JPH05310777A - 2'-deoxy-2'-methylidynecytidine compound - Google Patents

Abstract

PURPOSE:To obtain a new compound having a group hydrolyzable in vivo, enhanced in carcinostatic activity and antiviral action and raised in biological utilization ratio. CONSTITUTION:A compound of formula I (R is H, halogen, alkyl, etc.; R<1> is H or a group hydrolyzable in vivo; R<2> is H, group hydrolyzable in vivo or arylalkyl; R<3> is H or group hydrolyzable in vivo, phosphoric acid ester residue, etc., with the proviso that R<1> and R<3> are simultaneously H and when one of them is alkanoyl, the others are not alkanoyl or H), e.g. 2'-deoxy-2'-methylidyne- N<4>-cyclopropylcarbonylcytidine. This compound of formula I is obtained by subjecting a compound of formula II (Z is H or protecting group of OH) to N<4>-carbonylation reaction with an acid halide or an activated ester, etc., in a solvent such a pyridine or water in the presence of an acid receptor such as triethylamine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a 2'-deoxy-2'-methylidene cytidine compound having an excellent antitumor or antiviral activity and useful as a medicine.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 63-230699 discloses a 2'-alkylidene pyrimidine nucleoside derivative having an antiviral effect, and 63-25881.
No. 8 discloses that 2'-deoxy-2'-methylidene cytidine (hereinafter sometimes referred to as DMDC) has a carcinostatic action. In addition, JP-A-2-25
N ⁴ position of DMDC in JP 6698, 3 'and /
Alternatively, an acylated derivative is described at the 5'position.

[0003]

Since the above compounds show specificity of the structure and excellent action and effect, they are currently under intensive research and development as a carcinostatic agent, but their bioavailability is further increased. In addition, there is a demand for the development of a drug with reduced side effects such as gastrointestinal disorders. The present invention is
It is another object of the present invention to provide novel 2'-deoxycytidine compounds having excellent antitumor action and antiviral action.

[0004]

[Means for Solving the Problems] As a result of repeated research to develop a novel compound having an excellent action effect as a carcinostatic agent and an antiviral agent, the present inventors have found that it is easily hydrolyzed in vivo. It has been found that DMDCs substituted with a group having an activity are enhanced in activity, bioavailability is increased, and side effects such as gastrointestinal disorders are reduced.
The present invention has been completed. The present invention has the general formula

[0005]

[Chemical 2]

[Wherein R is hydrogen, halogen, alkyl,
Alkenyl, alkynyl, haloalkyl, haloalkenyl or haloalkynyl, R ¹ is hydrogen or a group hydrolyzable in vivo, R ² is hydrogen, a group hydrolyzable in vivo or arylalkyl, and R ³ is hydrogen. , An in vivo hydrolysable group, an arylalkyl or a phosphate residue. However, R ¹ , R ² and R ³ do not represent hydrogen at the same time. Further, when at least one of R ¹ , R ² and R ³ is an alkanoyl group which is hydrolyzable in vivo, the others are neither hydrogen nor alkanoyl. ] The 2'-deoxy-2'-methylidene cytidine compound represented by the following (it may be hereafter called compound (I)).

In the compound (I), a preferable group of compounds is a compound represented by the general formula (I) in which R ¹ is a hydrolyzable group in vivo, such as di- or trimethoxybenzoyl, arylalkanoyl, arylalkenoyl and cyclo. Alkylcarbonyl, cycloalkylalkanoyl, cycloalkylalkenoyl, heteroarylcarbonyl, heteroarylalkanoyl, heteroarylalkenoyl, optionally substituted carboxyl, optionally substituted carbamoyl or aminoalkanoyl, R ² is hydrogen Or arylalkyl, R ³ is hydrogen, alkanoyl, aminoalkanoyl, arylalkyl or 2′-deoxy-, which represents a phosphoric acid ester residue.
2'-methylidene cytidine compound is mentioned.

The symbols used in this specification will be described below. The halogen represented by R means fluorine, chlorine, bromine and iodine.

The alkyl represented by R has 1 to 1 carbon atoms.
Four linear or branched alkyl groups are preferable, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl.

Alkenyl represented by R has 2 carbon atoms.
~ 4 straight or branched alkenyl are preferred,
For example vinyl, 1-propenyl, 2-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl and the like can be mentioned.

Alkynyl represented by R has 2 carbon atoms.
-4 linear or branched alkynyls are preferred,
For example, ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl and the like can be mentioned.

The haloalkyl represented by R is preferably a haloalkyl in which the alkyl part is a linear or branched alkyl having 1 to 4 carbon atoms, and examples thereof include chloromethyl, bromomethyl, fluoromethyl, iodomethyl, trifluoromethyl, It means bromoethyl, iodoethyl, trifluoroethyl, trifluoropropyl and the like.

The haloalkenyl represented by R is preferably a haloalkenyl in which the alkenyl part is a linear or branched alkenyl having 2 to 4 carbon atoms, for example, 2-
It means bromovinyl, 2-fluorovinyl and the like.

The haloalkynyl represented by R is preferably a haloalkynyl in which the alkynyl moiety is a straight-chain or branched alkynyl having 2 to 4 carbon atoms, such as 2-
It means bromoethynyl, 2-fluoroethynyl and the like.

In vivo hydrolyzable groups represented by R ¹ , R ² and R ³ include alkanoyl, alkenoyl,
Arylcarbonyl, arylalkanoyl, arylalkenoyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylalkenoyl, heteroarylcarbonyl, heteroarylalkanoyl,
By heteroarylalkenoyl, optionally substituted carboxyl, optionally substituted carbamoyl, or aminoalkanoyl.

Here, the alkanoyl and the alkanoyl in the arylalkanoyl, cycloalkylalkanoyl and heteroarylalkanoyl are linear or branched alkanoyl having 2 to 22 carbon atoms, such as acetyl, propionyl, 2 -Methylpropionyl, butyryl, dimethylacetyl, hexanoyl, octanoyl, decanoyl, tetradecanoyl,
Octadecanoyl and the like can be mentioned, preferably having 2 carbon atoms.
˜8, more preferably linear or branched alkanoyl having 2 to 4 carbon atoms.

The alkanoyl in aminoalkanoyl is a straight-chain or branched alkanoyl having 2 to 22 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 4 carbon atoms, like the above alkanoyl. And may be substituted with aryl, cycloalkyl or heteroaryl (these have the same meanings as described below). Amino may be substituted with one or two substituents (substituents include alkyl and arylalkyl), or cyclic amino [1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 1- Substitution-4-
Piperazinyl (substituents include alkyl and arylalkyl) and the like.

Alkenoyl and arylalkenoyl, cycloalkylalkenoyl and heteroarylalkenoyl in heteroarylalkenoyl have 2 to 2 carbon atoms.
22 straight or branched chain alkenoyls,
Examples thereof include acryloyl, methacryloyl, crotonoyl, hexenoyl, octenoyl, decenoyl, tetradecenoyl, octadecenoyl, etc., preferably a straight chain or branched chain alkenoyl having 2 to 8 carbon atoms, more preferably 2 to 4 carbon atoms. is there.

Aryl in arylcarbonyl, arylalkanoyl and arylalkenoyl means optionally substituted phenyl or naphthyl,
As the substituent, 1 to 3 halogen, alkyl, alkenyl, haloalkyl (these are as defined above), alkoxy (a straight or branched alkoxy having 1 to 4 carbon atoms, for example, methoxy, ethoxy, Propoxy, isopropoxy, butoxy, tertiary butoxy, etc.), hydroxyl group, amino, nitro.

Cycloalkylcarbonyl, cycloalkylalkanoyl and cycloalkyl in cycloalkylalkenoyl are preferably optionally substituted cycloalkyl having 3 to 7 carbon atoms (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
(Eg, cycloheptyl), and the substituent is 1 to 3
Individual halogen, alkyl, alkenyl, haloalkyl,
Alkoxy (these are as defined above), hydroxyl group, amino,
Selected from Nitro.

The heteroaryl in the heteroarylcarbonyl, heteroarylalkanoyl and heteroarylalkenoyl is preferably an optionally substituted 5- to 6-membered ring (which may be condensed with a benzene ring) (for example, a heterocycle). (Thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, etc.), and the substituents are 1 to 3
Individual halogen, alkyl, alkenyl, haloalkyl,
Alkoxy (these are as defined above), hydroxyl group, amino,
Selected from Nitro.

The substituent in the optionally substituted carboxyl and the optionally substituted carbamoyl is alkyl, aryl (these are as defined above), arylalkyl (the aryl part and the alkyl part are as defined above), For example, benzyl, 1-phenylethyl, 2-
Phenylethyl, 4-phenylbutyl, chlorobenzyl, methylbenzyl, methoxybenzyl, dimethoxybenzyl, trifluoromethylbenzyl, nitrobenzyl and the like).

The arylalkyl in R ² and R ³ is the same as described above, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, 4-phenylbutyl, chlorobenzyl, methylbenzyl, methoxybenzyl, dimethoxybenzyl and trialkyl. Examples thereof include fluorobenzyl and nitrobenzyl.

The phosphoric acid ester residue in R ³ is a mono-, di- or triphosphoric acid ester residue, or an alkyl phosphoric acid ester having an alkyl having 1 to 22 carbon atoms (for example, hexyl phosphoric acid ester, octyl phosphoric acid ester, Decyl phosphate ester, dodecyl phosphate ester, tetradecyl phosphate ester, hexadecyl phosphate ester, heptadecyl phosphate ester, octadecyl phosphate ester, icosyl phosphate ester, docosyl phosphate ester and the like).

In the compound (I) of the present invention, when R ¹ in the general formula (I) is hydrogen, it may be in the form of a salt,
Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid, or organic acids such as fumaric acid, tartaric acid, succinic acid, citric acid and methanesulfonic acid. You can Further, the compound of the present invention or a salt thereof may be a hydrate or a solvate.

The compound (I) of the present invention has the general formula

[0027]

[Chemical 3]

A compound represented by the formula (wherein Z represents a hydrogen or hydroxyl protecting group and R has the same meaning as described above) is subjected to a N ⁴ -position carbonylation reaction, or is thus obtained. The N ⁴ -carbonyl compound subjected to 5′-position carbonylation reaction, 5′-position arylalkylation reaction, 5′-position phosphoric acid esterification reaction and / or 3′-position carbonylation reaction, 3′-position arylalkylation reaction Is obtained by

Further, in the compound (I) wherein R ¹ is hydrogen, the N ⁴ -position amino group of the compound of the general formula (II) is protected by a protecting group (eg benzyloxycarbonyl, phenoxycarbonyl, trifluoroacetyl, etc.). Protecting this, 5'position carbonylation reaction, 5'position arylalkylation reaction, 5'position phosphoric acid esterification reaction and /
Alternatively, it can be obtained by subjecting to a 3′-position carbonylation reaction and a 3′-position arylalkylation reaction, and finally removing the amino-group protecting group. The compound in which R ² is hydrogen is obtained by subjecting the compound of the general formula (II) to a N ⁴ -position carbonylation reaction, which is subjected to a 5′-position carbonylation reaction, a 5′-position arylalkylation reaction, and a 5′-position phosphate ester. 3'after being subjected to the chemical reaction
It is obtained by removing the protective group for the hydroxyl group at the position. R
^A compound in which ³ is hydrogen is a compound of the general formula (II) with N ⁴
Position carbonylation reaction, this is subjected to 3'position carbonylation reaction, 3'position arylalkylation reaction,
It is obtained by removing the protective group for the hydroxyl group at the 5'position.

The protective group for the hydroxyl group represented by Z is, for example, benzyl, methoxybenzoyl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl,
It means tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, methoxymethyl, (2-methoxyethoxy) methyl, tetrahydropyranyl, or the like. Furthermore, cyclic acetal, cyclic ketal, cyclic carbonate, cyclic orthoester or cyclic 1,3-
It also means (1,1,3,3-tetraisopropyl) disiloxanediyl derivatives. These hydroxyl-protecting groups can be removed by a conventional method.

The carbonylation reaction is alkanoylation, alkenoylation, arylcarbonylation, arylalkanoylation, arylalkenoylation, cycloalkylcarbonylation, cycloalkylalkanoylation, cycloalkylalkenoylation, heteroarylcarbonylation,
Heteroarylalkanoylation, heteroarylalkenoylation, carboxylation, carbamoylation, or aminoalkanoylation reaction is carried out according to a method known per se.

For example, the corresponding acid halide, acid anhydride, mixed acid anhydride, activated ester (eg N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 4-nitrophenyl ester, etc.), acyl azide or mixed carbonic anhydride. In a solvent such as pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, methanol, ethanol, water, or in a mixture of two or more of the above solvents, triethylamine, pyridine, pyricon, dimethylaminopyridine, lutidine. , N-dimethylaniline, alkali metal hydroxides, alkali metal carbonates, alkali metal phosphates and the like in the presence of acid acceptors.

The arylalkylation reaction and phosphoric acid esterification reaction are also carried out according to methods known per se.

When the compound of the present invention or a salt thereof is used as a medicine, an effective amount of compound (I) or a salt thereof is mixed with a pharmaceutically acceptable carrier, excipient, diluent or the like to prepare a powder, granules, tablets. , Sugar-coated tablets, capsules, syrups, suppositories, external preparations, injections, infusion solutions and the like, but oral preparations are preferred. The dose may vary depending on the target disease, administration route, dosage form and the like, but in general, in the case of an oral preparation, it is 10 to 400 per day as compound (I) or a salt thereof.
mg / kg body weight, preferably 50 to 200 mg / kg body weight, and 1 to 10 mg / kg body weight daily for injections, preferably 1
~ 5 mg / kg body weight. The frequency of administration can be appropriately selected within the range of 1 to 4 times a day.

[0035]

[Action and effect] The compound of the present invention or a salt thereof has a remarkable effect of suppressing the growth of various cultured tumor cell lines, has a long-lasting effect, has a high bioavailability, and is free from side effects such as gastrointestinal disorders. It is useful as a carcinostatic agent because of its reduced toxicity and low toxicity. Further, it shows an antiviral effect against herpes simplex virus (HSV) and cytomegalovirus (CMV), and may be used in the field of treatment of viral infections.

[0036]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.

[0037] Example 1 2'-deoxy-2'-methylidene -N ⁴ - (3,4,
Synthesis of 5-trimethoxybenzoyl) cytidine

(1) 2.0 g of 2'-deoxy-2'-methylidene cytidine, molecular sieve (molecular sieve / 4Å)
2 g was added to 40 ml pyridine. The suspension was stirred at room temperature for about 1 hour, 1.9 g of t-butyldimethylsilyl chloride was added, and the mixture was stirred at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was treated by silica gel column chromatography (elution solvent: 10% methanol / chloroform mixed solvent) to give 5'-Ot-butyldimethylsilyl-2'-deoxy-. 2.6 g (amorphous) of 2'-methylidene cytidine was obtained.

NMR (DMSO-d ₆ , 90MHz) δppm: 0.01
(6H, s, -CH ₃ × 2), 0.83 (9H, s, t-butyl), 3.56-
3.87 (3H, m, 4 ', 5', 5'-H), 4.39 (1H, m, 3'-H), 5.24
(1H, br.s, 2'-methylidene), 5.33 (1H, br.s, 2'-methylidene), 5.91 (1H, d, J = 7.6Hz, 5-H), 6.46 (1H,
s, 1'-H), 7.61 (1H, d, J = 7.6Hz, 6-H)

(2) 2.6 g of 5'-Ot-butyldimethylsilyl-2'-deoxy-2'-methylidene cytidine
Was dissolved in 40 ml of pyridine, 2.0 g of 3,4,5-trimethoxybenzoyl chloride was added dropwise, and the mixture was stirred overnight. After the reaction, pyridine was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography (elution solvent: 4% methanol / chloroform mixed solvent) to give 5'-O-.
t- butyldimethylsilyl-2'-deoxy-2'-methylidene -N ⁴ - was obtained (3,4,5-trimethoxybenzoyl) cytidine 2.85 g (amorphous).

NMR (CDCl ₃ ) δppm: 0.14 (6H, s,
Methyl), 0.97 (9H, s, t-butyl), 3.89 (3H, s, p-methoxy), 3.95 (6H, s, m-methoxy × 2), 3.60-4.23
(4H, m, 3 ', 4', 5 ', 5'-H), 4.80 (1H, m, 3'-OH), 5.52
(1H, s, 2'- methylidene), 5.68 (1H, s, 2'- methylidene), 6.85 (1H, s, 1'-H), 7.18-7.53 (3H, m, 5-H, P
hH × 2), 8.25 (1H, d, J = 6.8Hz, 6-H)

[0042] (3) 5'-O-t- butyldimethylsilyl-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5 g of 4,5-trimethoxybenzoyl) cytidine was dissolved in 50 ml of 50 ml of tetrahydrofuran, 6 ml of 1N-tetra-n-butylammonium fluoride in tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. .. After completion of the reaction, the reaction solution was concentrated, the residue was treated by silica gel column chromatography (elution solvent: 10% methanol / chloroform mixed solvent), and the obtained crystals were recrystallized from methanol to give colorless needle crystals 2 '. - was obtained (3,4,5-trimethoxybenzoyl) cytidine monohydrate 770 mg - deoxy-2'-methylidene -N ^4.
Melting point 117-119 [deg.] C.

NMR (DMSO-d ₆ ) δppm: 3.70 (3H, s,
p-methoxy), 3.83 (6H, s, m-methoxy × 2), 3.40-
4.09 (4H, m, 3 ', 4', 5 ', 5'-H), 5.08 (1H, m, 5'-OH),
5.15 (1H, s, 2'-methylidene), 5.32 (1H, s, 2'-methylidene), 5.78 (1H, br.s, 3'-OH), 6.63 (1H, s, 1 '
-H), 6.67 (1H, d, J = 8Hz, 5-H), 7.25 (1H, d, J = 8Hz,
6-H), 7.42 (2H, s, Ph-H × 2) UV (in methanol): 303.8, 259.3 nm Elemental analysis value (C ₂₀ H ₂₃ N ₃ O ₈・ 1H ₂ O): Theoretical value C, 53.21 ;
H, 5.14; N, 9.31. Measured value C, 53.64; H, 5.53; N, 9.35. [Α] _D = +8.9 ° (methanol, C = 0.5)

[0044] EXAMPLE 2 2'-deoxy-2'-methylidene -N ⁴ - (3,4,
5-tri-methoxybenzoyl)-5'-O-stearoyl Cie synthesis of cytidine 2'-deoxy-2'-methylidene -N ⁴ - (3,4,
200 mg of 5-trimethoxybenzoyl) cytidine was dissolved in 5 ml of pyridine, and stearoyl chloride 1 was added to this.
50 mg was added dropwise at room temperature and stirred for 21 hours. After the reaction, the reaction solution was poured into ice, the solvent was distilled off, partitioned with ethyl acetate, and dried. After the solvent was distilled off, the resulting oily matter was converted into methanol /
Purification by silica gel column chromatography eluting with chloroform (1:25), evaporation of the solvent and recrystallization from methanol gave 80 mg of the title product. Melting point 83-84 [deg.] C.

NMR (CDCl ₃ , 90 MHz) δppm: 7.85 (1
H, d, J = 9.3Hz, 6-H), 7.57 (1H, d, J = 9.3Hz, 5-H),
7.29 (2H, s, Ph-H × 2), 6.78 (1H, s, 1'-H), 5.60
(2H, br.s, 2'-methylidene), 4.40-4.73 (4H, m,
3 ', 4', 5 ', 5'-H), 3.95 (9H, s, methoxy × 3), 2.39 (2
H, t, J = 10.0Hz, -CH ₂ COO-), 1.26 (30H, br.s, methylene), 0.90 (3H, t, J = 7.0Hz, methyl) UV λmax (in methanol): 269.6 nm IR (KBr): 1740 cm ^-1 (5'- ester part)

[0046] Example 3 2'-deoxy-2'-methylidene -N ⁴ - (3,4,
Synthesis of 5-trimethoxybenzoyl) -5-fluorocytidine

(1) 3 ', 5'-di-O- (1,1,3,
3. Tetraisopropyldisiloxane-1,3-diyl) -2'-deoxy-2'-methylidene-5-fluorouridine 6.7 g, triisopropylbenzenesulfonyl chloride 8.1 g, N, N-dimethylaminopyridine 3. 3 g of acetonitrile was added to 110 ml of acetonitrile, and the mixture was stirred under ice cooling, and 3.7 ml of triethylamine was added. The suspension was stirred under argon at room temperature overnight, 33.5 ml of concentrated aqueous ammonia was added, and the mixture was further stirred for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was treated with silica gel column chromatography (elution solvent: 4% methanol / chloroform mixed solvent) to give 3 ', 5'-di-O- (1,
1,3,3-tetraisopropyldisiloxane-1,3
-Diyl) -2'-deoxy-2'-methylidene-5-
5.6 g (amorphous) of fluorocytidine was obtained.

NMR (CDCl ₃ , 400MHz) δppm: 1.03-
1.12 (28H, m, isopropyl), 3.67-3.70 (1H, m,
4'-H), 4.04 (1H, dd, 5'aH, J = 2.7, 13.2Hz), 4.18
(1H, dd, 5'bH, J = 1.7, 13.2Hz), 4.78-4.81 (1H,
m, 3'-H), 5.39 (1H, dd, 2'-methylidene, J = 1.47, 2.4
4Hz), 5.69 (1H, dd, 2'-methylidene, J = 1.47, 2.44H
z), 6.58 (1H, t, 1'-H, J = 1.47Hz), 7.64 (1H, d, 6-
(H, J = 5.86Hz)

(2) 3 ', 5'-di-O- (1,1,3,
0.5 g of 3-tetraisopropyldisiloxane-1,3-diyl) -2'-deoxy-2'-methylidene-5-fluorocytidine, 1.0 g of 3,4,5-trimethoxybenzoic anhydride, triethylamine. 3 ml, N, N
-Dimethylaminopyridine 10 mg with acetonitrile 10
It was added to the mixture and stirred overnight at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography (elution solvent: 20% ethyl acetate / n-hexane mixed solvent) to give 3 ', 5'-di-O- (1 , 1, 3,
3-tetraisopropyl disiloxane-1,3-diyl) -N ⁴ - (3,4,5-trimethoxy-benzoyl)
0.4 g of 2'-deoxy-2'-methylidene-5-fluorocytidine (amorphous) was obtained.

NMR (CDCl ₃ , 400 MHz) δppm: 1.02-
1.14 (28H, m, isopropyl), 3.70-3.75 (1H, m,
4'-H), 3.92 and 3.94 (9H, each s, methoxy × 3), 4.
06 (1H, dd, 5'aH, J = 2.7, 13.6Hz), 4.21 (1H, dd,
5'bH, J = 1.5, 13.6Hz), 4.83- 4.86 (1H, m, 3'-H),
5.47 (1H, dd, 2'-methylidene, J = 1.46, 2.44Hz), 5.67
(1H, dd, 2'-methylidene, J = 1.46, 2.44Hz), 6.51 (1
H, t, 1'-H), 7.59 (2H, s, Ph-H × 2), 7.78 (1H, d, 6-
H, J = 5.86Hz), 13.0 (1H, br.d, N ⁴ -H, J = 4.88Hz)

(3) 3 ', 5'-di-O- (1,1,3,
3-tetraisopropyl disiloxane-1,3-diyl) -N ⁴ - (3,4,5-trimethoxy-benzoyl)
0.4 g of 2'-deoxy-2'-methylidene-5-fluorocytidine and 1.3 ml of tetrabutylammonium fluoride were added to 5 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2 hours under argon. After the reaction, the solvent was distilled off under reduced pressure, the residue was treated with silica gel column chromatography (elution solvent: 4% methanol / chloroform mixed solvent), and crystallized from ethyl acetate to give 2'-deoxy-2 as pale yellow crystals. '- methylidene -N ⁴ - (3,4,5-trimethoxybenzoyl) -5-fluorocytidine 0.2g
Got Melting point 139.5-140 [deg.] C.

NMR (DMSO-d ₆ ) δppm: 3.71-3.84
(12H, m, methoxy × 3, 4'-H, 5'-H × 2), 4.59 (1H, b
rs, 3'-H), 5.19 (1H, br.s, 5'-OH), 5.43 (1H, br.
s, 2'-methylidene), 5.40 (1H, br.s, 2'-methylidene),
5.70 (1H, d, 3'-OH, J = 6.35Hz), 6.51 (1H, s, 1'-
H), 7.34 (2H, s, Ph-H × 2), 8.35 (1H, br.s, 6-H),
11.51 (1H, br.s, NH) UV λmax (in methanol): 326.6, 212.2 nm Elemental analysis value (C ₂₀ H ₂₂ N ₃ O ₈ F): Theoretical value C, 53.21; H, 4.
91; N, 9.31. Measurements C, 53.24; H, 5.02; N, 9.26.

The following compounds are obtained in the same manner as above.

2'-deoxy-2'-methylidene-
N ⁴ - cyclopropylcarbonyl cytidine, mp 220
° C. (decomposition), 2'-deoxy-2'-methylidene -N ⁴ - nicotinoyl cytidine, mp one hundred and ninety-four to one hundred ninety-five ° C. (decomposition), 2'-deoxy-2'-methylidene -N ⁴ - thienylcarbonyl cytidine, mp 226 ° C. · 2'-deoxy-2'-methylidene -N ⁴ - furylcarbonyl cytidine, mp 207 ° C. (decomposition)

2'-deoxy-2'-methylidene-
N ⁴ - methoxycarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - ethoxycarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - propoxycarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - isopropoxycarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - butoxycarbonyl cytidine

2'-deoxy-2'-methylidene-
N ⁴ -t-butoxycarbonyl cytidine 2′-deoxy-2′-methylidene-N ⁴ -hexyloxycarbonyl cytidine 2′-deoxy-2′-methylidene-N ⁴ -octyloxycarbonyl cytidine 2′-deoxy- 2'-methylidene -N ⁴ - decyloxycarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - dodecyloxycarbonyl cytidine

2'-deoxy-2'-methylidene-
N ⁴ - tetradecyloxy carbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - hexadecyl oxycarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - octadecyloxycarbonyl cytidine-2'-deoxy 2'-methylidene -N ⁴ - icosyl oxycarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - docosyl oxycarbonyl cytidine

2'-deoxy-2'-methylidene-
N ⁴ - cyclopentylcarbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - cyclohexyl carbonyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - (3,
5-dimethoxybenzoyl) cytidine 2'-deoxy-2'-methylidene -N ⁴ - (3,
5-dimethoxyphenyl acetyl) cytidine 2'-deoxy-2'-methylidene -N ⁴ - (3,
5-dimethoxyphenylcinnamoyl) cytidine

2'-deoxy-2'-methylidene-
N ⁴ - cyclopentyl-acetyl cytidine, 2'-deoxy-2'-methylidene -N ⁴ - cyclohexyl acetyl cytidine, 2'-deoxy-2'-methylidene -N ⁴ - (3-
Cyclohexyl acryloyl) cytidine 2'-deoxy-2'-methylidene -N ⁴ - (2-
Pyridyl acetyl) cytidine 2'-deoxy-2'-methylidene -N ⁴ - (2-
Furylacetyl) cytidine

2'-deoxy-2'-methylidene-
N ⁴ - (2-thienylacetyl) cytidine 2'-deoxy-2'-methylidene -N ⁴ - (2-
Benzimidazolyl acetyl) cytidine 2'-deoxy-2'-methylidene -N ⁴ - [3-
(2-pyridyl) acryloyl] cytidine 2'-deoxy-2'-methylidene -N ⁴ - [3-
(2-furyl) acryloyl] cytidine 2'-deoxy-2'-methylidene -N ⁴ - [3-
(2-thienyl) acryloyl] cytidine

2'-deoxy-2'-methylidene-
N ⁴ - (3,4,5-trimethoxy-benzoyl) -5 '
-O- Barirushichijin-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl)-5'-O-benzyl-cytidine-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) cytidine-5'-O
- decyl ester, 2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) cytidine-5'-O
- dodecyl phosphate ester 2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) cytidine-5'-O
-Tetradecyl phosphate

2'-deoxy-2'-methylidene-
N ⁴ - (3,4,5-trimethoxy-benzoyl) cytidine-5'-O-heptadecyl phosphoric acid ester-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) cytidine-5'-O
- octadecyl phosphoric acid ester-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) cytidine-5'-O
- Ikoshirurin ester-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) cytidine-5'-O
- Dokoshirurin ester-2'-deoxy-2'-methylidene -N ⁴ - phenylcarbamoyl cytidine

2'-deoxy-2'-methylidene-
N ⁴ - dimethyl-acetyl cytidine, 2'-deoxy-2'-methylidene -N ⁴ - dimethylaminoacetyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - cyclopropylcarbonyl-5'-O-benzyl-cytidine &2'-deoxy-2'-methylidene -N ⁴ - ethylcarbamoyl cytidine-2'-deoxy-2'-methylidene -N ⁴ - methoxycarbonyl-5-fluorocytidine

2'-deoxy-2'-methylidene-
N ⁴ -ethoxycarbonyl-5-fluorocytidine 2′-deoxy-2′-methylidene-N ⁴ -propoxycarbonyl-5-fluorocytidine 2′-deoxy-2′-methylidene-N ⁴ -isopropoxycarbonyl-5 - fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - butoxycarbonyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ^{4-t-butoxycarbonyl-5-fluorocytidine}

2'-deoxy-2'-methylidene-
N ⁴ - hexyloxy-5- fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - octyloxy-5- fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - decyloxycarbonyl 5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - dodecyloxy-5- fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - fluoro-5-tetradecyloxy carbonyl cytidine

2'-deoxy-2'-methylidene-
N ⁴ - hexadecyl oxycarbonyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - octadecyloxycarbonyl 5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - icosyl oxy-5- fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - docosyl oxycarbonyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - cyclopropylcarbonyl-5- Fluorocytidine

2'-deoxy-2'-methylidene-
N ⁴ - cyclopentyl-5- fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - cyclohexyl-5- fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl)-5'-O-stearoyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - nicotinoyl-5-fluorocytidine

2'-deoxy-2'-methylidene-
N ⁴ - thienylcarbonyl 5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - furyl-5- fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - (3,
5-dimethoxybenzoyl) -5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - (3,
5-dimethoxyphenyl-acetyl) -5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - (3,
5-dimethoxyphenylcinnamoyl) -5-fluorocytidine

2'-deoxy-2'-methylidene-
N ⁴ - (3,4,5-trimethoxy-benzoyl) -5 '
-O- valyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl)-5'-O-benzyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl) -5-fluorocytidine-5'-O-decyl ester, 2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl) -5-fluorocytidine-5'-O-dodecyl phosphate ester 2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) -5-fluorocytidine-5'-O-tetradecyl phosphate

2'-deoxy-2'-methylidene-
N ⁴ - (3,4,5-trimethoxy-benzoyl) -5-
Fluorocytidine-5'-O-hexadecyl phosphoric acid ester-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl) -5-fluorocytidine-5'-O-heptadecyl phosphoric acid ester-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl) -5-fluorocytidine-5'-O-octadecyl phosphoric acid ester-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-tri-methoxybenzoyl) -5-fluorocytidine-5'-O-Ikoshirurin ester-2'-deoxy-2'-methylidene -N ⁴ - (3,
4,5-Trimethoxybenzoyl) -5-fluorocytidine-5'-O-docosyl phosphate ester

2'-deoxy-2'-methylidene-
N ⁴ - phenylcarbamoyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - dimethyl-acetyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - dimethylaminoacetyl -5 - fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - cyclopropylcarbonyl-5'-O-benzyl-5-fluorocytidine, 2'-deoxy-2'-methylidene -N ⁴ - ethylcarbamoyl -5 -Fluorocytidine

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Joji Yasuoka 3-7-25 Oyata, Iruma-shi, Saitama Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Institute (72) Toshiyuki Ohara 3-7-25 Oyada, Iruma-shi, Saitama (72) Inventor Shinji Sakata 5-372-2 Matsumoto-cho, Choshi-shi, Chiba Prefecture (72) Inventor Takanori Miyashita 1-12, Suehiro-cho, Choshi-shi, Chiba Prefecture (72) Yuichi Yoshimura, Chiba Prefecture 1-12 Suehiro-cho, Choshi City (72) Inventor Kazuko Saito 1-40-4 Shinsei-cho, Choshi City, Chiba Prefecture

Claims (2)

[Claims] 1. A general formula: [In the formula, R is hydrogen, halogen, alkyl, alkenyl,
Alkynyl, haloalkyl, haloalkenyl or haloalkynyl, R ¹ is hydrogen or a group hydrolyzable in vivo, R ² is hydrogen, a group hydrolyzable in vivo or an arylalkyl, R ³ is hydrogen, a group Indicates a group capable of being hydrolyzed in the body, an arylalkyl or a phosphate residue. However, R ¹ , R ² and R ³ do not represent hydrogen at the same time. Further, when at least one of R ¹ , R ² and R ³ is an alkanoyl group which is hydrolyzable in vivo, the others are neither hydrogen nor alkanoyl. ] The 2'- Deoxy-2'-methylidene cytidine compound represented by these. Wherein of the groups R ¹ may be hydrolyzed in the in vivo, di- or tri-methoxybenzoyl, aryl alkanoyl, aryl alkenoyl, cycloalkylcarbonyl, cycloalkyl alkanoyl, cycloalkyl alkenoyl, heteroarylcarbonyl, Heteroarylalkanoyl, heteroarylalkenoyl, optionally substituted carboxyl, optionally substituted carbamoyl or aminoalkanoyl, R ² is hydrogen or arylalkyl, R ³ is hydrogen, alkanoyl, aminoalkanoyl, aryl The 2'-deoxy-2'-methylidene cytidine compound according to claim 1, which represents an alkyl or phosphate residue.