2-hexynyl) -3-
(4-methoxybenzoyl) -α, α, α-trifluorothymidine, 3′-O- (5-methyl-2-hexynyl) -5′-O-pivaloyl-3- (4-methoxybenzoyl) -α, α, α-trifluorothymidine, 5′-
O-methoxymethyl-3′-O- (5-methyl-2-hexynyl) -3- (4-methoxybenzoyl) -α,
α, α-trifluorothymidine, 3′-O- (5-methyl-2-hexynyl) -3- (2-furoyl) -α,
α, α-trifluorothymidine, 5′-Ot-butyldimethylsilyl-3′-O- (5-methyl-2-hexynyl) -3- (2-furoyl) -α, α, α-trifluoro Thymidine, 5'-O-acetyl-3'-O- (5-
Methyl-2-hexynyl) -3- (2-furoyl)-
α, α, α-trifluorothymidine, 5′-O-pivaloyl-3′-O- (5-methyl-2-hexynyl) -3
-(2-furoyl) -α, α, α-trifluorothymidine, 5′-O-methoxymethyl-3′-O- (5-methyl-2-hexynyl) -3- (2-furoyl) -α,
α, α-trifluorothymidine.

The following general formula (6) which is one embodiment of the present invention:
The compound trifluorothymidine derivative of the formula (9) is represented by F3
It can be obtained by reacting a compound in which the 5′-position of Thd or F3Thd is protected with a protecting group, that is, a compound of the general formula (3) with a compound of the general formula (4) in a suitable solvent in the presence of a base.

[0030]

Embedded image (Wherein, R1 represents a hydrogen atom or an alkyl group C1 -C4, R2 is saturated or unsaturated alkyl-substituted carbonyl group of _C 1 _{-C 30,} alkyl substituted benzoyl group, _{C 1}
Alkyloxycarbonyl group -C _4, dimethylaminoethyl oxycarbonyl _group, alkyloxymethyl group of C 1 -C _4, butoxyethoxy acetyl group, a benzyl _group, an alkyl-substituted silyl group of _C 1 _{~C 20,} C 1 _~C
10 alkyl and phenyl substituted silyl groups, C ₁ -C
₃₀ cyclic or chain alkyl-substituted carbamoyl groups, diethylaminopropylcarbamoyl groups, N-alkylpiperazinylacetyl groups, N-alkylprolyl groups, valyl groups, trityl groups, alkyl-substituted phosphoryl groups or bropargyl groups, preferably C ₁ alkyl-substituted silyl group -C _20, C 1 _-C alkyl and phenyl substituted silyl group or a trityl group _10, particularly preferably _C 1 -C ₄
X represents a halogen atom such as fluorine, chlorine, bromine and iodine. Most of the compounds of the general formula (3) as the raw materials are known compounds. These can be manufactured by a known method or a similar method. That is, R ₂ is an unsaturated alkyl-substituted carbonyl group, an alkyl-substituted benzoyl group, a C ₁ -C ₄ alkyloxycarbonyl group, a dimethylaminoethyloxycarbonyl group, a butoxyethoxyacetyl group, an N-alkylpiperazinylacetyl group, an N- In the case of an alkylprolyl group, a valyl group or the like, it can be easily obtained by reacting a known trifluorothymidine with a corresponding acid halide or acid anhydride in the presence of a base. Also, when R ₂ is C _1-
Alkyloxymethyl group of C _4, benzyl group, Torichiriru group, in the case of such propargyl group is obtained by reacting an alkyl halide corresponding with trifluorothymidine known in the presence of a base. Further, when R ₂ is C _1-
If alkyl and phenyl substituted silyl group of the alkyl-substituted Shiruriru group or C ₁ -C ₁₀ to C ₂₀ obtained by the presence reaction of a base silyl halide corresponding with trifluorothymidine known. When R ₂ is a C ₁ to C ₃₀ cyclic or chain alkyl-substituted carbamoyl group or diethylaminopropylcarbamoyl group, it can be obtained by reacting a known trifluorothymidine with a corresponding isocyanate in the absence of a catalyst or in the presence of a base. . Further, R ₂ is the case of the alkyl-substituted phosphoryl group obtained by alkoxy phosphoryl halide reaction in the presence of a base corresponding to trifluorothymidine known.

The solvent used in this reaction is not limited as long as it does not affect the reaction, but specific examples thereof include ether, tetrahydrofuran (THF), dioxane,
An aprotic solvent such as benzene, 1,2-dimethoxyethane, dimethylformamide and the like can be used.

Examples of the base used include organic bases such as trialkylamine, pyridine, picoline, lutidine, and imidazole. Examples of the inorganic bases include sodium hydride, potassium hydride, potassium hydroxide, potassium t-butoxide, and hydroxide. Sodium, sodium carbonate, sodium hydrogen carbonate and the like can be mentioned.

The amount of each substance used in the reaction may be 1 to 10 times the molar amount of the compound (4) and 1 to 10 times the molar amount of the base, based on the compound (3).
It is desirable to use 1 to 5 times mol of the compound (4) and 2 to 5 times mol of the base. The reaction temperature is usually in the range of under ice cooling to the boiling temperature of the solvent, preferably in the range of under ice cooling to room temperature. The reaction time is usually 1 to 72 hours. If necessary, R is reacted with an acyl halide, carboxylic anhydride, or the like in a suitable solvent or in the absence of a solvent in the presence of a base.
₃ is an alkyl group of C ₁ -C _4, benzyl group, benzoyl group, an alkyl-substituted benzoyl C ₁ -C _4, the general formula of the present invention is an alkyl substituted carbonyl group furoyl group or a C ₁ -C ₄ ( The compound of 1) can be obtained.

The solvent used at this time is not limited as long as it does not affect the reaction, and specific examples include chloroform, dichloromethane, benzene, dimethylformamide, dimethylsulfoxide, ether, THF, dioxane and the like. As the base, an inorganic base such as sodium hydride, or an organic base such as trialkylamine or pyridine can be used. As acyl halides, benzoyl halide, 4-methoxybenzoyl halide, 2-furoyl halide, acetyl halide,
Pivaloyl halide and the like. Examples of the carboxylic anhydride include acetic anhydride, pivalic anhydride, and benzoic anhydride. The reaction temperature is not particularly limited, but is usually under ice-cooling to the boiling temperature range of the solvent, and the reaction time is 1 to
72 hours.

In order to produce a compound in which R ₂ is a hydrogen atom in the general formula (1), the compound represented by the general formula (6) or (1) obtained by the above method (where R ₁ is Wherein R ₂ represents a C ₁ -C ₂₀ alkyl-substituted silyl group, a C ₁ -C ₁₀ alkyl and a phenyl-substituted silyl group, a trityl group, R ₃ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a benzoyl group, an alkyl-substituted benzoyl C ₁ -C _4, furoyl group, C ₁ -C ₄
5 'position of the alkyl oxymethyl group or C ₁ -C alkyl substituted carbonyl group of ₄₎ compounds may be deprotected. That is, the reaction is performed in a suitable solvent in the presence of a suitable catalyst. The solvent used here is not limited as long as it does not affect the reaction.Specifically, dichloromethane, chloroform, haloalkanes such as dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, etc. And ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane. As the catalyst, various catalysts used in this type of reaction can be used. Specifically, fluorides such as tetrabutylammonium fluoride, hydrofluoric acid, and cesium fluoride, hydrochloric acid, and sulfuric acid are used. Examples thereof include inorganic acids, organic acids such as toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and acetic acid, and acidic ion exchange resins.

Further, the compound in which R ₂ is other than a hydrogen atom in the general formula (1) can be obtained by converting the above-obtained compound in which R ₂ is a hydrogen atom in a suitable solvent or without solvent.
It can also be obtained by reacting with an acyl halide, a carboxylic anhydride, an alkyl halide or the like in the presence of a base. The solvent used at this time is not limited as long as it does not affect the reaction, and specific examples include chloroform, dichloromethane, benzene, dimethylformamide, dimethylsulfoxide, ether, THF, dioxane and the like.

As the base, an inorganic base such as sodium hydride and the like, and an organic base such as trialkylamine and pyridine can be used. As the acyl halide, benzoyl halide, 4-methoxybenzoyl halide,
2-furyl halide, acetyl halide, pivaloyl halide and the like can be mentioned. Examples of the carboxylic anhydride include acetic anhydride, pivalic anhydride, and benzoic anhydride. Examples of the alkyl halide include methoxymethyl halide, ethoxymethyl halide, triphenylmethyl halide, benzyl halide and the like. The reaction conditions are usually under ice-cooling to the boiling temperature of the solvent, and the reaction time is 1 to 72 hours.

When the compound of the present invention is used as an agent for preventing and treating tumor progression, the dosage and dosage form of the compound naturally vary depending on the physical properties of the compound, the symptoms of the administration subject, and the like. 50 to 1000 mg is divided into one or several times, and as tablets, granules, powders, suspensions, capsules, and the like, and when administered parenterally, 50 to 1000 mg
1000 mg may be divided into one or several doses and administered, for example, as a suppository.

The composition may be prepared from an effective amount of the compound of the present invention and a pharmaceutically acceptable carrier. For example, in the case of tablets, crystalline cellulose, soft silicic anhydride or the like is used as an adsorbent, and corn starch, lactose, calcium phosphate, magnesium stearate or the like is used as an excipient.

[0040]

The present invention will be described more specifically below with reference to examples. Example 1 5'-O- (t-butyldimethylsilyl) -3'-O-
Propargyl-α, α, α-trifluorothymidine (a) 5′-O- (t-butyldimethylsilyl) -α, α,
α-trifluorothymidine 197 mg α, α, α-trifluorothymidine, chloro t-butyldimethylsilane 11
0 mg, imidazole 58.9 mg and DMF 3.9
The ml mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography to obtain 5'-O- (t-butyldimethylsilyl) -α, α, α
-Trifluorothymidine was obtained. Yield 220 mg (b) 5'-O- (t-butyldimethylsilyl)-
3′-O-propargyl-α, α, α-trifluorothymidine 5′-O- (t-butyldimethylsilyl) -α, α, α-
7.8 g of trifluorothymidine was dissolved in 234 ml of THF, and 1.75 g of sodium hydride (purity 60%) was added at room temperature.
Was added. After 15 minutes, 3.39 g of propargyl bromide was added dropwise, and the mixture was reacted at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into ice-water, extracted with ethyl acetate, concentrated, purified by column chromatography, and purified by 5′-O- (t-butyldimethylsilyl) -3′-O-propargyl-α, α. ,
α-trifluorothymidine was obtained. Yield 7.9g

Example 2 3'-O-propargyl-α, α, α-trifluorothimi
Gin 3′-O-propargyl-5′-O- (t-butyldimethylsilyl) -α, α, α-trifluorothymidine 0.9
3 g was dissolved in 20 ml of THF, and 2.1 ml of tetra-n-butylammonium fluoride (1M in THF) was added. After reacting for 11 hours, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate, washed with ice water, extracted, concentrated and purified by column chromatography to give 3'-O-propargyl-
α, α, α-trifluorothymidine was obtained. Yield 0.85g

Example 3 3-N: 5'-O-dipivaloyl-3'-O-propal
Gil-α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine (0.4 g) was dissolved in dichloromethane (5.5 ml), and triethylamine (0.35 ml) was added. 0.31 ml of pivaloyl chloride was added dropwise. After reacting at room temperature for 12 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was vigorously stirred, and extracted with ethyl acetate.
Washed with N hydrochloric acid and saturated aqueous sodium hydrogen carbonate. The extract was concentrated and purified by column chromatography to obtain 3-N: 5′-O-dipivaloyl-3′-O-propargyl-α, α, α-trifluorothymidine. Yield 0.31g

Example 4 5'-O-pivaloyl-3'-O-propargyl-α,
α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine 430 mg, pyridine 0.52 g and a catalytic amount of 4
-Dimethylaminopyridine was dissolved in 13 ml of dichloromethane, and 1.20 g of pivalic anhydride was added dropwise under ice cooling. After stirring at room temperature for 2 days, water was added and the mixture was extracted with dichloromethane, concentrated and purified by column chromatography.
5′-O-pivaloyl-3′-O-propargyl-α,
α, α-trifluorothymidine was obtained. Yield 450mg

Example 5 5'-O- (t-butyldimethylsilyl) -3'-O-
Propargyl-3-benzoyl-α, α, α-trifluoro
Rotymidine 5'-O- (t-butyldimethylsilyl) -3' -O-
Propargyl-α, α, α-trifluorothymidine 5.4
In a mixed solvent of 5 g of 1.60 g of triethylamine and 164 ml of dichloromethane, 1.88 g of benzoyl chloride was added dropwise under ice cooling. After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The extract was washed with dilute hydrochloric acid and saturated saline, concentrated, purified by column chromatography, and 5′-O- (t-butyldimethylsilyl) -3′-O-propargyl-3-benzoyl-α,
α, α-trifluorothymidine was obtained. Yield 4.45g

Example 6 3-benzoyl-3'-O-propargyl-α, α, α-
Trifluorothymidine 5'-O- (t-butyldimethylsilyl) -3'-O-
A mixed solution of 4.45 g of propargyl-3-benzoyl-α, α, α-trifluorothymidine in 45 ml of acetic acid, 22 ml of water and 22 ml of THF was heated at 60 ° C. for 4 hours. After completion of the reaction, the mixture was concentrated, and further concentrated by adding toluene. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, concentrated, and the residue was recrystallized from ethanol-water to obtain 3 ′ -O-propargyl-3-benzoyl-α, α, α-trifluorothymidine was obtained. Yield 2.20 g

Example 7 5'-O-isopropyldimethylsilyl-3'-O-prop
Lopargyl-α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine (0.8 g) was dissolved in pyridine (10 ml), and isopropyldimethylsilyl chloride (0.54 ml) was added dropwise thereto. After standing at room temperature overnight, the reaction mixture was concentrated,
The residue was dissolved in ethyl acetate, washed with water, extracted, concentrated and purified by column chromatography. Further recrystallization from ethanol-water (1: 1) gave 5′-O-isopropyldimethylsilyl-3′-O-propargyl-α, α, α-.
Trifluorothymidine was obtained. Yield: 565 mg Alternative method: (a) 5′-O-isopropyldimethylsilyl-α, α,
α-trifluorothymidine α, α, α-trifluorothymidine 1.0 g, imidazole 1.3 g DMF 10 ml
0.58 m of isopropyldimethylsilyl chloride in the solution
1 was added dropwise. After standing at room temperature overnight, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate, washed with water, extracted, concentrated, and recrystallized with ethanol-water (1: 1) to give 5 ′.
-O-isopropyldimethylsilyl-α, α, α-trifluorothymidine was obtained. Yield 646 mg (b) 5'-O-isopropyldimethylsilyl-3'-
O-propargyl-α, α, α-trifluorothymidine 5′-O-isopropyldimethylsilyl-α, α, α-trifluorothymidine 0.64 g, sodium hydride 10
3 mg was dissolved in 5 ml of THF and stirred at room temperature for 15 minutes. To this, 0.167 ml of propargyl bromide was dropped,
It was left at room temperature overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated. The obtained crude oil was purified and crystallized in the same manner as described above to give 5′-O-isopropyldimethylsilyl-3′-O-propargyl-
α, α, α-trifluorothymidine was obtained. Yield 586mg

Example 8 5'-O- (N, N-octadecylmethylcarbamoyl
-3'-O-propargyl-α, α, α-trifluorothio
Thymidine 3'-O- propargyl -α, α, α- trifluorothymidine 1.41 g, 1,1'-carbonyldiimidazole 0.89g was reacted overnight at room temperature and dissolved in 30 ml of THF. 2.4 g of octadecylmethylamine is added thereto,
After standing at room temperature overnight, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate, washed with water, extracted, concentrated and purified by column chromatography. Further, it is crystallized from ether-ethanol to give 2-deoxy-5'-O-methyloctadecylcarbamoyl-3'-O-propargyl-5-.
Trifluoromethyluridine was obtained. Yield 1.96g

Embodiment 95'-O-palmitoyl-3'-O-propargyl-
α, α, α-trifluorothymidine 3'-O-propargyl-α, α, α-trifluorothimi
Chlorinated pallets were added to a solution of 1.5 g of gin in 20 ml of pyridine
1.48 g of mitoyles were added dropwise. Release at room temperature overnight
After the reaction, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
Wash, concentrate and purify by column chromatography
5'-O-palmitoyl-3'-O-propargyl-
α, α, α-trifluorothymidine was obtained. Yield 1.79g

Example 10 3'-O-propargyl-5'-O-lignocelloyl-
α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine 0.54 g, lignoceric acid 660 mg and N, N
To a solution of -dimethylaminopyridine (catalytic amount) in 15 ml of dichloromethane was added 370 mg of N, N'-dicyclohexylcarbodiimide at room temperature. After allowing the mixture to stand at room temperature overnight, insolubles were removed by filtration, and the filtrate was concentrated.
The obtained residue was recrystallized from methanol-water (4: 1) to give 3'-O-propargyl-5'-O-lignocelloyl-.
α, α, α-trifluorothymidine was obtained. Yield 1.10 g

Embodiment 11Dihydrochloric acid = 5'-O- ｛2- (4-nonylpiperazine-1
-Yl) acetyl {-3'-O-propargyl-α,
α, α-trifluorothymidine (A) 5.34 g of 1-nonanoylpiperazine nonanoyl chloride and 2,4-dichlorofuran
5.33 g) of 1,2-dichloroethane 16
To a 0 ml mixed solution was added 3.61 g of triethylamine under ice-cooling.
It was dropped. After stirring for 2 hours, an additional 12.8 g of piperazine was added.
A solution of 1,2-dichloroethane (50 ml) was added dropwise under ice cooling.
Was. After stirring for 2 hours, insolubles were removed by filtration, and the filtrate was diluted with water and 10%
Washed sequentially with sodium hydroxide, water and saturated saline. Charcoal
After drying over potassium phosphate, concentrate and concentrate to 1-nonanoylpiperazine
Was obtained. Yield 6.9 g (b) 1-nonylpiperazine 1-nonanoylpiperazine 7.0 g in 90 ml of THF
The solution was cooled under ice-cooling to lithium aluminum hydride 1.76.
g of THF in 50 ml of suspension. Stir at room temperature for 2 hours
After stirring, crush excess reagent with hydrous ether,
And filtered. The filtrate was concentrated to give 1-nonylpiperazine.
Obtained as a yellow oil. Yield 5.28 g (c) 2- (4-nonylpiperazin-1-yl) acetic acid =
Ethyl 1-nonylpiperazine 3.0 g, α-bromoacetic acid = ethyl
2.48 g of triethylamine and 1.57 g of triethylamine in THF
The 90 ml solution was stirred at room temperature for 1.5 hours. End of reaction
Thereafter, insolubles were removed by filtration and the filtrate was concentrated. Residue column
Purified by chromatography, 2- (4-nonylpiperazine
1-yl) ethyl acetate was obtained. Yield 2.90 g (d) 2- (4-nonylpiperazin-1-yl) acetic acid 2- (4-nonylpiperazin-1-yl) acetic acid = ethyl
2.90 g of potassium hydroxide in 87 ml of ethanol solution
87 ml of an aqueous solution of 2.73 g was added and stirred at room temperature for 1 hour.
did. After completion of the reaction, ethanol was distilled off and neutralized with hydrochloric acid.
After that, it was extracted with butanol. After evaporation of the solvent, methanol
The resulting insolubles are removed by filtration, the filtrate is concentrated and concentrated.
-(4-Nonylpiperazin-1-yl) acetic acid was obtained. Yield 2.75 g (e) dihydrochloride = 5'-O- {2- (4-nonylpiperazine)
1-yl) acetyl {-3'-O-propargyl-
α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine
1.03 g of midine, 2- (4-nonylpiperazine-1-
Il) 1.25 g of acetic acid and 935 mg of triethylamine
Of bis (2-dichloroethane in a 31 ml solution of 1,2-dichloroethane
Oxo-3-oxazolidinyl) phosphinic chloride
Add 1.18 g and stir at room temperature for 3 hours.
Shed. After 6 hours, concentrate, add water, and extract with ethyl acetate.
After taking out, wash with aqueous sodium bicarbonate and dry over magnesium sulfate.
Was. After distilling off the solvent, it was purified by column chromatography.
Then treated with 4N hydrochloric acid-dioxane as ethyl acetate solution
And dihydrochloride = 5'-O- {2- (4-nonylpiperazine)
-1-yl) acetyl {-3'-O-propargyl-
α, α, α-trifluorothymidine was obtained. Yield 0.75g

Example 12 5'-O- {2- (2-butoxyethoxy) acetyl}
-3'-O-propargyl-α, α, α-trifluoro
Thymidine (a) 2- (2-butoxyethoxy) acetic acid = t-butyl 1.18 g of 2-butoxyethanol, 20 ml of 50% aqueous sodium hydroxide solution, α-bromoacetic acid = tert-
To a solution of 19.5 g of butyl and 3.4 g of tetrabutylammonium hydrogen sulfate in 3.2 ml of dichloromethane was added 20 ml of a 50% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. Concentrate and purify by column chromatography.
(Butoxyethoxy) acetic acid = t-butyl was obtained. Yield 2.3 g (b) 2- (2-butoxyethoxy) acetic acid 2- (2-butoxyethoxy) acetic acid = t-butyl 1.4
To a solution of 2 g of 43 ml of dichloromethane was added 1.4 ml of trifluoroacetic acid under ice-cooling, followed by stirring at room temperature for 5 hours. After completion of the reaction, the residue obtained by concentration was purified by column chromatography to obtain 2- (2-butoxyethoxy) acetic acid. Yield 1.0 g (c) 5′-O- {2- (2-butoxyethoxy) acetyl} -3′-O-propargyl-α, α, α-trifluorothymidine 3′-O-propargyl-α, α , Α-trifluorothymidine 1.07 g, 2- (2-butoxyethoxy) acetic acid 848 mg and triethylamine 974 mgl)
To a 32 ml solution of F was added 1.23 g of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride, and the mixture was stirred at room temperature for 3 hours and further heated to reflux. After 3 hours, the mixture was concentrated, added with water, extracted with ethyl acetate, washed with aqueous sodium bicarbonate, and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography to give 5'-O- ｛2- (2-
(Butoxyethoxy) acetyl} -3′-O-propargyl-α, α, α-trifluorothymidine was obtained. Yield 0.81g

Example 13 5'-O- (triethylsilyl) -3'-O-propal
511 mg (3.39 mmol) of chlorotriethylsilane was added dropwise to a solution of 1.03 g of gil-α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine in 21 ml of pyridine under ice cooling. Then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. After washing with 10% hydrochloric acid and saturated saline, the extract was dried over magnesium sulfate and concentrated. The residue was purified by chromatography and 5'-O-
(Triethylsilyl) -3′-O-propargyl-α,
α, α-trifluorothymidine was obtained. Yield 1.0g

Embodiment 14Hydrochloric acid = 5'-O- (N-dodecyl-L-prolyl)-
3′-O-propargyl-α, α, α-trifluorothio
Midines (A) N-dodecyl-L-proline (S) -L-proline 1.66 g of ethanol 50 ml
3.19 g of bromododecane and potassium carbonate are added to the solution.
19 g was added and the mixture was stirred at 80 ° C. for 2 hours. End of reaction
Thereafter, insolubles were removed by filtration, and the filtrate was concentrated. Flash residue
Purified by column chromatography, N-dodecyl-
L-proline was obtained. Yield 2.32 g (b) Hydrochloric acid = 5'-O- (N-dodecyl-L-proly
) -3'-O-propargyl-α, α, α-trifur
Orothymidine 3'-O-propargyl-α, α, α-trifluorothio
1.15 g of midine, N, N'-dicyclohexylcarbo
1.06 g of diimide, 1-hydroxybenztriazole
697 mg and N-dodecyl-L-proline 1.47
g of THF (35 ml) was stirred at room temperature for 24 hours.
After completion of the reaction, the insolubles were removed by filtration, and the filtrate was concentrated to obtain a residue.
Was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and saturated saline.
Was. After drying over magnesium sulfate, concentrate and concentrate the residue on a column.
After purification by chromatography, dissolve in ethyl acetate
And treated with 4N hydrochloric acid-dioxane to give hydrochloric acid = 5'-O-
(N-dodecyl-L-prolyl) -3'-O-propal
Gil-α, α, α-trifluorothymidine was obtained. Yield 1.53g

Example 15 Hydrochloric acid = 5'-O- (D-valyl) -3'-O-propal
Gil-α, α, α-trifluorothymidine (a) 5′-O- (N-tert-butoxycarbonyl-D-valyl) -3′-O-propargyl-α, α, α
-Trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine 930 mg, N-tert-butoxycarbonyl-D-valine 665 mg, N, N′-dicyclohexylcarbodiimide 631 mg, and a catalytic amount of 4-dimethyl 28 ml of aminopyridine in dichloromethane and THF2
5 ml of the mixed solution was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated and the residue was purified by column chromatography to give 5'-O- (N-tert-butoxycarbonyl-D-valyl) -3'-O-propargyl-α, α, α
-Trifluorothymidine was obtained. Yield 1.32 g (b) Hydrochloric acid = 5′-O- (D-valyl) -3′-O-propargyl-α, α, α-trifluorothymidine 5′-O- (N-tert-butoxycarbonyl-D −
(Varyl) -3'-O-propargyl-α, α, α-trifluorothymidine 1.32 g of 4N hydrochloric acid / dioxane 4
The ml solution was stirred at 80 ° C. for 30 minutes. After the reaction,
The oily substance obtained by concentration was crystallized from ether to give hydrochloric acid =
5'-O- (D-valyl) -3'-O-propargyl-
α, α, α-trifluorothymidine was obtained. Yield 0.92g

Example 16 3,5'-bis (methoxymethyl) -3'-O-propa
2. Lugyl-α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine 1.04 g, ethyl diisopropylamine
1.2 ml of methoxymethyl bromide was added dropwise to a 25 ml solution of dichloromethane in 31 ml under ice-cooling. 24 at room temperature
After stirring for an hour, water was added, and the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. Concentrate,
The residue was purified by column chromatography to give 3,5 '
-Bis (methoxymethyl) -3'-O-propargyl-
α, α, α-trifluorothymidine was obtained. Yield 630mg

Example 17 5'-O-methoxymethyl-3'-O-propargyl-
A solution of 568 mg of α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine in 5 ml of THF was added dropwise to a suspension of sodium hydride (150 mg as 60% oily) in 12 ml of THF at room temperature. . After 15 minutes butyl lithium 1.2
ml (1.4 Mn-hexane solution) was added dropwise at -78 ° C, and after 5 minutes, 144 mg of chloromethyl methyl ether was added dropwise. After stirring at room temperature for 1 hour, the mixture was concentrated by adding ice water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. After concentration, the residue was purified by column chromatography to give 5'-O-methoxymethyl-
3′-O-propargyl-α, α, α-trifluorothymidine was obtained. Yield 227mg

Example 18 5'-O-dodecyloxyhydroxyphosphoryl-3 '
-O-propargyl-α, α, α-trifluorothymidine
Methyl dichlorophosphate in emissions pyridine 18ml phosphate 1.1
After adding 3 ml dropwise at room temperature, the mixture was stirred for 15 minutes. Further, 3.6 ml of dodecanol was added dropwise, and the mixture was stirred at room temperature for 1 hour. Next, 0.3 g of 3′-O-propargyl-α, α, α-trifluorothymidine was added, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, water was added, extracted with ethyl acetate, and concentrated. The resulting residue was purified by column chromatography to give 5'-O-dodecylhydroxyphosphoryl-3'-O
-Propargyl-α, α, α-trifluorothymidine was obtained. Yield 90mg

Example 19 5'-O- (2-oxo-1,3-dioxaphospho-2
-Yl) -3'-O-propargyl-α, α, α-tri
Fluoro thymidine 3'-O- propargyl-.alpha., alpha, the α- trifluorothymidine 0.5g was dissolved in dichloromethane 16 ml, here and triethylamine 0.36 ml 2-chloro-2-
0.32 g of oxo-1,3-dioxaphospholane was added. After standing at room temperature overnight, the mixture was concentrated as it was and purified by column chromatography to obtain 5'-O- (2-oxo-1,
3-Dioxaphospho-2-yl) -3′-O-propargyl-α, α, α-trifluorothymidine was obtained. Yield 120mg

Example 20 3 ', 5'-Di-O-propargyl-α, α, α-tri
Fluoro thymidine sodium hydride 0.9g dropwise Kendakushi propargyl alcohol 0.75ml in 15 ml of THF, trichloroacetonitrile 1.5ml of this reaction solution was cooled with ice
Was added to a 15 ml solution of ether and reacted for 2.5 hours. 50m pentane containing a small amount of methanol
and the resulting amorphous powder was collected by filtration. The filtrate is concentrated, 15 ml of dichloromethane is added, and 0.4 g of 3′-O-propargyl-α, α, α-trifluorothymidine is added thereto.
Was dissolved, and 6 drops of trimethylsilyl triflate were added, and the mixture was reacted at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, concentrated, purified by column chromatography, and purified with 3 ′, 5′-di-O-propargyl-α, α,
α-trifluorothymidine was obtained. Yield 142mg

Example 21 5'-O-butoxycarbonyl-3'-O-propargyi
636 mg of chlorobutyl formate was added dropwise to a solution of 519 mg of le-α, α, α-trifluorothymidine 3′-O-propargyl-α, α, α-trifluorothymidine in 16 ml of pyridine under ice-cooling. 2 at room temperature
After stirring for days, the mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. After concentration, the residue was purified by column chromatography to obtain 5′-O-butoxycarbonyl-3′-O-propargyl-α, α, α-trifluorothymidine. Yield 380mg

Example 22 5'-O- (N-cyclohexylcarbamoyl) -3 '
-O-propargyl-α, α, α-trifluorothymidine
A solution of 1.64 g of 3'-O-propargyl-α, α, α-trifluorothymidine and 1.03 g of 1,1'-carbonyldiimidazole in 49 ml of THF was stirred at room temperature for 6 hours. Further, 1.95 g of cyclohexylamine was added dropwise, and the mixture was stirred with heating under reflux for 7 hours. After completion of the reaction, the mixture was concentrated, 10% hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. After concentration, the residue was subjected to column chromatography and recrystallized from ethanol-water to give 5'-O- (N-cyclohexylcarbamoyl) -3'-O-propargyl-α, α, α-trifluorothymidine. Obtained. Yield 1.24g

Example 23 3-Ethyl-5'-O- (N-cyclohexylcarbamo
Yl) -3'-O-propargyl-α, α, α-trif
Luorothymidine 3'-O-propargyl-α, α, α-trifluorothymidine (108 mg) and ethyl iodide (40.3 mg) were added to a solution of cesium fluoride (82.1 mg) in DMF (3.2 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. After concentration, the residue was purified by column chromatography to give 3-ethyl-5'-O- (N-cyclohexylcarbamoyl) -3'-O-propargyl-α,
α, α-trifluorothymidine was obtained. Yield 100mg

Examples 24 to 42 The compounds prepared by the same methods as in Examples 1 to 23 and the physical properties of each compound are shown in Table 1.

Next, the anticancer effect and blood concentration test of the compound of the present invention will be described based on the test results. Pharmacological test example 1 Method for measuring antitumor activity value 1) Administration method; Examples 1, 2, 6, 7, 11, 13, 1
The compounds of the present invention obtained in 4, 28, 29, 32, 45 and 47 were made into a uniform suspension with a 0.5% carboxymethylcellulose solution containing 0.1% Tween 80 using an agate mortar. 2) Animal used: Female CDF ₁ , 6-week-old mouse was used. 3) Tumor used; Meth A fibrosarcoma 4) Test method: 2 × 10 ⁶ tumor cells were implanted subcutaneously in the right rear part of the mouse. On the following day (day 1), these mice were randomly divided into groups and subjected to oral gavage for 7 consecutive days (day 1-7) using an oral probe. 5) Evaluation of antitumor activity; tumors were excised on day 14 and weighed, and the tumor growth rate (T / C%) was calculated as [{(average tumor weight of drug-treated group)} (average tumor weight of control group) ｝ × 1
00]. Table 2 shows the results.

Pharmacological test example 2 (blood kinetic test)animal After pre-breeding 6-week-old male SD rats for 1 week,
It was used for the experiment at the age of 7 weeks. Drug administration and extraction 1) Administration to rats and blood collection The books obtained in Examples 1, 2, 7, 9, 13, 27, and 30
The compound of the present invention was 0.1% Tween 80, 0.5% C
Suspended in MC and orally administered to rats using an oral probe.
Was. After 1, 2, 4, 6, and 8 hours, chloroform anesthesia was performed.
The abdominal rat is opened and 5 ml of blood is collected from the abdominal descending vena cava.
I took it. 2) Extraction 200 μl of plasma collected by centrifugation, 5-FU (H
Used as internal standard for analysis by PLC) 10 μg / 2
After adding 00 μl and 4 ml of ethyl acetate, shake and centrifuge.
Was done. Then transfer 3 ml of ethyl acetate layer to another test tube.
And evaporated to dryness under a stream of nitrogen. 200 in the residue
μl of 50% acetonitrile / 25 mM sodium phosphate
(PH 4.0) and dissolved by sonication.
Thereafter, insoluble materials were removed by centrifugation, and the supernatant was collected.HPLC analysis 80 μl of the above supernatant was applied to a gel filtration column (Asa) for nucleic acid analysis.
by HPLC using HIPAK GS-320H)
Analyzed. Analysis was performed at a flow rate of 0.5 ml / min and a wavelength of 2
The measurement was performed at 54 nm. 50% acetonitrile for moving bed
Lil using 25 mM sodium phosphate (pH 4.0)
Was. Quantification of F3Thd was carried out using a chromatocoder 12.
This was performed by the absolute calibration method. Fig. 1 shows the results of this test.
You. From FIG. 1, the compound of the present invention is administered for 1 to 4 hours after administration
Up to 8 hours after administration
It was found to maintain detectable concentrations.

Pharmacological Test Example 3 Comparison of the average prolongation of the survival days with F3Thd 1) Administration method: 0.1% Tween 80 was added to the compound of the present invention obtained in Example 1 using an agate mortar.
A uniform suspension was prepared using a 5% carboxymethylcellulose solution, and F3Thd was dissolved in a phosphate buffered saline. 2) Animal used: Female CDF ₁ , 6-week-old mouse was used. 3) Tumor used; L1210 4) Test method; 5 × 10 ⁴ tumor cells were transplanted intraperitoneally into mice. On the following day (day 1), these mice were randomly grouped and used for 7 consecutive days (d
ay1-7) Gavage administration was performed. 5) Evaluation of average survival days extension rate; average survival days of each treatment group were determined, and Increase in Life Spa
n (ILS: average survival time extension rate:%) is [{(average survival time of drug-treated group) − (average survival time of control group)}}
(Average surviving days of control group) × 100]. The results are shown in FIG. As shown in FIG.
It was found that a smaller dose than the 3Thd showed a high effect of prolonging the average survival days. The other compounds of the present invention also showed the same tendency.

[0067]

[Table 1]

[0068]

[Table 2]

[0069]

[Table 3]

[0070]

[Table 4]

[0071]

[Table 5]

[0072]

[Table 6]

[0073]

[Table 7]

[0074]

[Table 8]

[0075]

[Table 9]

[0076]

[Table 10]

[0077]

[Table 11]

[0078]

[Table 12]

The trifluorothymidine derivative of the present invention has improved oral absorption, longer duration in blood, reduced side effects, and a higher anticancer effect than F3Thd. Therefore, it is very clinically expected as an anticancer drug.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the plasma concentration of F3Thd produced by the decomposition of the compound of the present invention in rats.

FIG. 2: Representative compounds of the invention and F3T in mice
It is a figure showing average survival days extension rate of hd.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Osamu Yano 1900, Togo, Togo, Mobara City, Chiba Prefecture Inside of Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Daiji Iwata 1,900, Togo, Togo, Mobara City, Chiba Prefecture 1 Within Chemical Co., Ltd. (72) Inventor Osamu Nakanishi 1900-1 Togo, Togo, Mobara City, Chiba Prefecture Inside (72) Inventor Kazushi Etsugi 1, 1900 Togo Togo, Mobara City, Chiba Prefecture Mitsui East Pressure Chemical Co., Ltd. Examiner Shinichi Naito

Claims (7)

(57) [Claims] 1. A compound represented by the general formula (1): (Wherein, R ₁ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and R ₂ represents a hydrogen atom, a C ₁ -C ₃₀ saturated or unsaturated alkyl-substituted carbonyl group, an alkyl-substituted benzoyl group, a C ₁ -C ₄ group. alkyloxycarbonyl group C _4, dimethylaminoethyl oxycarbonyl group, alkyloxymethyl group of C ₁ -C _4, butoxyethoxy acetyl group,
Benzyl _group, an alkyl-substituted silyl group of C 1 _{-C 20,} C
Alkyl and phenyl-substituted silyl group having ₁ -C _10, C
₁ -C ₃₀ cyclic or chain alkyl-substituted carbamoyl group, diethylamino propylcarbamoyl group, N- alkyl piperazinyl acetyl, N- alkyl prolyl group, valyl group, a trityl group, an alkyl-substituted phosphoryl group or flop Roparugiru group R ₃ represents a hydrogen atom, C ₁ to
Alkyl C _4, benzyl group, benzoyl _{group, C} 1 ~
Alkyloxy substituted benzoyl group C _4, furoyl group,
A C ₁ -C ₄ alkyloxymethyl group or C ₁ -C ₄
Represents an alkyl-substituted carbonyl group. A trifluorothymidine derivative represented by the formula: 2. A compound of the general formula (2) (Wherein R ₄ , R ₅ , and R ₆ each independently represent a C ₁ -C ₂₀ alkyl group or a phenyl group, and R ₁ is the same as described above). Thymidine derivatives. 3. A compound of the general formula (3) Wherein R ₂ is a C ₁ -C ₃₀ saturated or unsaturated alkyl-substituted carbonyl group, an alkyl-substituted benzoyl group, a C ₁ -C ₄ alkyloxycarbonyl group, dimethylaminoethyloxy Carbonyl group, C ₁ -C ₄ alkyloxymethyl group, butoxyethoxyacetyl group, benzyl group, C ₁ -C ₂₀
Alkyl-substituted silyl _group, the alkyl and phenyl-substituted silyl _group, a cyclic or chain alkyl-substituted carbamoyl group of C 1 _{-C 30} of C 1 _{-C 10,} diethylamino propylcarbamoyl group, N- alkyl piperazinyl acetyl group, N- Alkylprolyl group, valyl group, trityl group,
Alkyl-substituted phosphoryl represents a group or a flop Roparugiru group) and the general formula (4) (Formula 4) ## STR4 ## (Wherein, R ₁ is the same as above; X represents a halogen atom.) A trifluorothymidine derivative represented by the general formula (1) characterized by reacting in the presence of a base: However, in the formula, R ₁ and R ₂ are the same as described above, and R ₃ is a hydrogen atom. 4. A trifluorothymidine derivative represented by the general formula (1) obtained by the method of claim 3, wherein R ₁ and R ₂ are the same as those in claim 3, and R ₃ is a hydrogen atom in is) and the general formula (5) (of 5) [of 5] (Wherein R ₈ represents a C ₁ -C ₄ alkyl group, a benzyl group,
Benzoyl group, C ₁ -C ₄ alkyloxy-substituted benzo
Yl group, furoyl group, C ₁ -C ₄ alkyloxymethyl
Or a C ₁ -C ₄ alkyl-substituted carbonyl group, X
Represents a halogen atom. ) Is converted to a base
A trifluorothymidine derivative compound represented by the general formula (1), wherein
In the formula, R ₁ and R ₂ are the same as in claim 3, and R ₃ is C ₁
To C ₄ alkyl, benzyl, benzoyl, C ₁
-C ₄ alkyloxy-substituted benzoyl group, furoyl group, C ₁ -C ₄ alkyloxymethyl group or C ₁ -C ₄
Method for producing an a) alkyl substituted carbonyl group of C _4. 5. A trifluorothymidine derivative compound represented by the general formula (1) obtained by the method of claim 3 or 4, wherein R ₁ is the same as above, and R ₂ is
R ₁ represents an alkyl-substituted silyl group of _{1 to} C ₂₀ , alkyl and phenyl-substituted silyl group of C _{1 to} C ₁₀ , or a trityl group;
The alkyl group of _hydrogen, C 1 -C _4, benzyl group, benzoyl group, C ₁ -C alkyl-substituted benzoyl groups _4, furoyl group, C ₁ alkyloxymethyl group or C ₁ -C ₄ in -C ₄ Represents an alkyl-substituted carbonyl group of
₂ is a trifluorothymidine derivative compound represented by the general formula (1), wherein R ₁ is the same as defined above,
R ₂ is a hydrogen atom, R ₃ is a hydrogen _atom, an alkyl group of C 1 -C _4, benzyl group, benzoyl group, an alkyl-substituted benzoyl C ₁ -C _4, furoyl group, alkyloxy C ₁ -C ₄ method for producing an alkyl-substituted carbonyl group of methyl or C ₁ ~C _4). 6. A trifluorothymidine derivative compound represented by the general formula (1) obtained by the method of claim 5, wherein R ₁ is the same as described above, R ₂ is a hydrogen atom, R ₃ Is a hydrogen atom, a C ₁ -C ₄ alkyl group, a benzyl group, a benzoyl group, a C ₁ -C ₄ alkyloxy-substituted benzoyl group, a furoyl group, a C ₁ -C ₄ alkyloxymethyl group or a C ₁ -C ₄ And an alkyl-substituted carbonyl group of the general formula (6) : (Wherein R ₉ is a C ₁ -C ₃₀ saturated or unsaturated alkyl)
Carbonyl group, alkyl-substituted benzoyl group, C ₁
-C ₄ alkyloxycarbonyl group, dimethylamino
Ethyloxycarbonyl group, C ₁ -C ₄ alkyloxy
Cimethyl group, butoxyethoxyacetyl group, benzyl
_Group, an alkyl-substituted silyl group of _C 1 ~C _20, C 1 ~C
₁₀ alkyl and phenyl substituted silyl groups, C ₁ -C
₃₀ cyclic or linear alkyl-substituted carbamoyl groups,
Ethylaminopropylcarbamoyl group, N-alkylpi
Perazinylacetyl group, N-alkylprolyl group, bali
Group, trityl group, alkyl-substituted phosphoryl group or
X represents a lopargyl group, and X represents a halogen atom. )
A trifluorothymidine derivative compound represented by the general formula (1), wherein R ₁ is the same as defined above, and R ₂
Saturated or unsaturated alkyl-substituted carbonyl group of _C 1 _{-C 30} is alkyl substituted benzoyl _group, an alkyloxycarbonyl group of C 1 -C _4, dimethylaminoethyl oxycarbonyl _group, alkyloxymethyl group of C 1 -C _4,
Butoxyethoxyacetyl group, benzyl group, C ₁ -C
₂₀ alkyl-substituted silyl groups, C ₁ -C ₁₀ alkyl and phenyl-substituted silyl groups, C ₁ -C ₃₀ cyclic or linear alkyl-substituted carbamoyl groups, diethylaminopropylcarbamoyl groups, N-alkylpiperazinylacetyl groups, N - alkyl prolyl group, valyl group, trityl group, an alkyl-substituted phosphoryl group or flop Roparugiru group,
R ₃ is a hydrogen _atom, an alkyl group of C 1 -C _4, benzyl group, benzoyl _group, an alkyl-substituted benzoyl C 1 -C _4, furoyl _group, C 1 -C alkyloxy methyl or _C 1 ~ ₄ C ₄ represents an alkyl-substituted carbonyl group). 7. A compound of the formula (1) wherein R ₁ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, R ₂ represents a hydrogen atom, a C ₁ -C ₃₀ saturated or unsaturated alkyl-substituted carbonyl. group, an alkyl-substituted benzoyl _group, an alkyloxycarbonyl group of C 1 -C _4, dimethylaminoethyl oxycarbonyl _group, alkyloxymethyl group of C 1 -C _4, butoxyethoxy acetyl group, a benzyl _{group, C} 1 ~
C ₂₀ alkyl-substituted silyl _group, the alkyl and phenyl-substituted silyl _group, a cyclic or chain alkyl-substituted carbamoyl group of C 1 _{-C 30} of C 1 _{-C 10,} diethylamino propylcarbamoyl group, N- alkyl piperazinyl acetyl group, N- alkyl prolyl group, valyl group, a trityl group, an alkyl-substituted phosphoryl group or flop Roparugiru group, _{R 3} is a hydrogen _atom, an alkyl group of C 1 -C _4, benzyl group, benzoyl _group, C 1 -C ₄ Alkyloxy-substituted benzoyl group, furoyl group, C ₁ -C ₄ alkyloxymethyl group, and C ₁ -C ₄ alkyl-substituted carbonyl group. An anticancer agent containing a trifluorothymidine derivative represented by the formula (1) as an active ingredient.