HK1054751A

HK1054751A - Phosphonate nucleotide compound

Info

Publication number: HK1054751A
Application number: HK03107118.9A
Authority: HK
Inventors: Ubasawa Masaru; Sekiya Kouichi
Original assignee: 三菱制药株式会社
Priority date: 2000-02-29
Filing date: 2001-02-26
Publication date: 2003-12-12

Description

Phosphonate nucleotide compounds

Technical Field

The present invention relates to a novel phosphonate nucleotide compound. More particularly, it relates to novel phosphonate nucleotide compounds and salts thereof, and hydrates and solvates thereof, which have antiviral activity and are useful as pharmaceutical products.

Background

Infectious viral diseases are recognized as medically important problems, and for the purpose of treating such diseases, research and development of a drug having antiviral activity and no inhibitory activity against the proliferation of normal cell lines is being conducted. For example, phosphonate nucleotides, as selective antiviral agents, are currently being extensively studied, and specifically, 9- (2-phosphonomethoxy) ethyl adenine (PMEA), 9- (2-phosphonomethoxy) ethyl-2, 6-diaminopurine (PMDAP), and the like, have been reported to be effective against herpes simplex types 1 and 2 (HSV-1 and HSV-2), Human Immunodeficiency Virus (HIV), and human Hepatitis B Virus (HBV) (Trattda et al, Antimicrob. Agents Chemother., 35, 394 (1991); Votruba et al, mol. Pharmacol., 32, 524 (1987)).

However, these known phosphonate nucleotides may have safety problems to organisms such as toxicity and mutagenicity represented by inhibition of bone marrow cell growth (Antiviral Research, 16, 77 (1991)). These compounds are not orally absorbable (De Clercq et al, antimicrob. agents chemicother., 33, 185(1989)), and thus, in order to obtain the necessary blood concentration for their effects, the administration method must be limited to parenteral administration such as intravenous injection and intramuscular injection. The treatment by parenteral administration is difficult for patients who are not hospitalized, that is, there is no ideal treatment for AIDS and hepatitis B virus diseases which require long-term treatment.

On the other hand, the present inventors have found that a specific ester derivative of a phosphonate nucleotide exhibits high oral absorbability (EP 632048A), and further, that an antiviral agent free from toxicity such as bone marrow cell growth inhibition and mutagenicity can be obtained by introducing a base moiety into a specific structure, but it has not been put into practical use at present.

Disclosure of Invention

The present invention addresses the problem of providing an antiviral agent that is free from such toxicities as bone marrow cell growth inhibition and mutagenicity. Another object of the present invention is to provide an inexpensive antiviral agent with a few production steps.

The present inventors have made extensive studies to solve the above problems and as a result, have found that specific 2-amino-6-arylthiopurine phosphonates, which are not specifically disclosed in the above EP 632048 and EP 785208, have high antiviral activity and that these compounds are inexpensive, easy to synthesize, and excellent in safety compared with the compounds proposed in the past, and thus have completed the present invention.

Namely, the present invention provides a phosphonate nucleotide compound represented by the following general formula (I) or a salt thereof, or a hydrate or solvate thereof:

in the formula, R¹Represents a hydroxyl group; r²And R³Each independently represents a hydrogen atom or C₁-C₂₂An alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with 1 or more halogen atoms; r⁴Represents a hydrogen atom, C₁-C₄Alkyl radical, C₁-C₄Hydroxyalkyl, or C substituted by more than 1 halogen atom₁-C₄An alkyl group; x represents CH or a nitrogen atom.

According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising a substance selected from the above-mentioned compounds and salts thereof, and hydrates or solvates thereof, and a pharmaceutically acceptable additive for pharmaceutical preparations; an antiviral agent containing as an active ingredient a substance selected from the above-mentioned compounds and salts thereof, and hydrates or solvates thereof. Further, according to another embodiment of the present invention, provided is a use of a substance selected from the above-mentioned compound and a salt thereof, and a hydrate and a solvate thereof for producing the above-mentioned pharmaceutical composition; and a method for treating viral infections, which comprises administering an effective amount of a substance selected from the group consisting of the above-mentioned compounds and salts thereof, and hydrates or solvates thereof to mammals including humans.

Best mode for carrying out the invention

The present invention is explained in detail below

In the phosphonate nucleotide compounds of the above general formula (I), R is used as²And R³Is represented by C₁-C₂₂Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, a heneicosyl group.

As by R²And R³Examples of the acyloxymethyl group include an acetyloxymethyl group, a propionyloxymethyl group, a butyryloxymethyl group, an isobutyryloxymethyl group, a valeryloxymethyl group, an isovaleryloxymethyl group, and a pivaloyloxymethyl group.

As by R²And R³Examples of the acylthioethyl group include acetylthioethyl group, propionylthioethyl group, butyrylthioethyl group, isobutyrylthioethyl group, valerylthioethyl group, isovalerylthioethyl group and pivaloylthioethyl group.

In the presence of R²And R³In the ethyl group represented by 1 or more halogen atoms, the type of the halogen atom may be any 1 of a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples of the ethyl group substituted with 1 or more halogen atoms include a 1-fluoroethyl group, a 2-fluoroethyl group, a 1-chloroethyl group, a 2-bromoethyl group, a 2, 2-difluoroethyl group, a 2, 2-dichloroethyl group, a 2, 2-dibromoethyl group, a 2, 2, 2-trifluoroethyl group, a 2, 2, 2-trichloroethyl group, and a 2, 2, 2-tribromoethyl group. It is preferably substituted at the 2-position of the ethyl group, and the halogen atom is preferably a fluorine atom. R²And R³Of these, at least one is an ethyl group substituted with 1 or more halogen atoms, and particularly preferred is a 2, 2, 2-trifluoroethyl group.

As by R⁴Is represented by C₁-C₄Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butylButyl, t-butyl, and the like. As by R⁴Is represented by C₁-C₄Examples of the hydroxyalkyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl and 4-hydroxybutyl. As by R⁴C represented by 1 or more halogen atoms₁-C₄Examples of the alkyl group include those having a halogen atom such as a fluorine atom or a chlorine atom bonded to a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, etc. Specific examples thereof include fluoromethyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, chloroethyl group, fluoropropyl group, chloropropyl group, fluorobutyl group, chlorobutyl group and the like.

In the present invention, the 1 st condition of a preferred compound includes R²And R³Each independently is a hydrogen atom, C₁-C₂₂Or an ethyl group substituted with 1 or more halogen atoms. Further, the 2 nd condition of a preferred compound includes R²And R³Each independently is a hydrogen atom, C₁-C₂₂Or 2, 2, 2-trifluoroethyl, R⁴Is a hydrogen atom or a methyl group.

For example, the following compounds can be cited as specific preferable compounds satisfying these conditions:

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (3-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (2-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (4-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (3-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (2-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purinyl-methyl (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (3-hydroxyphenylthio) purinyl-methyl (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (2-hydroxyphenylthio) purinyl-methyl (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (4-hydroxyphenylthio) purinyl-methyl (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (3-hydroxyphenylthio) purinyl-methyl (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (2-hydroxyphenylthio) purinyl-methyl (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purine (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (3-hydroxyphenylthio) purine (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (2-hydroxyphenylthio) purine (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (4-hydroxyphenylthio) purine (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (3-hydroxyphenylthio) purine (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (2-hydroxyphenylthio) purine (2, 2, 2-trifluoroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (3-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (2-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (4-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (3-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (2-hydroxyphenylthio) purine.

In addition, the 3 rd condition of the preferred compound in the present invention includes R²And R³Is 2, 2, 2-trifluoroethyl, R⁴Is a hydrogen atom or a methyl group. As specific compounds satisfying this condition, the following compounds can be cited:

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (2-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester.

Further, the 4 th condition of a preferred compound is R²And R³Is 2, 2, 2-trifluoroethyl, R⁴Is a hydrogen atom. As specific preferable compounds satisfying this condition, the following compounds can be cited:

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (2-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester.

The phosphonate nucleotide compound of the present invention represented by the above general formula (I), when present as a salt, is included in the scope of the present invention regardless of which salt the compound forms. Examples of such a salt include pharmaceutically acceptable salts. For example, when an acidic group is present, salts that can be formed by the acidic group include metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, ammonium salts such as ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, and dicyclohexylammonium salt, and the like. In addition, when an amino group is present, examples of salts that can be formed include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, metaphosphate, and the like, organic acid salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, whale, lactic acid, beryl acid, gimatic acid, stearic acid, oleic acid, lactobionic acid, erythromycin succinic acid, hemisuccinic acid, butyric acid, palmitic acid, carminic acid, gluconic acid, lauric acid, salicylic acid, ラオクル acid, tannic acid, butylsulfonate, and the like.

The phosphonate nucleotide compound and the salt thereof of the present invention represented by the above general formula (I) may exist in the form of a hydrate or a solvate. Any hydrate or solvate formed by the phosphonate nucleotide compound of the invention represented by the above general formula (I) or a salt thereof, containing the above specifically preferred compound, either one is included in the scope of the present invention. Examples of the solvent that can form a solvate include methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, and diisopropyl ether.

The following table shows specific examples of the compound of the present invention (in the table, Me represents a methyl group, Et represents an ethyl group, i-Pr-represents an isopropyl group, and t-Bu represents a tert-butyl group).

TABLE 1 number R¹ R² R³ R⁴ X1 2-OH CF₃CH₂- CF3CH₂- H CH2 3-OH CF₃CH₂- CF3CH₂- H CH3 4-OH CF₃CH₂- CF3CH₂- H CH4 2-OH CF₃CH₂- CF3CH₂- H N5 3-OH CF₃CH₂- CF3CH₂- H N6 4-OH CF₃CH₂- CF3CH₂- H N7 2-OH CF₃CH₂- Me- H CH8 3-OH CF₃CH₂- Me- H CH9 4-OH CF₃CH₂- Me- H CH10 2-OH CF₃CH₂- Me- H N11 3-OH CF₃CH₂- Me- H N12 4-OH CF₃CH₂- Me- H N13 2-OH CF₃CH₂- Et- H CH14 3-OH CF₃CH₂- Et- H CH15 4-OH CF₃CH₂- Et- H CH16 2-OH CF₃CH₂- H H CH17 3-OH CF₃CH₂- H H CH18 4-OH CF₃CH₂- H H CH19 2-OH CF₃CH₂- H H N20 3-OH CF₃CH₂- H H N21 4-OH CF₃CH₂- H H N22 2-OH H H H CH23 3-OH H H H CH24 4-OH H H H CH25 2-OH H H H N26 3-OH H H H N27 4-OH H H H N28 2-OH CF₃CH₂- CF₃CH₂- Me- CH29 3-OH CF₃CH₂- CF₃CH₂- Me- CH30 4-OH CF₃CH₂- CF₃CH₂- Me- CH31 2-OH CF₃CH₂- CF₃CH₂- Me- N32 3-OH CF₃CH₂- CF₃CH₂- Me- N33 4-OH CF₃CH₂- CF₃CH₂- Me- N34 2-OH CF₃CH₂- Me- Me- CH35 3-OH CF₃CH₂- Me- Me- CH36 4-OH CF₃CH₂- Me- Me- CH37 2-OH CF₃CH₂- Me- Me- N38 3-OH CF₃CH₂- Me- Me- N39 4-OH CF₃CH₂- Me- Me- N40 2-OH CF₃CH₂- Et- Me- CH41 3-OH CF₃CH₂- Et- Me- CH42 4-OH CF₃CH₂- Et- Me- CH43 2-OH CF₃CH₂- Et- Me- N44 3-OH CF₃CH₂- Et- Me- N45 4-OH CF₃CH₂- Et- Me- N46 2-OH CF₃CH₂- H Me- CH47 3-OH CF₃CH₂- H Me- CH48 4-OH CF₃CH₂- H Me- CH49 2-OH CF₃CH₂- H Me- N50 3-OH CF₃CH₂- H Me- N51 4-OH CF₃CH₂- H Me- N52 2-OH H H Me- CH53 3-OH H H Me- CH54 4-OH H H Me- CH55 2-OH H H Me- N56 3-OH H H Me- N57 4-OH H H Me- N58 2-OH -CH₂O-CO-t-Bu -CH₂O-CO-t-Bu H CH59 3-OH -CH₂O-CO-t-Bu -CH₂O-CO-t-Bu H CH60 4-OH -CH₂O-CO-t-Bu -CH₂O-CO-t-Bu H CH61 2-OH -CH₂O-CO-t-Bu -CH₂O-CO-t-Bu Me- CH62 3-OH -CH₂O-CO-t-Bu -CH₂O-CO-t-Bu Me- CH63 4-OH -CH₂O-CO-t-Bu -CH₂O-CO-t-Bu Me- CH64 2-OH -CH₂CH₂S-CO-i-Pr -CH₂CH₂S-CO-i-Pr H CH65 3-OH -CH₂CH₂S-CO-i-Pr -CH₂CH₂S-CO-i-Pr H CH66 4-OH -CH₂CH₂S-CO-i-Pr -CH₂CH₂S-CO-i-Pr H CH67 2-OH -CH₂CH₂S-CO-i-Pr -CH₂CH₂S-CO-i-Pr Me- CH68 3-OH -CH₂CH₂S-CO-i-Pr -CH₂CH₂S-CO-i-Pr Me- CH69 4-OH -CH₂CH₂S-CO-i-Pr -CH₂CH₂S-CO-i-Pr Me- CH

As a process for producing the compound of the present invention, R in the compound of the general formula (I)²And R³Is also C₁-C₂₂Alkyl group of (2) or ethyl group substituted with 1 or more halogen atomsThe compound (4) can be synthesized, for example, according to the following reaction scheme (1) or (2) (in the following reaction scheme, R¹、R⁴And X is as defined, R⁵Is represented by C₁-C₂₂Or an ethyl group substituted with 1 or more halogen atoms. W represents a leaving group such as a halogen atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc.).

First, the compound of the above formula (II) is reacted with the compound of the above formula (III) at a temperature of 10 to 250 ℃, preferably 130 to 200 ℃, for 0.1 to 100 hours, preferably 3 to 24 hours. The compound of the general formula (IV) obtained by the above reaction is separated and purified by a common separation and purification means such as distillation, adsorption, and partition chromatography, if necessary. The compound of the general formula (IV) may be isolated and purified as described above, but may be supplied to the next reaction without purification. Then, the compound represented by the above general formula (IV) is reacted with the compound represented by the above general formula (V) in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, triethylamine, diazabicycloundecene or the like in an appropriate solvent such as acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylpyrrolidone or the like at a temperature of 10 to 200 ℃, preferably 50 to 150 ℃, for 0.1 to 100 hours, preferably 1 to 10 hours, to obtain the compound represented by the above general formula (I').

The source of the starting materials of the reaction scheme (1), that is, the compound of the above general formula (II), the compound of the above general formula (III) and the compound of the above general formula (V) is not particularly limited, and for example, commercially available reagents or reagents appropriately synthesized by known methods can be used. For example, the compound of the general formula (V) can be synthesized by heating a compound of the general formula (VI) and a compound of the formula (VIII) described later in an appropriate solvent such as acetonitrile or dimethyl sulfoxide at 50 to 100 ℃.

The compounds of the above general formula (ICan be produced by the following method (in the following reaction scheme, R¹、R⁴、R⁵X and W are defined).

The compound of the general formula (VII) can be obtained by reacting the compound of the general formula (IV) obtained in the reaction scheme (1) with the compound of the general formula (VI) in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, triethylamine, diazabicycloundecene or the like in an appropriate solvent such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone or the like at a temperature of 10 to 200 ℃, preferably 50 to 150 ℃ for 0.1 to 100 hours, preferably 0.5 to 10 hours. Then, the compound of the general formula (VII) is reacted with a thiol represented by the general formula (VIII) or a salt thereof, for example, a sodium salt, a potassium salt, a lithium salt, a triethylamine salt or the like, in an appropriate solvent such as acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylpyrrolidone or the like, in the presence of an appropriate tertiary amine, at a temperature of 10 to 200 ℃, preferably 70 to 120 ℃, for 0.1 to 100 hours, preferably 0.5 to 12 hours, to obtain a compound of the general formula (I'). The compounds of the formula (I') correspond to R in the formula (I)²And R³At the same time is C₁-C₂₂Alkyl groups or ethyl compounds substituted with 1 or more halogen atoms. The starting materials of the reaction scheme (2), i.e., the source of the compound of the above general formula (VI), is not particularly limited, and for example, commercially available reagents may be used, or reagents appropriately synthesized by known methods may be used.

By further modifying the phosphate moiety of the above compound of formula (I '), R of the compound of formula (I') can be obtained⁵Compounds of formula (I) which are converted to other substituents. For example, R in the formula (I)²And R³The compounds which are also hydrogen atoms can be obtained by hydrolyzing the compounds of the above general formula (I'). In the general formula (1), R³Is a hydrogen atom, C₁-C₂₂Alkyl, thioethyl, or ethyl substituted with 1 or more halogen atoms, R²Is C₁-C₂₂The alkyl group or the ethyl group substituted with 1 or more halogen atoms of (a) can be prepared by reacting a compound of the above general formula (I') with a compound of the general formula (IX): r⁶OH(R⁶Represents a hydrogen atom, C₁-C₂₂Alkyl group, thioethyl group, or ethyl group substituted with 1 or more halogen atoms) in the absence of a solvent or in a suitable solvent, for example, a chlorine-containing solvent such as methylene chloride, or a solvent such as pyridine, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or methylpyrrolidone, optionally in the presence of an acid or a base, at a temperature of 10 to 100 ℃, preferably 20 to 30 ℃ for 0.1 to 100 hours. Preferably 5 to 12 hours.

(in the above reaction scheme, R¹、R⁴、R⁵、R⁶And X is as defined)

In the general formula (I), R²And R³Each independently is a hydrogen atom, C₁-C₂₂The alkyl group, thioethyl group or ethyl group substituted with 1 or more halogen atoms can be obtained by the following method (in the following reaction scheme, R is¹、R⁴And X is as defined, R⁷And R⁸Each independently is a hydrogen atom, C₁-C₂₂An alkyl group, an acylthioethyl group, or an ethyl group substituted with 1 or more halogen atoms. However, R⁷And R⁸Cannot be simultaneously hydrogen atoms. )

First, the compound of the above (I') is reacted with trimethylsilyldiethylamine in a suitable solvent, for example, a chlorine-containing solvent such as dichloromethane, dichloroethane, chloroform, etc., at about room temperature for about 1 hour. In this case, 2mol or more of trimethylsilyl diethylamine is used with respect to 1mol of the compound of the above general formula (I'). Subsequently, the reaction solution is concentrated to dryness, and the residue is dissolved in an appropriate solvent, for example, a chlorine-containing solvent such as methylene chloride, 2mol or more of oxalyl chloride is added to 1mol of the compound of the general formula (I ″), and the mixture is reacted in the presence of a catalytic amount of dimethylformamide for 1 hour under ice-cooling and then at about room temperature for 1 hour.

The compound of the formula (X) obtained by distilling off the solvent is reacted with the compound of the formula (XI) and/or the compound of the formula (XII) in an appropriate solvent, for example, a chlorine-containing solvent such as methylene chloride, or a solvent such as pyridine, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or methylpyrrolidone, at a temperature of 10 to 100 ℃, preferably 20 to 30 ℃ for 0.1 to 100 hours, preferably 5 to 12 hours, usually without purification. The compound of formula (XIII) obtained corresponds to the compound of formula (I) in which R is²And R³Each independently is a hydrogen atom, C₁-C₂₂A compound of an alkyl group, an acylthioethyl group, or an ethyl group substituted with 1 or more halogen atoms (provided that R is²And R³Not both hydrogen atoms). The compound of the formula (I ') as the starting material for the reaction may be obtained by hydrolyzing a compound of the formula (I ') wherein R is represented by the formula (I ') as described above⁵Is C₁-C₂₂The alkyl compound of (2) can react with triiodosilane and trimethylbromosilane to obtain better effect.

In the general formula (I), R²And R³Compounds which are both acyloxymethyl groups, or compounds in which one is an acyloxymethyl group and the other is hydrogen, can be prepared by the following process: reacting a compound of the above general formula (I') with the following general formula (XIV): r⁹Y(R⁹An acyloxymethyl halide represented by an acyloxymethyl group, Y represents a chlorine atom, a bromine atom or an iodine atom), in the presence of a base, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, triethylamine, pyridine, diazabicycloundecene, N' -dicyclohexyl-4-morpholine カルポキサミジン, or the like, in acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone, or the likeIn a suitable solvent such as an alkanone at a temperature of 0 to 200 deg.C, preferably 10 to 100 deg.C for 1 to 300 hours, preferably 10 to 200 hours. At R²And R³When both are acyloxymethyl compounds, it is preferred to react the compound of the formula (I') with 2 times the molar amount of the compound of the formula (XIV), and when one is an acyloxymethyl compound, it is preferred to carry out the reaction in equimolar amounts.

Furthermore, R²And R³One is acyloxymethyl and the other is C₁-C₂₂The compound of (1) an alkyl group, an acylthioethyl group or an ethyl group substituted with 1 or more halogen atoms can be produced by the following method: first of all, preparation of R²And R³One of them is C₁-C₂₂Or an ethyl group substituted with 1 or more halogen atoms, the other being a hydrogen atom, and then reacting the compound with a compound of the general formula (XIV) according to the above-mentioned method.

Considering the thiophenol derivative (compound of the general formula (VIII)) used in the above production method, the alkoxy-substituted thiophenol derivative exemplified in EP 632048 is synthesized from a commercially available hydroxy-substituted thiophenol through several steps (3 steps), which increases the number of production steps and greatly affects the cost of the original synthesis. In contrast, in the synthesis of the compound of the present invention, commercially available hydroxy-substituted thiophenols can be supplied as they are to the following production steps. That is, the compound described in EP 632048 requires 3 more production steps than the compound of the present invention. The increase in the number of manufacturing steps has a significant impact on the cost of the synthesis of the starting material. Therefore, the present invention can provide inexpensive drugs by greatly reducing the cost of synthesis of the starting material.

The salt of the compound represented by the general formula (I) can be synthesized, for example, by the following method. Namely, the compound of the formula (I ') can be synthesized by reacting the compound of the formula (I') with the corresponding acid in an appropriate solvent such as ethyl acetate, isopropyl alcohol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methylpyrrolidone or the like at a temperature of-10 to 100 ℃, preferably 10 to 50 ℃ for 0.1 to 20 hours, preferably 0.3 to 1 hour, with stirring.

The above-mentioned production method is only one example of a method for producing the compound of the general formula (I) of the present invention. The method for producing the compound of the present invention is not limited to these methods. In the examples of the present specification, since the production method of the compound of the present invention is more specifically described, the compound included in the above general formula (I) can be produced by those skilled in the art by appropriately modifying the above general description and the specific description of the examples as necessary. The compound of the general formula (1) or a salt thereof produced by the above method can be purified or separated by appropriately selecting a purification and separation method of a nucleotide, for example, recrystallization, adsorption, ion exchange, chromatography, or the like, as necessary.

The compound of the present invention is useful as an active ingredient of a pharmaceutical product, and more specifically, as an active ingredient of an antiviral agent shown in test examples described below. In addition, as seen in other ionic phosphonate nucleotide analogs, it is desirable to have anti-tumor activity. The target virus to which the medicament of the present invention is applied is not particularly limited, but specifically, RNA viruses such as human immunodeficiency virus, influenza virus and hepatitis C virus, and DNA viruses such as herpes simplex virus I, herpes simplex virus II, cytomegalovirus, varicella zoster virus and hepatitis B virus, and more preferably, hepatitis B virus.

When the compound of the present invention is used as a medicament, it may be administered alone, but it is preferable to administer the compound as a pharmaceutical composition in which pharmaceutically acceptable additives for pharmaceutical preparations are used and the compound is used as an active ingredient. The composition of the pharmaceutical composition may be determined according to the solubility, chemical properties, route of administration, administration schedule, etc. of the compound. For example, it can be made into granule, fine granule, powder, tablet, hard syrup, soft capsule, sugar tablet, syrup, emulsion, soft gelatin capsule, gel, paste, suspension, and ribose microparticles for oral administration. Alternatively, the injection may be administered by intravenous injection, intramuscular injection, or subcutaneous injection. Alternatively, the powder for injection may be prepared and used.

As pharmaceutically acceptable additives for pharmaceutical preparations, organic or inorganic solid or liquid carriers suitable for oral, enteral, parenteral or topical administration can be used. Examples of the solid carrier used for producing a solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, agar, pectin, stearic acid, magnesium stearate, lecithin, and sodium chloride. Examples of the liquid carrier used in the production of an oral liquid preparation include glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, physiological saline, and water. The above pharmaceutical composition may contain, in addition to the above carrier, adjuvants such as wetting agents, suspension aids, flavoring agents, aromatics, coloring agents, preservatives and the like. Liquid formulations may be presented for use in capsules of ingestible substances such as gelatin. Examples of the solvent or suspension for the production of a preparation for parenteral administration, i.e., an injection and the like, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like.

The compounds of the present invention, particularly the ester derivatives represented by the above general formula (I'), have high oral absorbability, which can be easily inferred from the properties of known compounds, and thus oral administration is the best administration route of the drugs of the present invention. The preparation of each of the above-mentioned preparations can be carried out by a conventional method. The clinical dose of the drug of the present invention is usually 0.1 to 500mg/kg, preferably 1 to 50mg/kg per day as the weight of the compound of the present invention when orally administered. However, the dose can be increased or decreased as appropriate depending on age, condition, symptom, simultaneous administration, and the like. The above daily dose is preferably administered once daily, or at appropriate intervals, in 2 to several times daily, or may be administered intermittently every several days. When used as an injection, the weight of the compound of the present invention is 0.01 to 50mg/kg, preferably 0.1 to 5mg/kg per day for an adult.

Examples

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the following examples. It is to be noted that the compound numbers in the examples correspond to the compound numbers in Table 1.

Example 1

Preparation of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester (Compound No. 3)

87g (670mmol) of 2-chloroethyl chloromethyl ether was reacted with 200g (610mmol) of tris (2, 2, 2-trifluoroethyl) phosphite at 160 ℃ for 7 hours to give quantitative 2- [ bis (2, 2, 2-trifluoroethyl) phosphonomethoxy ] ethyl chloride.

206g of 2- (phosphonomethoxy) ethyl chloro bis (2, 2, 2-trifluoroethyl) ester were dissolved in 2000ml of methyl ethyl ketone and refluxed together with 270g of sodium iodide for 8 hours. After the reaction, the reaction mixture was cooled to room temperature and then concentrated to dryness. The residue was dissolved in chloroform/hexane and then adsorbed on a silica gel column, eluting with chloroform/hexane to give quantitative 2- (phosphonomethoxy) ethyl iodobis (2, 2, 2-trifluoroethyl) ester.

15.0g (88mmol) of 2-amino-6-chloropurine are suspended in 360ml of dimethylformamide and the suspension is reacted with 13.9ml (93mmol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene at 80 ℃ for 1 hour. Then, 23.8ml of 2- (phosphonomethoxy) ethyl iodobis (2, 2, 2-trifluoroethyl) ester was added to the above reaction mixture, and reacted at 100 ℃ for 5 hours. After the reaction, the reaction mixture was cooled to room temperature and then concentrated to dryness. The residue was dissolved in chloroform and then adsorbed on a silica gel column, followed by elution with 5% methanol-chloroform to give 23.3g (yield: 56%) of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6-chloropurine bis (2, 2, 2-trifluoroethyl) ester.

To a solution of 2g of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6-chloropurine bis (2, 2, 2-trifluoroethyl) ester in dimethylformamide (10ml) were added 0.8ml of pyridine and 0.64g of 4-hydroxythiophenol, followed by stirring at 100 ℃ for 2 hours. The reaction mixture was cooled to room temperature and then concentrated to dryness. The residue was dissolved in chloroform and then adsorbed on a silica gel column, followed by elution with 5% to 20% methanol-chloroform to give 1.3g (yield 55%) of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester.

¹H-NMR(DMSO-d6，δ)：3.85-3.88(m，2H)、4.14(d，J＝8.1Hz，2H)、4.19-4.22(m，2H)、4.62-4.71(m，4H)、6.27(s，2H)、6.84(d，J＝8.7Hz，2H)7.7(d，J＝8.7Hz，2H)、7.89(s，1H)、9.85(s，1H)

Example 2

Preparation of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purinyl-methyl (2, 2, 2-trifluoroethyl) ester (Compound No. 9)

100mg of 2-amino-9- [ 2- [ bis (2, 2, 2-trifluoroethoxy) phosphonomethoxy ] ethyl ] -6- (4-hydroxyphenylthio) purine (Compound No. 3) was dissolved in 0.35N methanolic ammonia, and after leaving at room temperature for 40 minutes, the solvent was distilled off to obtain the objective compound.

¹H-NMR(DMSO-d6，δ)：3.66(d，J＝4.5Hz，3H)、3.83-3.87(m，2H)、4.00(d，J＝8.1Hz，2H)、4.18-4.22(m，2H)、4.52-4.60(m，2H)、6.23(s，2H)、6.83(d，J＝8.4Hz，2H)、7.37(d，J＝8.4Hz，2H)、7.89(s，1H)、9.81(s，1H)

Example 3

Preparation of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purine (2, 2, 2-trifluoroethyl) ester (Compound No. 18)

60mg of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purin-bis (2, 2, 2-trifluoroethyl) ester (Compound No. 3) was dissolved in 1N aqueous ammonia solution, and after standing at room temperature for 3 hours, the solvent was distilled off to obtain the objective compound.

¹H-NMR(DMSO-d6，δ)：3.51-3.54(m，2H)、3.74-3.77(m，2H)、4.03-4.12(m，2H)、4.14-4.16(m，2H)、6.20(s，2H)、6.82(d，J＝8.4Hz，2H)、7.12(b，3H)、7.36(d，J＝8.4Hz，2H)、8.00(s，1H)、9.81(s，1H)

Example 4

Preparation of 2-amino-8-aza-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purine (Compound No. 27)

The same procedures used in example 1 were repeated except for using triisopropyl phosphite instead of tris (2, 2, 2-trifluoroethyl) phosphite used in example 1 to give 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6-chloropurine diisopropyl ester.

To an acetonitrile (37ml) solution of 3.7g of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6-chloropurine diisopropyl ester was added 4.1ml of trimethylbromosilane, and after stirring at 25 ℃ for 16 hours, the solvent was evaporated under reduced pressure, and the residue was crystallized from 45ml of acetone and 15ml of water to give 2.4g of 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6-chloropurine. To a DMF (5ml) solution of 308mg of the resulting compound were added 304mg of 4-hydroxythiophenol and 0.32ml of pyridine, followed by heating at 100 ℃ for 4 hours. The solvent was distilled off, and the desired compound was isolated by high pressure liquid chromatography.

¹H-NMR(DMSO-d₆，δ)：3.57-3.60(m，2H)、3.81-3.84(m，2H)、6.83(d，J＝8.7Hz，2H)、7.38(d，J＝8.7Hz，2H)、7.96(s，1H)

Test example 1

Inhibitory effect on Hepatitis B Virus (HBV) proliferation

The inhibitory effect on HBV proliferation of the compounds of the present invention was determined according to a known method (K.UEDA, et al, VIROLOGY, 169, 213-216 (1989)). 2 x 10 to⁴HB611 cells (HBV-producing group replaced human hepatoma cells) contained 10%. Bovine fetal serum, streptomycin (100. mu.g/ml), penicillin (100IU/ml) and ジェネテイシン (trade name, anti-DNA manufactured by ライフテクノロジ - ズ Co., Ltd.)Biotin) (0.2mg/ml) was cultured at 37 ℃ in ダルベツコ ME medium. After exchanging the medium on days 2 and 5, the test compound was replaced in the medium containing the final concentration of 0.005 to 100. mu.M on days 8, 11 and 14, and after 17 days of culture, the DNA of the cells was recovered. The amount of HBV-DNA in and out of the cells was measured by サザンブロシト to determine the 50% inhibitory concentration of HBV-DNA synthesis in the cells. In addition, the concentration of the compound required to kill 50% of HB611 cells was determined. The results are shown in Table 2. The compound numbers in the table correspond to the compound numbers in table 1.

For reference, the evaluation results of the compound disclosed in EP 785208 publication are also listed in table 2. That is, Table 2 shows that the compound No. 3 of the present application shows the same activity as the compounds of reference examples 1 to 3 having a similar structure (bis (2, 2, 2-trifluoroethyl) ester) described in EP 785208. TABLE 2 test Compound HBV-DNA 50% on HB611 cells

Cytotoxic concentration of 50% Synthesis inhibition

(. mu.M) No. 3 No. 0.05 > 1,000 reference example 1 (R of A)¹2-OMe) 0.08 > 1,000 reference example 2 (R of A)¹3-OMe) 0.04 > 1,000 reference example 3 (R of A)¹＝4-OMe) 0.05 ＞1,000

Reference example Compound

Possibility of industrial utilization

The phosphonate nucleotide compound has excellent antiviral activity, high oral absorbability and high safety to organisms. In addition, it has the advantage of short manufacturing steps and can be manufactured inexpensively compared to similar compounds of the prior art. Therefore, it is considered that an inexpensive antiviral agent having few production steps and free from toxicity such as bone marrow cell growth inhibition and mutagenicity can be provided.

It is noted that the present application claims priority from Japanese patent application No. 2000-54675.

Claims

1. A phosphonate nucleotide compound represented by the following general formula (I) or a salt thereof, or a hydrate or solvate of the compound

In the formula, R¹Represents a hydroxyl group; r²And R³Each independently represents a hydrogen atom or C₁-C₂₂An alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with 1 or more halogen atoms; r⁴Represents a hydrogen atom, C₁-C₄Alkyl radical, C₁-C₄Hydroxyalkyl, orC substituted by 1 or more halogen atoms₁-C₄An alkyl group; x represents CH or a nitrogen atom.

2. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate of either or both, according to claim 1, wherein R is²And R³Each independently is a hydrogen atom, C₁-C₂₂An alkyl group, or an ethyl group substituted with 1 or more halogen atoms.

3. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate of either or both, according to claim 1, wherein R is²And R³Each independently is a hydrogen atom, C₁-C₂₂Alkyl, or 2, 2, 2-trifluoroethyl; r⁴Is a hydrogen atom or a methyl group.

4. The phosphonate nucleotide compound or salt thereof, or a hydrate or solvate thereof according to claim 3, which is selected from the group consisting of:

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purinyl methyl (2, 2, 2-trichloroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (4-hydroxyphenylthio) purinyl methyl (2, 2, 2-trichloroethyl) ester;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (3-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (2-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (4-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (3-hydroxyphenylthio) purine;

2-amino-9- [ 2- (phosphonomethoxy) propyl ] -6- (2-hydroxyphenylthio) purine.

5. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate of either or both, according to claim 1, wherein R is²And R³Is 2, 2, 2-trifluoroethyl; r⁴Is a hydrogen atom or a methyl group.

6. The phosphonate nucleotide compound or salt thereof, or a hydrate or solvate thereof according to claim 5, which is selected from the group consisting of:

7. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate of either or both, according to claim 1, wherein R is²And R³Is 2, 2, 2-trifluoroethyl; r⁴Is a hydrogen atom.

8. The phosphonate nucleotide compound according to claim 7, wherein the phosphonate nucleotide compound is 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (2-hydroxyphenylthio) purine bis (2, 2, 2-trifluoroethyl) ester, a salt thereof, or a hydrate or solvate thereof.

9. The phosphonate nucleotide compound according to claim 7, wherein the phosphonate nucleotide compound is 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (3-hydroxyphenylthio) purine bis (2, 2, 2-trifluoroethyl) ester, a salt thereof, or a hydrate or solvate thereof.

10. The phosphonate nucleotide compound according to claim 7, wherein the phosphonate nucleotide compound is 2-amino-9- [ 2- (phosphonomethoxy) ethyl ] -6- (4-hydroxyphenylthio) purine bis (2, 2, 2-trifluoroethyl) ester, a salt thereof, or a hydrate or solvate thereof.

11. A pharmaceutical composition comprising a compound selected from the compounds and salts thereof recited in any one of claims 1 to 10, and hydrates and solvates thereof, and a pharmaceutically acceptable formulation additive.

12. An antiviral agent comprising as an active ingredient a compound selected from the group consisting of the compounds and salts thereof, and hydrates and solvates thereof as claimed in any one of claims 1 to 10.

13. The antiviral agent according to claim 12, wherein said virus is hepatitis b virus.