WO1993022327A1

WO1993022327A1 - 2'-methylidenenucleoside compound and pharmaceutical use thereof

Info

Publication number: WO1993022327A1
Application number: PCT/JP1993/000514
Authority: WO
Inventors: Akira Matsuda; Masafumi Arita; Joji Yasuoka; Toshiyuki Kohara; Shinji Sakata; Takanori Miyashita
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.; Yamasa Corporation
Priority date: 1992-04-23
Filing date: 1993-04-19
Publication date: 1993-11-11

Abstract

A 2'-methylidenenucleoside compound represented by general formula (I) or a salt thereof, a process for the production thereof, and an antineoplastic or antiviral agent containing the same as the active ingredient, wherein one of R?1 and R2¿ represents hydrogen, halogen, alkyl, cyano, optionally substituted carboxy or optionally substituted carbamoyl, and the other represents halogen, alkyl, cyano, optionally substituted carboxyl or optionally substituted carbamoyl; R?3 and R4¿ may be the same or different from each other and each represents hydrogen, an in vivo hydrolyzable group, or a residue of mono-, di- or triphosphoric acid or an ester thereof; R5 represents hydrogen or an in vivo hydrolyzable group; and R6 represents hydrogen, halogen, alkyl, alkenyl, alkynyl or haloalkyl. The compound and the salts have enhanced antineoplastic and antiviral effects and an improved bioavailability and are reduced in side effects such as gastrointestinal diseases.

Description

Specification

2'-methylidene nucleoside compounds and their pharmaceutical uses

Technology field

The present invention has an excellent anticancer action or antiviral action, and is useful as a medicament.

2′—Methylidene nucleoside compound or salt thereof, and pharmaceutical use thereof.

Background art

According to Japanese Patent Application Laid-Open No. 2-17882272, 2'-fluoromethylidene nucleoside compounds containing 2'-deoxy-2,1-fluoromethylidene cytidine (hereinafter also referred to as FM dC) may be used as antioxidants. It is described as having a virus and anticancer effect. Also, the corresponding adenosine compound is disclosed in JP-A-2-16769.

The above compounds are expected to be useful as medicaments due to their structural specificity, but there is also a need for the development of drugs that have increased bioavailability and reduced side effects such as gastrointestinal disorders.

An object of the present invention is to provide novel 2′-methylidene nucleoside compounds having a further excellent antitumor action and antiviral action.

Disclosure of the invention

The present inventors have repeatedly studied to develop a novel compound having excellent action and effect as an anticancer agent and an antiviral agent, and as a result, a group which is easily hydrolyzed in a living body or phosphoric acid or its phosphate The present inventors have found that FM d Cs substituted by an ester residue have particularly enhanced activity, increased bioavailability, and reduced side effects such as gastrointestinal disorders, and completed the present invention.

The present invention provides a compound represented by the general formula (I): R ⁴ 0H ₂ C (I)

(In the formula, ^one of R ¹ and R ² is hydrogen, halogen, alkyl, cyano, optionally substituted carboxyl or optionally substituted carbamoyl, and the other is halogen, alkyl, cyano, or substituted. R ³ and R ⁴ may be the same or different, and may be hydrogen, a group that can be hydrolyzed in vivo, or mono- or di-substituted carboxyl or optionally substituted carbamoyl. R ⁵ represents hydrogen or a group capable of being hydrolyzed in vivo; R ⁶ represents hydrogen, halogen, alkyl, alkenyl, alkynyl or tialkyl; 2′-methylidene nucleoside compound (hereinafter, also referred to as compound (I)) or a salt thereof, and the use thereof as a carcinostatic or antiviral agent.

(In the formula, R ¹ , R ² , and R ⁶ are as defined above, and R ^ie and R ¹¹ are each hydrogen, It may show a hydrolyzable group or a hydroxy protecting group in the body, or may combine with it to form a cyclic hydroxy protecting group. R ¹² represents hydrogen, a group which can be hydrolyzed in a living body, or an amino protecting group. However, R ^ie , R ¹¹ and R ¹² do not simultaneously represent a protecting group or a group that can be hydrolyzed in vivo. And a compound represented by the general formula (III)

XCOR ⁷ (III)

(Wherein, X represents a deprotecting group, R ⁷ represents a hydrogen atom, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl, aryl, amino or substituted amino.) Or a compound represented by the general formula Formula (IV)

YCOR ¹³ (IV)

Wherein, Y represents a halogen atom, R ¹³ is wherein R ⁸ 0- or R ⁹ S- (wherein,

R ⁸ and R 0 represent alkyl or aralkyl). And a method for producing a 2′-methylidene nucleoside compound or a salt thereof by removing a protecting group if necessary.

The symbols used in this specification are described below.

R ¹ ; Halogen represented by R ² and R ⁶ means fluorine, chlorine, bromine and iodine.

The alkyl represented by R ¹ , R ² and R ⁶ is preferably a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and secondary butyl. , Tertiary butyl, pentyl, isopentyl, hexyl and the like.

As a substituent in the optionally substituted carboxyl or optionally substituted carbamoyl represented by R ¹ and R ² , a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms (as described above) And alkyl is a straight-chain or branched-chain alkylene having 1 to 6 carbon atoms. (The phenyl may have about 1 to 3 halogens, alkyl, alkoxy, hydroxyl, nitro, etc.) May be substituted).

Here, the halogen and alkyl as substituents in the phenyl of the phenylalkyl are the same as those described above, and the alkoxy is a linear or straight-chain having 1 to 6 carbon atoms. Examples include branched alkoxy (methoxy, ethoxy, propoxy, butoxy, benzyloxy, hexyloxy, etc.).

The group capable of being hydrolyzed in vivo represented by R ³ , R ⁴ , and R ⁵ is R ⁷ CO—, R ⁸⁰ C 0— or R ⁹ SCO— (where R ^T is a hydrogen atom, alkyl , Cycloalkyl, oxoalkyl, alkenyl, aralkyl, aryl, amino or substituted amino, and R ⁸ and R ⁸ represent alkyl or aralkyl).

The alkyl represented by R ^7, the number 1-2 one linear or branched technique chain Al Kill carbon, such as methyl, Echiru, propyl, isopropyl, butyl, isobutyl, secondary butyl, first Tertiary butyl, pentyl, isopentyl, hekinl, isohexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptanyldecyl, octadecyl, nonadecyl, icosyl, henycosyl, etc. is there. It is preferably a straight-chain or branched chain having 5 to 2 I carbon atoms, and more preferably a straight-chain alkyl having 9 to 17 carbon atoms.

Thus, in closed R ^T CO-, Asechiru, propionyl, butyryl, Viva Royle, valeryl, to Kisameiru, Okutanoiru, Dekanoiru, lauroyl, myristoyl Risutiru, palmitic toyl, is stearoyl, etc. 7 & exemplified. Here, hexanoyl, octanoyl, decanoyl, radiloyl, myristoyl, palmitoyl, and stearoyl are preferred-octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, and stearoyl are more preferred.

The alkyl represented by R ⁸ and R ⁹ is a linear or branched alkyl having 1 to 22 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, secondary butyl, Tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pennodecinole, hexadecyl, hepnodecyl, ogutadecyl, nonadecyl, icosyl, docosyl, etc. It is.

At the terminal of the alkyl represented by R ⁷ , R & and R ⁸ , a C 3-7 It may have a cycloalkyl (such as cyclobutyl pill, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).

The alkyl chain may have amino, mono- or dialkylamino, cyclic amino or acylamino as a substituent.

The mono- or dialkylamino alkyl is preferably a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms. Cyclic amino is a compound that forms a 5- to 6-membered ring with a nitrogen atom, such as 1-pyrrolidinyl, piperidino, morpholino, and 4-monosubstituted 1-piperazinyl. The acyl of an acylamino is an alkanol having 2 to 6 carbon atoms (eg, acetyl, propionyl, butyryl, bivaloyl, valeryl) or an optionally substituted benzoyl. (4) Substituents in mono-substituted 1-piperazinyl and benzoyl which may be substituted include about 1 to 3 halogens (same as described above), alkyl (1 to 6 carbon atoms, straight chain or unsubstituted). (Chain-like alkyl), alkoxy (C1-C6 straight-chain or branched-chain alkoxy), hydroxyl group, nitro, amino, haloalkyl (Chain of C1-C6 straight chain) Is haloalkyl which is a branched chain alkyl).

The cycloalkyl represented by R ^7, and preferably all SANYO number 3 to 1 0 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylene, etc. cyclohexyl and Adamanchiru.

The oxo and soalkyl represented by R ⁷ preferably have 2 to 4 carbon atoms, and include, for example, acetyl, propionyl, butyryl, 2-oxopropyl, 2-oxobutyl and 3-oxobutyl.

The alkenyl represented by R ⁷ means an optionally substituted alkenyl having 2 to 20 carbon atoms, and examples of the substituent include alkyl, phenyl and halogen having 1 to 22 carbon atoms . Specifically, bur, aryl, butenyl, 3-methyl-2-butenyl, 1-methyl-2-propenyl, hexenyl, decenyl, pentadecenyl, tridecenyl, pentadecenyl, heptadecenyl, heptadecadienyl, pentadecadienyl, nonadecenyl , Nonadecadienyl, nonadecatetraenyl, 2-phenylvinyl, 2-chlorovinyl and 2-odobul. The aralkyl represented by R ^T , R ⁸ , or R ⁸ means an aralkyl which may be substituted, and the substituent may be a halogen, an alkyl having 1 to 6 carbons, an alkyl having 1 to 6 carbons. Examples thereof include alkoxy, nitro, amino and hydroxyl groups. The alkyl moiety of aralkyl preferably has 1 to 3 carbon atoms. Specific examples include benzyl, 1-phenylethyl, methylbenzyl, fluorobenzyl, cyclobenzyl, methoxybenzyl, dimethoxybenzyl, nitrobenzyl, aminobenzyl, hydroxybenzyl, phenethyl, picolyl, and 3-indolylmethyl.

The Ariru represented by R ^7, means a good Ariru be substituted, halogen as the substituent, the number 1-2 2 alkyl carbons, number 1-6 alkoxy carbon atoms, a nitro, Shiano Alkanoyl having 2 to 10 carbons, alkamoyl, alkamoyl having 2 to 20 carbons, and alkylthio having 1 to 1 carbons are provided. Specifically, phenyl, tolyl, xylyl, mesityl, cumenyl, ethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, odophenyl, etc .: 2_ fluor, chlorophenyl, methoxyphenyl, dimethoxyphenyl, Dimethoxyphenyl, ethoxyphenyl, ethoxyphenyl, triethoxyphenyl, propoxyphenyl, methylenedioxyphenyl, methylthiophenyl, ditrophenyl, cyanophenyl, cetylphenyl, Examples include carbamoylphenyl, methoxycarbonylphenyl, naphthyl, biphenylyl, cetyl, methylthenyl, furyl, virolyl, methylpyrrolyl, imidazolyl, virazolyl, pyridyl, methylpyridyl and virazinyl.

The substituted amino represented by R ⁷ includes mono- or dialkylamino (same as described above), monophenylamino (the phenyl may be substituted), cyclic amino (same as described above), Means asilamino (as above).

Here, the substituents in phenyl include about 1 to 3 halogens (similar to those described above), alkyl (1 to 6 carbon atoms or straight-chain or branched alkyl), alkoxy (carbon atoms) 1-6 straight-chain or branched alkoxy), hydroxyl group, nitro, amino, haloalkyl (haloalkynole where alkyl part is straight-chain or branched-chain alkyl having 1-6 carbon atoms) can give. In the mono-, di- or triphosphates represented by R ³ and R ⁴ or ester residues thereof, the group forming the ester residue is a linear or branched alkyl having 1 to 22 carbon atoms, For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, bentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl , Penyu decyl, Hexadecyl, Hep decyl, Octadecyl, Nonadecyl, Icosyl, Docosyl.

The alkenyl represented by R ⁶ is preferably a straight-chain or branched-chain alkenyl having 2 to 6 carbon atoms, and examples thereof include butyl, aryl, 1-probenyl, 1-butenyl, and 2-butenyl.

Preferably a linear or branched technique chain Aruki sulfonyl number 2 to 6 carbon and alkynyl represented by R ^6, for example Echuru, 1 Burobiniru, propargyl, 1 one Petit sulfonyl, such as 2-heptynyl and the like.

As R ⁶ , loanorealkyl is preferably a haloalkyl wherein the alkyl portion is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, for example, chloromethyl, bromomethyl, fluoromethyl, jordomethyl, trifluoromethyl, Bromoethyl, trifluoroethyl, pennofluorethyl, trifluoropropyl (which may have an unsaturated bond in the alkyl chain) and the like.

In a preferred group of compounds of the present invention, at least one of the hydrogen atom of the amino group and the hydroxyl group of FM d C is substituted with a group that can be hydrolyzed in vivo, or the hydroxyl group, particularly the 5′-hydroxyl group is phosphoric acid. Or a compound substituted by its ester residue.

The compound (I) of the present invention may be in the form of a salt. Examples of such a salt include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid, or fumaric acid, tartaric acid, succinic acid, and citric acid. Acid addition salts with organic acids such as methanesulfonic acid, or when R ³ and Z or R ⁴ represent a phosphoric acid residue, metal water such as sodium hydroxide, hydroxylating water, or water oxidizing water. A metal salt with an oxide or an ammonium salt can be exemplified. These salts are preferably pharmaceutically acceptable salts. In addition, the present invention Compound or salt thereof may be hydrate or solvate

The compound (Γ) of the present invention has the general formula (Π)

R ¹

(Wherein, R ¹ , R ² , and R ⁶ have the same meanings as described above, and R ^1D and R ¹¹ each represent hydrogen, a group that can be hydrolyzed in a living body, or a hydroxy-protecting group, or R ¹² represents hydrogen, a group which can be hydrolyzed in vivo, or an amino protecting group, provided that R ¹⁰ , R ¹¹ , and R ¹² are simultaneously a protecting group or in vivo. (Which does not show a hydrolyzable group) and a compound represented by the general formula απ)

XCOR ⁷ (III)

(Wherein, X represents a leaving group, and R ⁷ has the same meaning as described above.) (Hereinafter sometimes referred to as compound (11 [)), or a compound represented by the general formula (IV):

YCOR ¹³ (IV)

Wherein, Y represents a halogen atom, R ¹³ represents the formula, (wherein and R ⁸ are as defined above) R ⁸ 0- or R ⁹ S- and. (Hereinafter sometimes referred to as compound (IV)), and if necessary, the protective group is removed.

Examples of the hydroxy-protecting group represented by R ¹⁰ and R ¹¹ include, for example, benzyl, methoxibenbuyl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tertiary butyldimethylsilyl, tertiary butyldiphenylsilyl, texyl Examples include dimethylsilyl, aryl, methoxymethyl, (2-methoxyethoxy) methyl and tetrahydroviranyl.

The cyclic hydroxy protecting group formed by R ¹⁰ and R ¹¹ together includes, for example, cyclic acetal, cyclic ketal, cyclic carbonate, cyclic orthoester, and cyclic 1,3- (1,1,3,3- (Tetraisopropyl) disiloxane dil derivatives.

The Amiso protecting group represented by R ^12, for example, base Njiruokishi force Ruponiru, phenoxyethanol carbonyl, 2, 2, 2-trichloro port ethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and triflumizole Ruo b acetyl and the like .

The groups capable of being hydrolyzed in vivo represented by R ¹⁰ , RH and R ¹² are the same as those described above.

Examples of the leaving group for X include halogen, acyloxy, acyloxycarboxylic acid, i.o., phthalimidoxy, 4-nitrophenyl, azide, and 2,4,6-triisopropylbenzenesulfonyl. , Jetiloxyfoxy phosphoryloxy and the like.

The term “acyl” in “acyloxy” or “acyloxycarbonyloxy” refers to a C 2 to C 2 ₍ alkanol having 22 carbon atoms or an optionally substituted benzoyl. As this substituent, about 1 to 3 halogens (described above) The same as above), alkyl (straight-chain or branched-chain alkyl having 1 to 6 carbon atoms), alkoxy (straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms), hydroxyl group, nitro, Amino, haloalkyl (haloalkyl wherein the alkyl portion is a linear or branched alkyl having 1 to 6 carbon atoms) and the like.

The halogen atom for Y represents chlorine, bromine or iodine.

Compound (II) can be produced by the method described in the aforementioned patent application or literature (J. Am. Chem. So, 1991, 113, 7439-7440) or a method analogous thereto.

Compound (III) used in the above reaction may be an acid halide, an acid anhydride, or a mixed acid. Hydrate [prepared by reacting R ⁷ CO OH (wherein ^RT is as defined above) with 2,4,6-triisopropylbenzenesulfonyl chloride or getylglophosphosphate] Ester (eg, N-hydroxysuccinimide ester, N-hydroxyphthalimid ester, 412-trophenyl ester, etc.), acyl azide or mixed carbonic anhydride.

The compound (IV) used in the above reaction is an alkyloxycarbonyl halide, an aralkyloxycarbonyl halide, a (alkylthio) carbonyl halide, or a (aralkylthio) carbonyl halide.

The reaction of compound (II) with compound (11 [) or (IV) is carried out in a solvent such as pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, methanol, ethanol, water, etc. Done. 2 or more

o

Mixtures of the following solvents can also be used.

The reaction is carried out with acid acceptors such as triethylamine, pyridine, picoline, dimethylaminopyridine, ル; „Ν„ Ν ^ U ルルルルルルルルルアルカリ炭酸炭酸ル. The reaction temperature of the reaction can vary within a relatively wide range, generally the reaction is between 0 and 120, preferably between 0 and 70. In carrying out the reaction, 1 mol, 2 mol, 3 mol or an excess mol of compound (III) or (IV) can be used per 1 mol of compound (II). The protecting group can be removed after the reaction by a method well known to those skilled in the art.

In the compound (I) of the present invention, a compound in which R ³ and Z or R ⁴ represents a phosphate residue is produced by subjecting a compound in which R ³ and / or is hydrogen to a phosphorylation reaction known per se. be able to. Further, the phosphoric acid ester can be produced by subjecting the thus obtained phosphoric acid to a known esterification reaction.

The compounds provided by the present invention prepared in the above steps can be separated and purified by conventional techniques such as evaporation, filtration, extraction, precipitation, chromatography, recrystallization and combinations thereof. When the compound (I) of the present invention or a salt thereof is used as a medicament, an effective amount of the compound (I) or a salt thereof is mixed with a pharmaceutically acceptable carrier, excipient, diluent, or the like, and a powder, granule or tablet is prepared. Dragees, capsules, syrups, suppositories, external preparations, injections, infusions, etc., but oral preparations are preferred. The dose may vary depending on the disease to be administered, the administration route, the dosage form, etc. In general, in the case of an oral preparation, the compound (I) or a salt thereof is 10 to 40 OmgZkg body weight per day, preferably 50 to 40 mg / kg. The weight is 20 OmgZkg, and the weight of an injection is 1 to 10 mgZkg per day, preferably 1 to 5 mgZkg. The frequency of administration can be appropriately selected within the range of 1 to 4 times a day.

The compound (I) of the present invention and a salt thereof show a remarkable and sustained growth inhibitory effect on various cultured tumor cell lines, furthermore, increase the bioavailability and reduce side effects such as gastrointestinal disorders, It is useful as an anticancer agent because of its low toxicity. It also has antiviral activity against simple herpes virus (HSV) and cytomegalovirus (CMV) and may be used in the treatment of viral infections. ―

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1

(1) (E) —2, -Doxy 2 ′ —fluoromethylidene cytidine 15 Omg was dissolved in pyridine 5 ml, tertiary butylbutyldimethylsilane 11 Omg was added, and the mixture was stirred at room temperature overnight. After the reaction, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent: 10% methanol / Z-form form mixed solvent) to give an amorphous (E) — 5 '— 0-tertiary butyldimethyl ester Silyl mono 2'-doxy 2 'monofluoromethylidene cytidine 239 mg was obtained.

] H-NMR (DMSO-de) 5ppm: 0.09 (6H, s, methyl X2), 0.89 (9H, s, t-butyl), 3.70-4.13 (3H, m. 4'.5 ', 5'-H ) .4.79 (1H, m. 3'-H), 5.66 (1H, d, J = 7.2Hz.5-H), 6.70 (1H, s, Γ-Η), 7.21 (2H, br.s, 4 -NH ₂ ), 7.54 (1H, d, J = 7.2Hz, 6-H)

) (E) -5′-O—tertiary butyldimethylsilyl-1 2 ′ —doxy 2 ′ — Fluoromethylidene cytidine (239 mg) was dissolved in pyridine (5 ml), 3, '4,5-trimethoxybenzoyl chloride (16 Offlg) was added, and the mixture was stirred at room temperature for 10 minutes. After the reaction, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (4% methanol-Z-form-form mixed solvent) to give (E) —5′—0—tertiary butyldimethylsilyl 2,2-dequin-1 '—Fluorometilidene N ⁴ — (3,4,5-trimethoxybenzoyl) cytidine 22 Omg was obtained.

^ -NMR (DMS0-de) 5 ppm: 0.17 (6H, s, methyl X2), H.98 (9H, s, t-butyl), 3.61-4.28 (13H, m, 3 ', 4', 5 ', 5 '-H, methoxy X3), 5.19 (1H, m, 2'-methylidene), 6.86 (1H, s, Γ-H), 7.10-7.66 (3H, m, 5-H, Ph-Hx2), 8.38 ( (IH, d, J = 9Hz, 6-H)

③ (E) —5 ′ — 0—Tertiary butyldimethylsilyl-1 2′-doxy-2,1-fluoromethylidene N ⁴ — (3,4,5-trimethoxybenzoyl) cytidine in tetrahydrofuran Then, a tetrahydrofuran solution of tetra-n-butylammonium fluoride was added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. After completion of the reaction, concentrating the reaction solution, the residue was recrystallized crystals obtained by silica gel column chromatography, (E) - 2 '- Dokishi 2, one full O Lome Chile den over N ⁴ one (3,4,5-trimethoxybenzoyl) Cytidine was obtained. 127-128. C ₀

MS (m / z): 451 (M +)

UV (in methanol): 305.8, 260.1 nm

¹ H—NMR (DMSO—d ₆ ) ppm: 3.73 (3H, s, p-methoxy), 3.87 (6H, s, m-methoxy), 3.50-4.03 (4H, 3'.4 ', 5', 5 '-H), 4.85 (IH, m, 2, -methylidene), 5.02 (IH, t, J = 5Hz, 5'-0H). 5.69 (IH, d, J = 6Hz, 3'-OH), 6.73 (IH, s, Γ-Η), 7.38 (3H, m, 5_H, Ph-Hx2), 8.15 (IH, d. J = 8Hz, 6-H)

Elemental analysis C _2. H _{22 3} F 0 ₃ · H ₂ O

Calculated (¼) C, 51.17; 5.15; N, 8.95 '

Analytical value (%) 50.98: H, 5.20; N, 8.90

Example 2 (E) 1 2'-Doxy 2'-Fluoromethylidene cytidine hydrochloride (58 mg) was dissolved in dimethylformamide (2 ml). The mixture was added dropwise and stirred at room temperature for 14 hours. After the reaction, the reaction solution was neutralized with 8 ml of a saturated aqueous solution of sodium bicarbonate, partitioned with a filter and dried. After distilling off the solvent, the resulting oil was purified by silica gel chromatography, eluting with methanol-chloroform (1:25 v / v). After distilling off the solvent, (E) —2′-doxy 2′—full Orometylidene 5′10-stearoylcytidine was obtained. With a melting point of 115-118.

1H-NMR (CDC 13.90MHz) 5ppm: 7.40 (1H, d, J-10.0Hz, 6-H), 6.95 (1H, s, Γ-Η), 5.79 (1H, d, J-lO.OHz, 5-H), 4.91 (1H, s, 2'-methylidene), 4.11-4.50 (4H, m, 3 '-H, 4'-H and 5'-H), 2.36 (2H, t, J = 10.7 Hz, -CH ₂ C00-), 1.26 (30H, .br.s, methylene), 0.87 (3H, t, J = 6.6Hz, methyl)

UVAmax (in methanol): 261.7, 305.2 nm

IR i? 40—c _m -two (5:-! ^ Tel part)

Example 3

(E) —2, -Doxy-1 2′—fluoromethylidene cytidine 5 Omg was dissolved in pyridin 3 ml, and anhydrous pric acid 76 mg was added; the mixture was stirred at 50 for 90 minutes. The residue obtained by distilling off the reaction solution was purified by silica gel column chromatography (silica gel 30 g, elution solvent: 5% methanol, mixed solvent of Z-cloth form), and (E) 1-2′-dexoxy 2′—Fluoromelidene-N ⁴ —decanoylcytidine 37 mg was obtained.

Elemental analysis C ₂₀ H ₃₀ N ₃ 0 ₅ F-0.25 H ₂ 0

Calculated (%) C, 57.75; H, 7.39; N, 10.10

Analytical value (%) C, 58.01; H, 7.29; N. 10.38

^J HNR (CDC 13) <ppm: 0.87 (3H, t, J = 6.8Hz), 1.25 (12H, s), 1.65 (2H, m), 2.44 (2H, t, J = 7.3Hz), 3.91 ( 1H, dd, J = 12.2, 2.9Hz, 5'-Ha), 4.00 (1H, dd, J = 12.2, 2.4Hz, 5'-Hb), 4.11 (1H, m, 4'-H), 5.24 ( 1H, m, 3 '-H): 6.77 (1H, s, l'-H). 6.90 (1H, d, J _H. _F = 79.6Hz. 2 "-H), 7.48 (1H, d, J = 7.8Hz, 5-H), 8.11 (IH, d, J = 7.8Hz.6-H), 9.28 (IH, br.s, NH) "

Example 4

(E) — 2 ′ —Doxy 2 ′ —Use 5 Omg of fluoromethylidene citidine and 9 mg of anhydrous phosphoric acid, according to the same procedure as in Example 3 to obtain (E) —2,2-doxy

»—2 ′ —Fluorometilidene N ⁴ —Lauroylcytidine 39 mg was obtained.

^-MR (CDC 13) 5ppm; 0-87 (3H, t, J = 6.8Hz), 1.25 (16H, s), 1.65 (2H, m), 2.44 (2 t, J = 7.3Hz), 3.91 ( IH, dd.J = 12.2, 2.9Hz, 5'-Ha), 4.02 (IH.dd, J = 12.2, 2.4Hz, 5'-Hb), 4.11 (IH, m, 4'-H), 5.24 ClH , m,

3 '-H) v 6.77 (IH, s, l'-H), 6.91 (1H, d, J _HF = 80.1Hz, 2 "-H), 7.49 (IH, d, J-7.3HZ, 5-H ), 8.11 ClH, d, J = 7.3Hz, 6-H), 9.34 (IH, br.s, NH)

Example 5

(E) — 2 ′ —Deokin-1 2 ′ —Fluoromethylidene citidine 60 Omg and myristic anhydride 1.24 g, and the same operation as in Example 3 was carried out to obtain (E) —2′-dexoxy-1 43 Omg of 2 ′ difluoromethylidene-N ⁴ —myristoylcytidine was obtained.

Elemental analysis C ₂₄ H ₃₈ N _S 0 ₅ F

Calculated () 61.65; H, 8.19; N, 8.99

Analytical value (%) C, 61.95; 8.34; N, 8.63

1111 丽 R (CDC 13> 5 pm: 0.87 C3H.t, J = 6.8Hz), 1.25 (20H, s),

1.65 (2H, m), 2.43 (2H, t, J = 7.3Hz), 3.92 (IH, dd, J = 12.2, 2.9Hz, 5'-Ha), 4.02 (IH, dd, J-12.2, 2.4Hz , 5 '-Hb), 4.11 (IE m, 4' -H), 5.24 (IH, m,

3'-H), 6.77 (lH _r s, l'-H), 6.92 (IH, d, J _H .F = 79.6HZ, 2 "-H), 7.49 (IH, d, J = 7.3Hz, 5 -H), 8.11 (IR, d, J = 7.3Hz, 6_H), 9.12 (1H, br.s, NH)

Example 6

(E) -2'-deoxy 2 '-Using 5 Omg of fluoromethylidene citidine and 116 mg of palmitic anhydride, the same operation as in Example 3 was carried out, and (E) -2: -deoxy 2'- Fluorometilidene N ⁴ —palmi toyl cytidine 4 Omg was obtained.

Elemental analysis C ₂₆ H ₄₂ N ₃ 0 ₅ F Calculated (%) C, 63.01; H, 8.54; N, 8.48

Analytical value (%) C, 63.18; H, 8.67; N, 8.45

^{J H-NMR (CDC 13)} 5ppm:.. 0.88 (3H, t, J = 6.8Hz) 1.26 (. 24H s) 1.67 (2H, m), 2.42 (2H, t, J = 7.3Hz), 3.93 ( 1H, dd, J-12.2, 2.9Hz, 5'-Ha), 4.02 (1H, dd, J-12.2, 2.4Hz, 5'-Hb), 4.11 (1H, m, 4'-H), 5.24 ( 1H, m, 3 '-H), 6.77 (1H, s, l'-H), 6.98 (1H, d, J _H. _F = 80. OHz. 2 "-H), 7.46 (1H, d, J = 7.3Hz, 5-H), 8.06 (1H, d, J = 7.3Hz, 6-H), 9.07 (1H, br.s, NH) Example 7

(E) — 2 ′ — Deoxy 2 ′ — Fluoromethylidene citidine 5 Oing and stearic anhydride 1 29 mg, and the same operation as in Example 3 was carried out to obtain (E) — 2 ′ — Deoxy 2 ′ - give stearoyl Cie cytidine 4 Omg - full O Lome Chile den over N ^4. 'Η— NMR (CDC 13) 5ppm: 0.88 (3H, t, J = 6.8Hz), 1.26 (28H, s), 1.67 (2H, m), 2.42 (2H, t, J = 7.3Hz), 3.93 ( 1H, dd, J = 12.2, 2.9Hz 5 '-Ha), 4.04 OH, dd, J-12.2, 2.4Hz, 5' ~ Hb), 4.11 (1H, m, 4 '-H), 5.24 (1H, m, 3 '-H). 6.77 (1H, s, l'-H). 6.97 (1H, d. J _H .F = 79.1HZ.-H), 7.46 (1H, d, J = 7.8Hz, 5 -H), 8.06 (1H, d, J = 7.8Hz, 6-H), 9.02 (1H, br.s, NH)

The following compounds are produced in the same manner as in the above Examples.

(8) (E) Single 2 '- Dokishi 2' - Full O Lome Chile den over ^{N 4 - (3, 4,} 5- trimethyl butoxy base Nzoiru) Single 5 '- 0-stearoyl cie cytidine

(9) ■ (E) — 2 ′ —Doxy 2 ′ —Fluoromethylidene N ⁴ — (3,5 dimethyl benzoyl) 1 5 ′ — 0—Stearyl cytidine

(10) (E) One 2 '—Doxy 2' —Fluorometilidene N ⁴ —Cinnamoylcytidine

(11) (E) — 2 '— deoxydi 2' — fluorometilidene N ⁴ — nicotinoylcytidine

(12) (E)-2'-Doxy 2 '—Fluorometilidene N ⁴ —Tenyl Cutidine

(13) (E) — 2 ′ —Doxy 2 ′ —Fluoromelidene N ⁴ —Floyl Cytidine:

(14) (E) -2 'Dokishi 2' - Full O Lome Chile den over N ⁴ - Shikuropu port Pirukarubo two Rushichijin

(15) (E) — 2, -Doxy 2 ′ — Fluoromethylidene N ⁴ — Phenyl P-Acetyl 5 ′ — 0— Stearoylcytidine

(16) (E) 1 2 '—Doxy 1 2' —Fluorometilidene N ⁴ —Cinnamylyl 5,1 0—Stearoylcidine

(17) (E) -2'-Doxy-2,1-fluoromethylidene N ⁴ —Nicotinoylu 5 ′ — 0—Stearoylcytidine

(18) (E) —— 2 ′ —Doxy 2 ′ —Fluorometilidene N ⁴ —Tenyl-5′-1 0—Stearoylcytidine

(19) (E) — 2 ′ —Doxy-1 2 ′ —Fluorometilidene N ⁴ —Floyl-5′-1 0—Stearylcytidine

(20) (E) .— 2 ′ —deoki, 2 ′ —fluorometylidene N ⁴ —phenyl Power rubamoylcytidine

(21) (E) — 2 ′ —Doxy-1 2 ′ —Fluorometilidene N ⁴ —Etilka rubamoylcytidine

(22) (E) — 2,1-Doxy-1 2 '—fluoromethylidene-N ⁴ —Dimethylaminoacetylcytidine

(23) (E) 1,2-doxy-2,1-fluoromethylidene N ⁴ —propionirlucidine

(24) (E) —2 ′ —Doxy-1 2 ′ —Fluoromethylidene 5,10-0 —Stearylyladenosine

(25) (E) — 2 ′ —Doxy 2 ′ —Fluoromethylidene N ⁴ — (3,4,5-trimethoxybenzoyl) adenosine

(26) (B) one 2 '- Dokishi 2, one full O Lome Chile den over ^{N 4 - (3, 4,} 5- trimethoxy base Nzoiru> guanosine

(27) (E) — 2 ′ —Doxy 2 ′ —Fluorometyldensitidine 1 5 ′ — phosphoric acid

(28) (E) -2'-Doxy 2'-fluoromethylidene cytidine-1 5'-diphosphoric acid or its sodium salt

(29) (E) I 2'-Doxy 2'-Fluoromethylidenicitidine 1 5'-Triphosphoric acid or its sodium salt

(30) (E) I 2'-Doxy 2'-Fluorometyldensitidine I 5'-Stearyl phosphate

(31) (E) — 2, -Doxy 2 ′ —Fluoromethylidene-5-Fluorocytidine-1 5 ′ —Phosphoric acid

(32) (E) -2'-Doxy 2'-fluoromethylidene-5-fluorocytidine-1 5'-stearyl phosphate

(33) (E) — 2, -Doxy 2 ′ —Fluoromelidene 1 5 ′ — 0—St. Roylu 5—Fluorocytidine

(34). (E122 2nd day 1 2'-Fluoromethylidene-N ⁴ — (3,45-trimethoxybenzoyl) 1-5-Fluorocytidine

(35) (E) — 2 ′ —Doxy 2 ′ —Fluoromelidene-1 N ⁴ —Decanoy-Lou 5—Fluorocytidine

(36) (E) — 2 '-Doxy 2, monofluoromethylidene N ⁴ —Lauroi Lou 5—Fluorocytidine

(37) (E) One 2 '-Doxy 2'-Fluoromelidene One N 'Listoyl 5-Fluorocytidine

(38) (E) — 2, -Doxy 2 ′ — Fluoromethylidene-N ⁴ — Palmitoyl 5 — Fluorocytidine

(39) (E) — 2 ′ —Doxy 2 ′ —Fluoromelidene N ⁴ —Stear mouth—5—Fluorosidine

Claims

The scope of the claims

1. General formula (I)

(In the formula, ^one of R ¹ and R ² is hydrogen, halogen, alkyl, cyano, optionally substituted ruboxil or optionally substituted rubamoyl, and the other is halogen, alkyl, R ³ and R ⁴ may be the same or different, and include hydrogen, a group capable of hydrolyzing in vivo, and mono- or mono-substituted carboxyl or optionally substituted carbamoyl. R ⁵ represents hydrogen or a group capable of hydrolyzing in vivo, R ⁶ represents hydrogen, halogen, alkyl, alkenyl, alkynyl or haloalkyl. ] 2'-methylidene nucleoside compound or a salt thereof.

2. The 2′-methylidene nucleoside compound or a salt thereof according to claim ¹ , wherein ^one of R ¹ and R ² is hydrogen or halogen and the other is halogen.

3. The 2 ′ methylidene nucleoside compound or a salt thereof according to claim 1, wherein S.R ⁵ is R ⁷ CO— (where ^RT represents alkyl having 1 to 21 carbon atoms).

4. The 2, -methylidene nucleoside compound or a salt thereof according to any one of claims 1 to 3, wherein R ⁵ is R ⁷ C 0 1 and R ⁷ is alkyl having 5 to 21 carbon atoms. .

5. R ⁵ is R ⁷ CO— and R ⁷ is alkyl having 9 to 17 carbon atoms The 2′-methylidene nucleoside compound or a salt thereof according to any one of claims 1 to 4.

6. (E) —2 ′ —Doxy 2 ′ —Fluorometylidene N ⁴ —Decanyl cytidine, (E) -2′-Doxy 2 ′ —Fluorometylidene N ⁴ —Rau mouth ylcytidine, (E ) — 2 ′ —Doxy 2 ′ —Fluorometylidene N ⁴ —Myristoyl cytidine, (E) — 2 ′ —Doxy 2 ′ —Fluorometylidene N ⁴ —palmi toyl cytidine and (E) — 2 '- Dokishi one 2' - Furuoromechiri Den N ⁴ - methylidene nucleoside compound or a salt thereof - 2 'according to claim 1, wherein is selected from stearoyl Cie cytidine.

7. General formula (II)

R

(Wherein, R ¹ , R ² , and R ⁶ have the same ^{meanings as} described above, and R ^lfl and R ¹¹ each represent hydrogen, a group that can be hydrolyzed in a living body, or a hydroxy protecting group, or together form a cyclic amino group. R ¹² represents hydrogen, a group that can be hydrolyzed in vivo, or an amino protecting group, provided that R ¹⁰ , R ¹¹ , and R ¹² are simultaneously a protecting group or a group that is hydrolyzed in vivo. And a compound represented by the general formula (III):

XCOR ⁷ (III)

(Wherein X represents a leaving group, R ⁷ represents a hydrogen atom, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl, aryl, amino or substituted amino), or a compound represented by the general formula Formula (IV) YCOR ¹³ (IV)

[In the formula, Y represents a halogen atom, R ¹³ represents a formula, R ⁸⁰ — or R ⁹ S- (wherein, R ⁸ and R ⁸ represent alkyl or aralkyl). The method for producing a 2′-methylidene nucleode compound or a salt thereof according to claim 1, wherein the compound is reacted with a compound represented by the formula (1), and if necessary, the protecting group is removed.

8. A pharmaceutical composition comprising the 2′-methylidene nucleoside compound according to claim 1, or a salt thereof, and a pharmaceutically acceptable additive.

9. A carcinostatic agent comprising the 2′-methylidene nucleoside compound or a salt thereof according to claim 1 and a Ji-acceptable additive.

10. An antiviral agent comprising the 2'-methylidene nucleoside compound or a salt thereof according to claim 1, and a pharmaceutically acceptable additive.

11. A method for treating cancer or tumor using the 2′-methylidene nucleoside compound or a salt thereof according to claim 1.

11. A method for treating a viral infectious disease using a neemylidene nucleoside compound or a salt thereof.

Amended claims

[September 20, 1993 (20.09.93) Accepted by the International Bureau; Claim 2 at the time of filing was withdrawn; Claims 1, 3-5 at the time of filing were amended; The range is unchanged. (2 pages)]

(After correction) General formula (I)

[In the formula, ^one of R ¹ and R ² represents hydrogen, the other represents halogen, R ³ , R ⁴ , and R ⁵ represent hydrogen or a group capable of being hydrolyzed in a living body, and R ⁶ represents hydrogen or halogen. However, at least one of R ³ , R ⁴ , and R ⁵ represents a group that can be hydrolyzed in living organisms. ] 2'-methylidene nucleoside compound or a salt thereof.

2 (deleted)

3. The 2′-methylidene nucleoside compound or its salt according to claim 1, wherein R ⁵ is R ⁷ CO— (where R ⁷ represents alkyl having 1 to 21 carbon atoms). .

4. (After correction) The 2′-methylidene nucleoside compound or a salt thereof according to claim 1 or 3, wherein R ⁵ is R ⁷ CO— and R ⁷ is alkyl having 5 to 21 carbon atoms.

5. (after correction) R ⁵ is R ⁷ CO— and R ⁷ is alkyl with 9 to 17 carbon atoms The 2′-methylidene nucleoside compound or a salt thereof according to any one of claims 1, 3, and 4, wherein

6. (B) 12-, 2-Doxy-2,1-fluoromethylidene N ⁴ —decanoyl cytidine, (E) — 2 ′ —Doxy-12′-fluoromethylidene N ⁴ —lauguchi ylcytidine, ( E) — 2 ′ —Doxy 2 ′ —Fluoromethylidene N ⁴ —Myristylcytidine, (E) — 2, -Deoxy 2 ′ —Fluoromethylidene N ⁴ —palmitoyl cytidine and (E) — 2 - Dokishi 2 methylidene nucleoside compound or a salt thereof - '- Furuoromechiri den - N ⁴ - 2 in the range 1 Symbol ft claims selected from stearoyl Cie cytidine'.

7. —General formula (II)

(In the formula, R ¹ , R ² , and R ⁶ have the same ^{meanings as} described above, and R ^ie and R ¹¹ each represent hydrogen, a group that can be hydrolyzed in a living organism, or a hydroxy protecting group, or are taken together to form a cyclic amino group. R ¹² represents hydrogen, a group hydrolyzable in a living body, or an amino protecting group, provided that R ^ie , R ¹¹ , and R ¹² simultaneously represent a protecting group or an in vivo group. Does not show a group that can be hydrolyzed by) 'and a compound of the general formula air)

XCOR ⁷ (III)

(In the formula, X represents a deprotecting group, and R ⁷ represents a hydrogen atom, aralkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl, aryl, amino or substituted amino.) Or General formula (IV)