JPH07101976A - Carbinostatic agent - Google Patents

Abstract

PURPOSE:To obtain a new compound which is useful as a carcinostatic agent of high activity caused by the metabolism in living bodies by reaction of 3'- amino-2',3'-dideoxycytidine with N-substituted-L-phenylalanine derivative. CONSTITUTION:A new compound: 2',3'-dideoxy-3'-N-substituted-L-phenyl- alanylamidocytidine of the formula I (R is amino-protecting group), which is useful as a prodrug from which 3'-amino-2',3'-dideoxycytidine is cut out by chymotrypsin to develop excellent carcinostatic action which is more powerful than the direct action of the cytidine. The compound is obtained by reaction of 3'-amino-2',3'-dideoxycytidine of the formula II with N-substituted L- phenylalanine derivative of the formula III (R<1> is pentachlorophenyl, p- nitrophenyl, N-hydroxysuccinic imide).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2 ', 3'-dideoxy-3'-N-substituted-L-phenylalanylamidocytidine, its production method and its use.

[0002]

2. Description of the Related Art Drugs that have low activity or are inactive by themselves, but are metabolized into active form, that is, the fact that drugs are metabolized in the living body Drugs that aim to improve various actions by modifying the molecule are called prodrugs. The purpose of making prodrug is
(1) Sustained action, (2) Increased water solubility, (3) Improvement of bioavailability such as change of administration form,
It is roughly classified into (4) side effects / toxicity reduction, (5) stabilization, solution of problems in formulation such as improvement of taste and odor, and many prodrugs have been developed as pharmaceuticals so far.

Recently, prodrugs have been designed so that the active ingredient is preferentially cleaved in cancer cells. 3′-Amino-2 ′, 3′-dideoxycytidine is known as a compound, and its effect on L1210, a mouse leukemia cell, has been reported [TSLin, W.
R. Mancini; J. Medicinal Chemistry, 26, 544 (198
3)]. However, 3'-amino-2 ', 3'-dideoxycytidine is effective at the cellular level (in vitro), but its half-life in blood is short in vivo, and it is difficult to maintain its concentration in blood. There is a problem such as not showing.

Therefore, it has been desired to develop a drug that prolongs the half-life in the blood to prolong the pharmacological effect of the drug.

[0005]

The present invention is to develop a prodrug that produces excellent antitumor activity by prolonging the blood half-life of a drug and maintaining a high blood concentration thereof in vivo. With the goal.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have made 3′-amino-2 ′, 3′-dideoxycytidine react with an active ester. As a result, they succeeded in developing a prodrug that produces an excellent antitumor activity, and completed the present invention. That is, the present invention provides the following formula (I):

[0007]

[Chemical 6]

2 ', 3'-dideoxy-3'-N-substituted-L-phenylalanylamidocytidine represented by the formula (wherein R represents an amino-protecting group). The protecting group for the amino group of R is a t-butoxycarbonyl group, an acetyl group or the like having 20 or less carbon atoms, preferably 10 carbon atoms or less.
Specific examples thereof include aliphatic acyl groups or aromatic acyl groups such as benzoyl groups.

Further, the present invention provides the following formula (II):

[0010]

[Chemical 7]

3'-amino-2 ', 3'-dideoxycytidine represented by the following formula (III):

[0012]

[Chemical 8]

(Wherein R is the same as defined above, and R ¹ is pentachlorophenyl, p-nitrophenyl, N-hydroxysuccinimide, N-hydroxyphthalimide or hydroxytriazole).
The following formula (I) characterized by reacting with an L-phenylalanine derivative:

[0014]

[Chemical 9]

A method for producing 2 ', 3'-dideoxy-3'-N-substituted-L-phenylalanylamidocytidine represented by the formula (wherein R is the same as above). Furthermore, the present invention provides the following formula (I):

[0016]

[Chemical 10]

A carcinostatic agent containing 2 ', 3'-dideoxy-3'-N-substituted-L-phenylalanylamidocytidine represented by the formula (wherein R is the same as above) as an active ingredient. Hereinafter, the present invention will be described in detail. The compound represented by formula (I) is a prodrug of 3'-amino-2 ', 3'-dideoxycytidine, which is specifically cleaved and activated by chymotrypsin.

Compound of the present invention (hereinafter referred to as the present compound)
Can be obtained as follows. That is, an active ester of N-t-butoxycarbonylphenylalanine, acylphenylalanine or aromatic phenylalanine, which is phenylalanine having its amino group protected, and 3'-
It can be obtained by reacting (condensing) with amino-2 ′, 3′-dideoxycytidine, for example, at room temperature for 10 to 30 hours.

Examples of the active ester include pentachlorophenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, N
Examples thereof include hydroxyphthalimide ester and hydroxytriazole ester, and pentachlorophenyl ester is preferable. As the condensation method, the active ester method described above is used, but in addition, a mixed acid anhydride method,
N, N'-dicyclohexylcarbodiimide method (DCC
Method), the acid azide method, etc.

The present compound is specifically cleaved and activated by a protease in cancer cells. That is, 3'-amino-2 ', 3'-dideoxycytidine is preferentially cleaved by chymotrypsin in cancer cells. Therefore, the compound has a particularly remarkable antitumor effect on chymotrypsin-producing cancer cells. Moreover, since this compound remains inactive until 3′-amino-2 ′, 3′-dideoxycytidine is cleaved by chymotrypsin, the blood half-life can be prolonged and the blood concentration is high. Can be maintained. This has characteristics different from simple ester and amide type prodrugs. Moreover, when this compound is administered as an anticancer agent, it is effective mainly against leukemia strains.

The method of administering the present compound may be oral or parenteral, and oral administration includes sublingual administration. For parenteral administration, injection, such as subcutaneous, intraperitoneal, intramuscular, intravenous injection,
In addition to drip, it also includes suppositories. In addition, the dose varies depending on the age of the administration subject, the administration route, and the number of administrations, and can be widely varied. In this case, the effective amount administered as a composition of the effective amount of the present compound and a suitable diluent and pharmacologically usable carrier is 200 to 800 mg / kg body weight / day, and the dose may be once to several times a day. It is administered in 5 divided doses over 5 days.

When the present compound is orally administered, it may be used as tablets, granules, fine granules, powders and the like applied thereto, and especially granules, fine granules and powders are capsules if necessary. As a unit dose dosage form. These solid preparations for oral administration usually contain additives such as binders, inclusion agents, excipients, lubricants, disintegrants, and wetting agents, which are commonly used in formulation, in their compositions. The liquid preparation for oral use may be in any form such as an aqueous solution, suspension, emulsion and syrup for internal use, or may be a dry product to be redissolved when used. Further, the composition may contain either an additive or a preservative.

For parenteral administration, additives such as stabilizers, buffers, preservatives, and isotonicity agents are included and usually provided in a unit dose ampoule or a multi-dose container. .
The composition may be in powder form for reconstitution with a suitable carrier, eg, pyrogen-free, sterile water, when used. Here, the antitumor activity using the present compound will be described by giving test examples of the present compound as follows.

Test Example 1 Antitumor effect of this compound on mouse leukemia cells (anticancer activity) As this compound, 2 ′, 3′-dideoxy-3′-Nt-butoxy shown in Examples described later is used. Carbonyl-L-phenylalanylamido cytidine (hereinafter referred to as "t-Boc form" in this test example) was used. In addition to the above compounds, 3'-amino-2 ', 3'-dideoxycytidine (hereinafter referred to as "3'-amino-CdR") was also used. 10 ⁶ mouse leukemia cells P388 were transplanted into the abdominal cavity of mice (CDF ₁ , female, 8 weeks old) (6 mice per group). The t-Boc form or 3′-amino-CdR was dissolved or suspended in physiological saline, and a predetermined amount (see Table 1) was continuously administered once a day from the first day to the fifth day after transplantation of P388 cells. It was intraperitoneally administered to mice. The control group included
Only the physiological saline used to dissolve the compound was administered by the same method.

The body weight change and survival time 5 days after administration were measured. In addition, t-Boc form or 3'-amino-C
With the dR administration group as T and the control group as C, the antitumor effect of the administration group with respect to the control group was calculated, and the ratio T / C (%) was calculated using survival days as an index.

The results are shown in Table 1.

[0027]

[Table 1]

Each numerical value shown in the item of "Survival time" in Table 1 shows the average survival days per 6 mice ± standard error in the case of 3'-amino-CdR and t-Boc. . Further, the alphabets described in the item of "control" represent survival time and weight change of mice used as controls of each administration group (for the values of survival time and weight change, refer to the lower part of Table 1). As is clear from Table 1, this compound exerted a marked anticancer effect as compared with 3′-amino-CdR. [Test Example 2] Antitumor effect of this compound on mouse leukemia cells (anticancer activity) 2 ′, 3′-dideoxy-3′-Nt used in Test Example 1
-Butoxycarbonyl-L-phenylalanylamidocytidine instead of 3 '-[N- (acetyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine (hereinafter referred to as ""Acetylform"), 3 '-[N- (benzoyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine (hereinafter referred to as "benzoyl form" in this test example), 3 '
-[N- (hexanoyl) -L-phenylalanyl]-
Amino-2 ′, 3′-dideoxycytidine (hereinafter referred to as “hexanoyl form” in this test example) was used. The test method is the same as in Test Example 1. However, the number of mice used in this test was 5 per group. The results are shown in Table 2.

[0029]

[Table 2] Table 1 shows the numerical values shown in the item "Survival time" in Table 2 and the alphabets written in the item "Control".
Is synonymous with.

[0030]

EXAMPLES The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples. Example 1 Synthesis of 2 ′, 3′-dideoxy-3′-Nt-butoxycarbonyl-L-phenylalanylamidocytidine. 3′-amino-2 ′, 3′-dideoxycytidine can be prepared by the method of Lin et al. [TSLin, WR Mancini; J. Medicinal
Chemistry, 26, 544 (1983)].

900 mg (about 4 mmole) of 3'-amino-2 ', 3'-dideoxycytidine was dissolved in 10 ml of DMF, and 0.6 ml (1.1 equivalent) of triethylamine and 2.2 g of t-butoxycarbonyl-L-phenylalanine pentachlorophenyl ester were dissolved in this solution. (4.4 mmole) was added, and the mixture was stirred at room temperature for 24 hours. Then, after confirming the disappearance of the raw material by TLC (silica gel CHCl ₃ -ethanol 9: 1), DMF was distilled off under reduced pressure,
The residue was partitioned between ethyl acetate and water, the organic layer was dried and concentrated. This is applied to a column having 60 g of silica gel (manufactured by Merck) as a carrier, eluted with 2.5 to 25% ethanol in chloroform, dried under reduced pressure and crystallized from ethanol,
2 ′, 3′-Dideoxy-3′-Nt-butoxycarbonyl-L-phenylalanylamidocytidine was obtained. Yield: 1.6g (84%) mp: 163-165 ℃ An NMR chart is shown in FIG. [Example 2] Synthesis of 3 '-[N- (acetyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine. Commercially available N-acetyl-L-phenylalanine (1
mmole) was dissolved in DMF (3 ml), pentachlorophenol and DCC were added in 1.5 mmole, respectively, and the mixture was stirred at room temperature for 24 hours. After stirring, the solvent was removed under reduced pressure, dioxane (5 ml) was added, insoluble dicyclohexylurea was filtered off, and the solvent was removed again to obtain an active ester almost quantitatively. For active ester (1.0 mmole), 0.8 mmole of 3'-amino-2 ', 3'-dideoxycytidine was dissolved in 3 ml of anhydrous DMF together with 150 ml of triethylamine,
The mixture was stirred at room temperature for 24 hours. After stirring, the solvent was distilled off, and the residue was eluted with silica gel column chromatography (CHCl ₃ -ethanol 50: 1) using 25 g of silica gel as a carrier to yield 3′-
[N- (acetyl) -L-phenylalanyl] -amino-2 ', 3'-dideoxycytidine (m.p .: 168-171)
C) was obtained in a yield of 86%. Example 3 Synthesis of 3 '-[N- (benzoyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine. 3 '-[N- in the same manner as in Example 2 except that N-acetyl-L-phenylalanine used in Example 2 was changed to N-benzoyl-L-phenylalanine.
(Benzoyl) -L-phenylalanyl] -amino-
2 ', 3'-dideoxycytidine (mp: 75-77 ° C)
Was obtained in a yield of 89%. Example 4 Synthesis of 3 '-[N- (hexanoyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine. 3 '-[N was prepared in the same manner as in Example 2 except that N-acetyl-L-phenylalanine used in Example 2 was changed to N-hexanoyl-L-phenylalanine.
-(Hexanoyl) -L-phenylalanyl] -amino-2 ', 3'-dideoxycytidine (mp: 66-67 ° C)
Was obtained in a yield of 78%. Reference Example 1 With respect to each of the compounds obtained in Examples 2 to 4, each compound was reacted with chymotrypsin at a ratio of 1: 1.
This yielded amino-CdR and N-acyl-L-phenylalanine.

INDUSTRIAL APPLICABILITY The present invention can provide a prodrug that produces excellent antitumor activity. This compound is preferentially 3'-amino- by chymotrypsin.
Since 2 ', 3'-dideoxycytidine is cleaved and activated, the activity is stronger than that of 3'-amino-2', 3'-dideoxycytidine directly administered, and the bioavailability is excellent.

[Brief description of drawings]

FIG. 1 is a diagram showing an NMR chart in Example 1.

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[Procedure amendment]

[Submission date] November 11, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0031

[Correction method] Change

[Correction content]

900 mg (about 4 mmole) of 3'-amino-2 ', 3'-dideoxycytidine was dissolved in 10 ml of DMF, and 0.6 ml (1.1 equivalent) of triethylamine and 2.2 g of t-butoxycarbonyl-L-phenylalanine pentachlorophenyl ester were dissolved in this solution. (4.4 mmole) was added, and the mixture was stirred at room temperature for 24 hours. Then, after confirming the disappearance of the raw material by TLC (silica gel CHCl ₃ -ethanol 9: 1), DMF was distilled off under reduced pressure,
The residue was partitioned between ethyl acetate and water, the organic layer was dried and concentrated. This is applied to a column having 60 g of silica gel (manufactured by Merck) as a carrier, eluted with 2.5 to 25% ethanol in chloroform, dried under reduced pressure and crystallized from ethanol,
2 ′, 3′-Dideoxy-3′-Nt-butoxycarbonyl-L-phenylalanylamidocytidine was obtained. Yield: 1.6 g (84%) mp: 163-165 ° C An NMR chart is shown in FIG. [Example 2] Synthesis of 3 '-[N- (acetyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine. Commercially available N-acetyl-L-phenylalanine (1
mmole) was dissolved in DMF (3 ml), pentachlorophenol and DCC were added in 1.5 mmole, respectively, and the mixture was stirred at room temperature for 24 hours. After stirring, the solvent was removed under reduced pressure, dioxane (5 ml) was added, insoluble dicyclohexylurea was filtered off, and the solvent was removed again to obtain an active ester almost quantitatively. For active ester (1.0 mmole), 0.8 mmole of 3'-amino-2 ', 3'-dideoxycytidine was dissolved in 3 ml of anhydrous DMF together with 150 ml of triethylamine,
The mixture was stirred at room temperature for 24 hours. After stirring, the solvent was distilled off, and the residue was eluted with silica gel column chromatography (CHCl ₃ -ethanol 50: 1) using 25 g of silica gel as a carrier to yield 3'-
[N- (acetyl) -L-phenylalanyl] -amino-2 ', 3'-dideoxycytidine (mp: 168-171)
C) was obtained in a yield of 86%. Example 3 Synthesis of 3 '-[N- (benzoyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine. 3 '-[N- in the same manner as in Example 2 except that N-acetyl-L-phenylalanine used in Example 2 was changed to N-benzoyl-L-phenylalanine.
(Benzoyl) -L-phenylalanyl] -amino-
2 ', 3'-dideoxycytidine (mp: 75-77 ° C) was obtained with a yield of 89%. The NMR chart of the obtained compound is shown in FIG. In addition, NMR analysis data and UV data are shown below. UV (MeOH) λ _max 270 nm (ε9500), λ _min 260 nm (ε8900) MS (FAB-DI); m / z 478 [M + H] ¹ H NMR (DMSO-d6) δ (ppm) 8.64 (1H, d, J = 7.81Hz, NH-Phe
D ₂ O replaceable) 8.47 (1H, brs, NHBz, D ₂ O replaceable) 7.93 (1
H, d, J = 7.32Hz, 6-H) 7.82 (2H, d, J = 7.32Hz, 3,5-H of Bz)
7.50-7.14 (10H, m, 2,4,6-H of Bz and Ph and 4-NH) 7.
04 (1H, br, 4-NH D ₂ O replaceable) 6.24 (1H, m, 1'-H) 5.81 (1
H, d, J = 7.32Hz, 5-H) 5.03 (1H, brs, 5'-OH D ₂ O replaceable)
4.81 (1H, m, COCH) 4.37 (1H, m, 3'-H) 3.76 (1H, m, 4'-H) 3.
68 (1H, m, 5'-H) 3.55 (1H, m, 5'-H) 3.15 (1H, dd, J = 5.86,1
3.68Hz, CHPh) 3.07 (1H, dd, J = 9.27,13.68Hz, CHPh) 2.30-
2.10 (2H, m, 2'-H) [Example 4] Synthesis of 3 '-[N- (hexanoyl) -L-phenylalanyl] -amino-2', 3'-dideoxycytidine. 3 '-[N was prepared in the same manner as in Example 2 except that N-acetyl-L-phenylalanine used in Example 2 was changed to N-hexanoyl-L-phenylalanine.
-(Hexanoyl) -L-phenylalanyl] -amino-2 ', 3'-dideoxycytidine (mp: 66-67 ° C)
Was obtained in a yield of 78%. Reference Example 1 With respect to each of the compounds obtained in Examples 2 to 4, each compound was reacted with chymotrypsin at a ratio of 1: 1.
This yielded amino-CdR and N-acyl-L-phenylalanine. Example 5 3 ′-(N- (p-chlorobenzoyl)
Synthesis of -L-phenylalanyl) -amino-2 ', 3'-dideoxycytidine. Under nitrogen atmosphere, 3'-amino-
2.16 g (9.55 mmole) of 2 ', 3'-dideoxycytidine,
N- (p-chlorobenzoyl) -L-phenylalanine
3.19g (10.5mmole), N-hydroxysuccinimide 1.
A mixed solution of 21 g (10.5 mmol) of 30 ml of anhydrous DMF was cooled to 0 ° C., and 10.5 ml of 1M dicyclohexylcarbodiimide / anhydrous DMF solution was added dropwise to this solution. After stirring at that temperature for 30 minutes, the mixture was further stirred at room temperature for 15 hours. After completion of the reaction, dicyclohexylurea was removed by filtration, and the filtrate was removed under reduced pressure.
The mixture is dissolved in a small amount of a chloroform / methanol mixed solution, and silica gel column chromatography using 100 g of silica gel as a carrier (chloroform / methanol = 85 /
15) Elution, the eluate containing the title condensation product was concentrated to dryness under reduced pressure, and further crystallized from ethanol / ethyl ether to give 3 '-(N- (p-chlorobenzoyl) -L-
2.98 g of white crystals of phenylalanyl) -amino-2 ′, 3′-dideoxycytidine were obtained with a yield of 61%. The structural formula of the obtained compound is shown in the following formula IV. mp 220-222, UV (MeOH) λ _max 237nm (ε 21000) 270nm
(sh), λ _min 221nm (ε 16700) MS (FAB-DI); m / z 512 [M + H] ¹ H NMR (DMSO-d6) δ (ppm) 8.65 (1H, d, J = 8.3Hz, NH D ₂
8.53 (1H, d, J = 7.81Hz, NH D ₂ O replaceable)
7.85 (1H, d, J = 7.32Hz, 6-H) 7.83 (2H, d, J = 8.79Hz, p
-CIBz) 7.50 (2H, d, J = 8.79Hz, p-CIBz) 7.32 (2H, d, J
= 7.32Hz, Ph) 7.25 (2H, t, J = 7.32Hz, Ph) 7.16 (3H, t,
J = 7.32Hz, Ph, 4-NH D ₂ O replaceable) 7.04 (1H, brs, 4-N
HD ₂ O replaceable) 6.19 (1H, t, J = 6.35Hz, 1'-H) 5.73 (1
H, d, J = 7.32Hz, 5-H) 4.79 (1H, dd, J = 4.89, 5.37Hz,
5'-OH D ₂ O replaceable) 4.68 (1H, m, COCHN) 4.29 (1H, m,
3'-H) 3.70 (1H, m, 4'-H) 3.60 (1H, m, 5'-H) 3.49 (1
H, m, 5'-H) 3.06 (1H, dd, J = 5.37, 13.67Hz, CHPh) 2.9
9 (1H, dd, J = 10.26, 13.67Hz, CHPh) 2.18 (1H, m, 2'-H)
2.08 (1H, m, 2'-H)

[Chemical 11] [Example 6] 3 '-(N- (1-naphthoyl) -L-
Synthesis of (phenylalanyl) -amino-2 ', 3'-dideoxycytidine. Under nitrogen atmosphere, 3'-amino-2 ', 3'-
Dideoxycytidine 2.08g (9.19mmole), N- (1-
Naphthoyl) -L-phenylalanine 3.23 g (10.1 mmol
e), 1.16 g (10.1 mmol) of N-hydroxysuccinimide
Anhydrous DMF (30 ml) mixed solution was cooled to 0 ° C, and 1M dicyclohexylcarbodiimide / anhydrous DMF solution was added to this solution.
10.1 ml was dropped. After stirring at that temperature for 30 minutes, the mixture was further stirred at room temperature for 15 hours. After completion of the reaction, the same post-treatment and purification as above were carried out to obtain 3 '-(N- (1-naphthoyl)-
2.46 g of white crystals of L-phenylalanyl) -amino-2 ′, 3′-dideoxycytidine were obtained with a yield of 51%. The structural formula of the obtained compound is shown in the following formula V. mp 134-135, UV (MeOH) λ _max 276nm (ε 13800) 222nm
(ε 6300), λ _min 251nm (ε 8800) ¹ H NMR (DMSO-d6) δ (ppm) 8.66 (1H, d, J = 8.3Hz, NH D ₂
8.56 (1H, d, J = 7.33Hz, NH D ₂ O replaceable)
7.97-7.83 (4H, m, aromatic H and 6-H) 7.53-7.23 (9H,
m, aromatic H) 7.16 (1H, brs, 4-NH D ₂ O exchangeable) 7.
06 (1H, brs, 4-NHD ₂ O replaceable) 6.23 (1H, t, J = 6.35Hz,
1'-H) 5.75 (1H, d, J = 7.32Hz, 5-H) 5.02 (1H, t, J = 5.
37Hz 5'-OH D ₂ O replaceable) 4.84 (1H, m, COCHN) 4.37 (1
H, m, 3'-H) 3.76 (1H, m, 4'-H) 3.64 (1H, m, 5'-H) 3.
54 (1H, m, 5'-H) 3.12 (1H, dd, J = 4.88, 13.68Hz, CHP
h) 2.95 (1H, dd, J = 10.74, 13.68Hz, CHPh) 2.23 (1H,
m, 2'-H) 2.14 (1H, m, 2'-H)

[Chemical 12] [Example 7] Synthesis of 3 '-(N-lauroyl-L-phenylalanyl) -amino-2', 3'-dideoxycytidine. Under a nitrogen atmosphere, 3'-amino-2 ', 3'-dideoxycytidine 3.0 g (13.3 mmole), N- (laruloyl)-
L-phenylalanine 5.07 g (14.6 mmole), N-hydroxysuccinimide 1.68 g (14.6 mmol) anhydrous DMF30
The ml mixed solution was cooled to 0 ° C., and 14.6 ml of 1M dicyclohexylcarbodiimide / anhydrous DMF solution was added dropwise to this solution. After stirring at that temperature for 30 minutes, the mixture was further stirred at room temperature for 15 hours. After completion of the reaction, the same post-treatment as above was carried out, and silica gel column chromatography (chloroform / methanol = 90/10 to 85/15) was repeated twice to obtain 3 '-(N- (lauroyl) -L-phenylalanyl)-. Amino-2 ',
3 g of 3'-dideoxycytidine was obtained with a yield of 41%. The structural formula of the obtained compound is shown in the following formula VI. mp 173-175 UV (MeOH) λ _max 272nm (ε 8500), λ _min 252nm (ε 660
0) MS (FAB-DI); m / z 556 [M + H] ¹ H NMR (DMSO-d6) δ (ppm) 8.38 (1H, d, J = 7.81Hz, 3'-N
HD ₂ O replaceable) 7.97 (1H, d, J = 8.30Hz, NH-Acyl D ₂ O replaceable) 7.84 (1H, d, J = 7.32Hz, 6-H) 7.26-7.15 (6H,
m, Ph and 4-NH D ₂ O exchangeable) 7.04 (1H, brs, 4-NH D
₂ O replaceable) 6.15 (1H, t, J = 6.35Hz, 1'-H) 5.72 (1H,
d, J = 7.32Hz, 5-H) 4.96 (1H, dd, J = 4.88,5.37Hz, 5'-O
HD ₂ O replaceable) 4.50 (1H, m, COCH) 4.26 (1H, m, 3'-
H) 3.63 (1H, m, 4'-H) 3.58 (1H, dd, J = 2.44, 12.2Hz,
5'-H) 3.44 (1H, dd, J = 3.90, 12.2Hz, 5'-H) 2.90 (1H,
dd, J = 5.37, 13.67Hz, CHPh) 2.77 (1H, dd, J = 9.28, 1
3.67Hz, CHPh) 2.18-2.01 (4H, m, 2'-H and COCH ₂ ) 1.3
6 (2H, m, CH ₂ ) 1.32-1.04 (16H, m, CH ₂ * 8) 0.86 (3H, t,
J = 6.34Hz, -CH ₃ )

[Chemical 13]

INDUSTRIAL APPLICABILITY The present invention can provide a prodrug that produces excellent antitumor activity. This compound is preferentially 3'-amino- by chymotrypsin.
Since 2 ', 3'-dideoxycytidine is cleaved and activated, the activity is stronger than that of 3'-amino-2', 3'-dideoxycytidine directly administered, and the bioavailability is excellent.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] Brief description of the drawing

[Correction method] Change

[Correction content]

[Brief description of drawings]

FIG. 1 is a diagram showing an NMR chart in Example 1.

2 is a diagram showing an NMR chart in Example 3. FIG.

[Procedure 3]

[Document name to be corrected] Drawing

[Name of item to be corrected] Figure 2

[Correction method] Added

[Correction content]

[Fig. 2]

Claims (3)

[Claims] 1. The following formula (I): (In the formula, R represents a protecting group for an amino group),
3'-dideoxy-3'-N-substituted-L-phenylalanylamidocytidine. 2. The following formula (II): And 3'-amino-2 ', 3'-dideoxycytidine represented by the following formula (III): (In the formula, R is the same as above, and R ¹ is pentachlorophenyl, p-nitrophenyl, N-hydroxysuccinimide, N-hydroxyphthalimide or hydroxytriazole.) N-substituted-L-phenylalanine The following formula (I) characterized by reacting with a derivative: (In the formula, R is the same as above), and 2 ′, 3′-
A method for producing dideoxy-3′-N-substituted-L-phenylalanylamidocytidine. 3. The following formula (I): (In the formula, R is the same as above), and 2 ′, 3′-
An anticancer agent containing dideoxy-3′-N-substituted-L-phenylalanylamidocytidine as an active ingredient.