JPH03161487A - New cyclopentane derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (B is purine base residue having substitution valence at the 9-position; R<1> and R<2> are OH which may be protected or phosphorylated). EXAMPLE:N<2>-(p-Methoxyphenyldiphenylmethyl)-9-[(1R,3R,4R)-3-acetoxy-4 -[(p- methoxyphenyldiphenylmethoxy)methyl]cyclopentyl]guanine. USE:An antiviral agent. PREPARATION:A compound {e.g. N<2>-(p-methoxyphenyldiphenylmethyl)-9-[(1R,3S,4 R)-3-(methanesulfonyloxy)-4-[(pmethoxyphenyldiphenylmethoxy) methyl]cyclopentyl]guanine} shown by formula II [X is organic residue; R<3> is (protected) OH] is reacted with a carboxylate, acyloxylated and hydrolyzed to give a compound shown by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cyclobencune derivative having antiviral activity and a method for producing the same.

Carbocyclic analogs of conventional technology purine nucleosides (
Since the discovery of natural compounds (alisteromycin, nebranocin A, etc.) and their antiviral activity, many carbocyclinocuprine nucleoside derivatives have been synthesized. Among them, 9-[(IR,
3S,4R)-3Hydroxy4-(hydroxymethyl)cyclopentyl]guanine has shown strong inhibitory activity against herpes simplex virus. (Unexamined Japanese Patent Publication No. 62-1
74097) Also, 9-[(l R,4 R)-4-(
Hydroxymethyl)-2-cyclopentenylcoguanine [Carbovir] is being considered for development as an effective antiviral agent for acquired immunodeficiency syndrome (AIDS) [Biochemical and Biophysical Research. Communication (BiochemB
iophis. Res. Con+mun. )l 5
Volume 6, page 1046 (1988).

Problems to be Solved by the Invention One of the reasons why carbocyclic nucleoside derivatives exhibit antiviral activity is that their chemical structures are similar to nucleosides. That is, it is believed that carbocyclinocnucleoside derivatives are mistaken for nucleosides and incorporated into viral DNA or RNA, resulting in antiviral activity. but,
In a derivative having a moiety 4 in which a hydroxymethyl group is substituted at the 4-position and a hydroxyl group is substituted at the 3-position of the cyclopentyl group moiety, which is a carbocyclic moiety, and these are trans-coordinated,
There is a possibility that it may be incorporated to some extent into host cell DNA or RNA and exhibit cytotoxicity. For example, 9-
[(IR,3S,4R)3-hydroxy-4-(hydroboxymethyl)cyclopentyl]guanine has the strongest anti-herpes simplex virus activity among the carbocyclinol derivatives obtained so far. However, it also shows strong toxicity to host cells.

Tanai derivative with a hydroxyl group at the 3-position of the cyclobentyl moiety,
That is, 2-hydroxy-4-(hydroxymethyl)
Cyclopentyl derivatives [Journal of Medicinal Chemistry (J. Med. Chew,) 30
Vol., pp. 1090-1094 (1987)], 4-(
Hydroxymethyl) cyclopentyl derivative 1 (JP-A-1983-1999-
10787) and 4-(hydroxymethyl)-2-cyclopentenyl derivatives (JP-A-64-22853) cannot extend the nucleic acid chain any further even if they are incorporated into host cell DNA or RNA. There is little possibility that these carbocyclinocnucleoside derivatives will be incorporated into DNA or RNA in cells.

Therefore, these derivatives can be expected to have lower cytotoxicity than trans-3-hydroxy-4-(hydroxymethyl)cyclopentyl derivatives. However, the derivatives synthesized so far are insufficient in terms of antiviral activity. For example, carbovir is less toxic or has less anti-herpes simplex virus activity than azidothymidine (AZT). Also, 2-hydroxy-4-(hydroxymethyl)
Cyclobentyl derivatives and 4-(hydroxymethyl)
All cyclopentyl derivatives are ineffective against herpes simplex virus.

On the other hand, since carbocyclic nucleoside derivatives are extremely stable against acids, antiviral agents containing them as active ingredients can be administered orally. That is, if carbocyclinocnucleoside derivatives with low toxicity and strong antiviral activity can be obtained, for example,
This is great news for patients who must take antiviral drugs for long periods of time.

The present inventors conducted research on the synthesis of novel carbocyclic nucleoside derivatives that are less likely to be incorporated into long-chain DNA or RNA in host cells.
9 -[(l R, 3 R, 4 R) 3-hydroxy-
4-(Hydroxymethyl)cyclobentyl 1-guanine derivative or 9-[(IR,3R,4R)-3-hydroxy-4-(hydroxymethyl)cyclobentyl] adenine derivative is a low toxicity, potent and broad-spectrum antiviral agent. I found that.

That is, the present invention relates to (1) the general formula [1FB (wherein, B is a purine base residue having a substituted hand at the 9-position, R
1 and R'' each represent a hydroxyl group which may be protected or phosphoric acid esterified) or a salt thereof, (2) General formula [2] oso, x (wherein, B is at the 9-position Purine base residue with bond, X
is a depriving residue and R3 is an optionally protected hydroxyl group) is reacted with a canolebonate salt to form an acyloxygen, and then subjected to hydrolysis [3] B (wherein B and R3 have the same meanings as above), (3) General formula [4] B (wherein B is a purine base residue having a bond at the 9-position) group, R
3 represents a hydroxyl group which may be protected) is subjected to a reduction reaction, with the general formula [3] B (wherein B and R3 have the same meanings as above) The present invention relates to a method for producing the represented compound.

In the compounds of general formulas [1] to [41], the purine base residue represented by B is, for example, those of the general formula [51 Y (wherein Yif-OH, -NH, or -SH, Z is -H, Examples include groups represented by N H ! or halogen). The amino group of these purine base residues may be protected, and the protecting group may be a protecting group used as a protecting group for the amine 7 group of a chemical purine type base of nucleic acids, such as an alkyl type protecting group or an aralkyl type protecting group. protecting group,
Allyl type protecting groups, Schiff base type protecting groups and acyl type protecting groups are used.

As the alkyl type protecting group, for example, a lower alkyl group having 1 to 5 carbon atoms; a lower alkyl group having 1 to 5 carbon atoms, a trisubstituted silyl group having a benzyl group as a substituent, a tetrahydropyranyl group, etc. are used.

Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, SeC-butyl, ter
L-butyl, pentyl; trimethylsilyl, Lert-
Examples include butyldimethylsilyl, tert-butyldiphenylsilyl, tetrahydropyranyl, and tetrahydrofuranyl.

As the aral protecting group, for example, a lower alkoxy group having 1 to 5 carbon atoms, a nitro group, a benzyl group which may be substituted with a halogen, and a triphenylmethyl group are advantageously used. Specific examples include benzyl, p-methoxyphenyldiphenyl, p-nitrobenzyl, p-chlorobenzyl, p-methoxyphenyldiphenylmethyl, and the like.

Examples of the allyl protecting group include lower alkoxy groups having 1 to 5 carbon atoms such as phenyl, p-methquinphenyl, and p-chlorophenyl, and phenyl groups which may be substituted with halogen.

Examples of Schiff base-type protecting groups include methylidene, N
, N-dimethylaminomethylidene, bezylidene, ethylidene, propylidene, butylidene, pentylidene, etc., and a lower alkylidene group having 1 to 5 carbon atoms which may be substituted with a phenyl group are used.

As the acyl-type protecting group, the acyl-type protecting group mentioned below in the hydroxyl group-protecting group can be used similarly.

Next, in general formulas [1], [2], [3], and [41], when R1, R2, and R3 are protected hydroxyl groups, the protecting groups are used as protecting groups for hydroxyl groups in sugar chemistry. Protecting groups such as ether type protecting groups and acyl type protecting groups are used.

Examples of the protective group include halogen, a lower alkyl group having 1 to 5 carbon atoms which may be substituted with a lower alkoxy group having 1 to 5 carbon atoms, a penzyloxy group, a phenyl group; a lower alkyl group having 1 to 5 carbon atoms; lower alkenyl group; carbon number 1-5
A tri-substituted silyl group whose substituent is a lower alkyl group, phenyl group, benzyl group, etc.; a lower alkoxy group having 1 to 5 carbon atoms, a benzyl group optionally substituted with a nitro group: a lower lower alkyl group having 1 to 5 carbon atoms; Alkoxy group; a tetrahydropyranyl group which may be substituted with halogen, etc. are used.

Examples of the above halogen include fluorine, chlorine, bromine, and iodine, and examples of the alkyl group having 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sea-butyl, tert-butyl, benzyl, and isobentyl. , neobentyl group, etc., and examples of the alkoxy group having 1 to 5 carbon atoms include methoxy, ethoxy, propoxy, butoxy, pentyloxy, pinyloxy, and allyloxy groups which may be substituted with halogen.

To further indicate the construction -terrain protection group, methyl, methoxymethyl, pengehoxymethyl, tert -butoximethyl, 2 -metoxyet beef cow. 2,2.2
-1 Licromethoxymethyl, ethyl. 1-ethoxyethyl, l-methyl-1-methoxyethyl, 2.2.2-
}Lichloroethyl, provil, isobrovir, butyl,
isobutyl, see-butyl, tert-butyl,
Ethoxyethyl, triphenylmethyl. p-methquinphenyldiphenylmethyl: allyl: trimethylsilyl,
tert-butyldimethylsilyl, tert~butyldiphenylsilyl; benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl; tetrahydropyranyl, 4-methoxytetrahydrobilanyl,
Tetrahydrofuranyl, etc.

Examples of acyl-type protecting groups include halogen, carbon number 1
~5 lower alkoxy groups, alkanoyl groups with 1 to 5 carbon atoms optionally substituted with phenoxy groups optionally having halogen, nitro groups, phenyl groups, carbon atoms 1 optionally substituted with halogens A benzoyl group optionally substituted with a lower alkyl group having ~5 carbon atoms, a benzoyl group optionally substituted with a lower alkyloxycarbyl group having 2 to 6 carbon atoms, and a benzoyl group optionally substituted with a halogen having 2 carbon atoms. ~
6, an alkoxycarbonyl group, an alkenyloxycarbonyl group having 3 to 5 carbon atoms, a lower alkoxy group having 1 to 5 carbon atoms, or a penzyloxycarbonyl group optionally substituted with a nitro group; Enoquine carbonyl group and the like are used.

As the above-mentioned halogen, lower alkoxy group having 1 to 5 carbon atoms, and alganyl group having 2 to 4 carbon atoms, the same ones as those shown in the bar for the ether type protecting group can be used.

More specific acyl protecting groups include formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, phenoxyacetyl, p-chlorophenoxyacetyl, probionyl, imbropionyl, 3 -phenylbrobionyl, imbutyryl, bivaloyl; benzoyl, p-nitrobenzoyl,
p-phenylbenzoyl, 0-(methoxy/tricarbonyl)benzoyl, 2,4.6-}limethylbenzoyl;
Methoxycarbonyl, 2,2.24-lichloroethoxycarbonyl, imbutyryloxycarbonylvinyloxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
3.4-dimethoxybenzyloxycarbonyl, p-nitropenzyloxycarbonyl: p-nitrophenoxycarbonyl, and the like.

In the compound of general formula [1], when R' and R' are hydroxyl groups which may be phosphoric acid esterified, the phosphoric acid ester residue is represented by general formula [6] (where n is 1 to 3
, R4 represents -H or a hydrocarbon residue having 1 to 14 carbon atoms), or Rl and R' together represent the general formula [7]1P1OR'
[7] Examples include a group represented by 0 (wherein R4 has the same meaning as above). Examples of the hydrocarbon residue for R4 include lower alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, proyl, isobrobyl, butyl, isobutyl, sec-butyl, tert-butyl, peshyl; benzyl. p
Examples include aralkyl groups such as -methoxybenzyl and p-methylbenzyl; phenyl groups and the like.

In the compound represented by the general formula [1], the purine base moiety represented by B can form a salt with an acid.

Such salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid. Inorganic acids such as phosphoric acid and nitric acid, such as acetic acid, malic acid,
Pharmaceutically acceptable salts with organic acids such as citric acid, ascorbic acid, mandelic acid, and methanesulfonic acid are used. In addition, Rl and/or Rt of general formula [1]
When R4 is a hydrogen atom in the compound represented by general formula [6] or [7], these phosphoric acid ester residues may form a pharmaceutically acceptable salt with a base. Examples of these salts include potassium, sodium, calcium, barium, and ammonium salts.

Next, a method for producing the compound of general formula [1] will be explained.

General formula [General formula [2] which is a raw material compound for one compound
Or the compound [4] is a known compound represented by the general formula [8coB0H (in the formula, Rt and B have the same meanings as above) (Japanese Unexamined Patent Publication No. 174097/1983 and European Patent Publication No. 0278501). Manufactured from.

Examples of the organic residue represented by X in the compound of general formula [21] include a lower alkyl group that may be substituted with halogen, a phenyl group that may be substituted with lower alkyl, or an imidazolyl group.

The compound represented by general formula [2] is, for example, general formula [5
17;) Methanesulfonyl chloride A sulfonyl chloride such as benzenesulfonyl chloride, toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, or a sulfonic acid anhydride such as trifluoromethanesulfonic anhydride is added to the compound, triethylamine. Viridine,
Methane can be produced by reacting in the presence of an organic base such as N,N-dimethylaniline, or by reacting sulfuryl chloride with imidazole, and if necessary, by removing the protective groups of hydroxyl and amino groups. A compound of general formula [21] which is an organic sulfonyloxylated compound such as sulfonyloxy, benzenesulfonynoleoxy, tonolenesnorefonyloxy, trifluoromethanesulfonyloxy, imidazolylsulfonyloxy, etc. can be obtained.

Further, the compound represented by the general formula [4] is, for example, the compound [81] dimethyl sulfoxide and acetic anhydride, dimethyl sulfoxide and trifluoroacetic anhydride. Dimethyl sulfoxide and phosphorus pentoxide, dimethyl sulfoxide and sulfur trioxide-pyridine complex, dimethyl sulfoxide and its activation reagent such as oxalyl chloride, mataha, chromium trioxide-pyridine complex, viridinium dichromate, nicotinium dichromate, It can be obtained by oxidizing with ruthenium oxide (■) or the like, and removing the protecting groups of hydroxyl group and amine 7 group, if necessary.

The compound represented by the formula B [1] is, for example, the compound represented by the formula [2]
By reacting the compound represented by a carboxylic acid salt with a substitution reaction of the acyloxy group accompanied by Walden inversion,
Furthermore, if necessary, it can be obtained by a hydrolysis reaction of an acyluoquine group.

Examples of carboxylic acid salts used in the substitution reaction of acyloxy groups include metal salts such as sodium, potassium, and cesium of carboxylic acids such as acetic acid, phenylacetic acid, propionic acid, bivaloic acid, benzoic acid, and p-methylbenzoic acid;
Examples include amine salts of these carboxylic acids such as triethylamine salts and tetrabutylammonium salts, and by using salts of these carboxylic acids, R1 can be converted to acetyloxy or phenylacetyloxy in the general formula [1].
Compounds exhibiting an acyloxy group such as propionyloxy, pivaloyloxy, penzoyloxy, and p-methylbenzoyloxy can be obtained.

In this reaction, cesium salts of carboxylic acids such as cesium acetate and cesium phenylacetate are advantageously used. The reaction is usually carried out in a solvent, and examples of preferred reaction solvents include nonpolar solvents such as benzene, toluene, and dichloroethane. The reaction temperature is normal. , room temperature to the reflux temperature of the solvent, preferably 70°C to 130°C. The reaction time varies depending on the reaction temperature, but is usually about 1 hour to 10 hours.

The hydrolysis reaction of the acyloxy group can be carried out by a method known per se in which an acid or base is reacted. Preferably, ammonia, tonoethylamine, sodium hydroxide, potassium hydroxide. This is done by reacting a base such as sodium methoxide. The reaction temperature is usually carried out at room temperature, but in some cases it may be cooled to 0°C or heated to the reflux temperature of the solvent. The reaction time varies depending on the type of base used and the reaction temperature, but is about several minutes to 24 hours.

In the general formula [1], a compound in which R+ is a hydroxyl group can be obtained by reducing the carponyl group of the compound of the general formula [4] to a hydroxyl group.

The reduction reaction is carried out using, for example, a metal hydride complex as a reducing agent, more specifically, a metal borohydride such as lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, cyanohydride, etc. This can be carried out using a metal cyanoborohydride such as lithium boron or a metal trialkylboron hydride such as lithium triethylborohydride. As the reaction solvent, a polar solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof is advantageously used. The reaction temperature is usually carried out at room temperature, but in some cases it may be cooled to 0°C or heated to the reflux temperature of the solvent. The reaction time varies depending on the type of base used and the reaction temperature, but is about several minutes to 24 hours.

In general formula [11], the compound in which R1 and/or R' is represented by general formula [6] or [7] is, for example,
The compound described in Eurosopa Patent Publication No. 027850 No. 1 in which R' in general formula [8] is general formula [6] may be used as a raw material compound, but in general formula [1], R' and/or R2 are It can also be obtained by subjecting a compound having a hydroxyl group to a phosphorylation reaction.

The phosphoric acid compound can be prepared by a method known per se using nucleotide chemistry, but usually by reacting with a non-oxidizing agent and then hydrolyzing if necessary. Examples of the phosphorylating agent used include phosphorus oxychloride, pyrophosphoryl tetrachloride, phosphorus trichloride, polyphosphoric acid, metaphosphoric acid, benzyl phosphate dichloride, morpholinophosphoric acid dichloride, phenylphosphoric acid dichloride, di-β-sia/ Ethyl phosphoric acid, dibenzyl phosphoric acid chloride, O-benzyl phosphorous acid-0.0
- Phosphorizing agents that may include an oxidation process, such as diphenylbiphosphoric acid. 1 of the theoretical amount of phosphorylating agent
It is used in an amount of 1.2 to 10 times the mole or more, preferably about 1.2 to 10 times the mole. Reaction c. Usually, trialkyl phosphate such as triethyl phosphate + trimethyl phosphate, phenol. r Phenols such as cresol,
The reaction is carried out in a solvent such as a polar solvent such as acetonitrile, dimethylformamide, or dimethyl sulfoxide, a nonpolar solvent such as toluene, henzene, dichloromethane, or chloroform, or a mixed solvent thereof, and the reaction temperature is -
78°C to reflux crystallinity of the solvent, preferably -20°C
to room temperature.

The reaction time varies depending on the phosphorylating agent used and the reaction temperature, but is about 10 minutes to 10 hours.

In addition, the monophosphate ester can be prepared using a method known per se. After leading to an active phosphoric acid ester by reacting 1-fluoro-2,4-dinitrobenzene, carbonyldiimidazole, etc., it is then reacted with an organic amine salt of orthophosphoric acid or pyrophosphoric acid such as biridine or triethylamine. A diphosphate ester or triphosphate can be produced by this method.

In compound [1], when R' and R'' are protected hydroxyl groups, and when B is a purine-type base with an amino group protected, the removal of the protecting groups of these hydroxyl groups and amine 7 groups is itself This can be done using a known method.

For example, protecting groups that can be removed with acids such as trityl group, tert-butyl group, and tetrahydroviranyl group are hydrochloric acid, acetic acid, trifluoroacetic acid, p-1 luenesulfonic acid, and sulfonic acid type? By hydrolyzing with acids such as on-exchange resins, ■■■1 For example, acyl '4U ('4 protecting groups are ammonia, triethylamine, sodium hydroxide, potassium hydroxide, sodium metkind, etc.) Furthermore, benzyl-type protecting groups such as benzyl group and p-methoxybenzyl group can be removed by hydrogenolysis by catalytic reduction.

The compounds represented by the general formulas [1], [2], [3] and [4] can be prepared by means known per se, such as concentration, vacuum concentration, furnace filtration. Centrifugation, drying, freeze-drying, adsorption, desorption, methods that utilize differences in solubility in various solvents (e.g., solvent extraction, diversion, precipitation, crystallization, recrystallization, etc.), chromatography (e.g., ion exchange resins, It can be isolated and purified by chromatography using activated carbon, high porous polymer, Sephadenox, Sephadex ion exchange resin, cellulose, ion exchange cellulose, silica gel, alumina, etc.

Since the compound represented by the general formula [1] of the present invention has weak cytotoxicity and exhibits strong antiviral activity over a wide range, it can be used for the treatment of diseases caused by viral infection and for the prevention of infection.

For example, 9- contained in the compound represented by general formula [1]
[(lR,3R,4R)-3-hydroxy-4=(hydroxymethyl)cyclobentyl]Burine derivatives are effective against various DNA viruses such as herpes simplex virus, varicella zoster virus, adenovirus, and influenza virus. It exhibits strong inhibitory activity against RNA-viruses, and its cytotoxicity to host cells is extremely low compared to its (IR, 3S, ↓R) monoisomer. That is, the compounds of the present invention can be widely used for the treatment and prevention of infections caused by viral infections in mammals including humans (e.g., herpetic eczema, generalized herpes zoster, viral encephalitis, and influenza virus). be able to. Furthermore, the compounds of the present invention are acid-stable and can be administered orally, making them useful for patients who must take antiviral agents for long periods of time.

When the compound of the present invention is used for the purpose of treating viral diseases, it can be prepared by itself or by adding an appropriate amount of auxiliary agents such as pharmacologically acceptable carriers, dispersants, excipients, etc., in a conventional manner, for example, in capsule form. , tablets, ointments, injections, granules,
It can be administered orally or parenterally in the form of a powder, solution, suspension, or elixir. Examples of adjuvants include lactose, starch, mineral oil, petroleum jelly, polyethylene glycol, propylene glycol, physiological saline for injection, and glyceride, which can be used depending on the purpose.

The dosage varies depending on the type of virus, symptoms, subject, administration method, etc., but for example, for adults with herpes virus infection, it is 1 to 100 mg per day, preferably 5 to 500 mg, and can be administered once or several times a day. Administer in divided doses.

Effects and Examples Below, the present invention will be explained in more detail by showing Reference Examples and Examples.

Measurement of antiviral activity and cytotoxicity of vello cells with IOOTCID
.

Antiviral activity (IDso: dose required to inhibit cell infection by virus by 5Q%) was measured 3 days after infection. The results are shown in Example 3 below. Control cells that were not administered at this time showed 100% cell infection. In addition, cytotoxicity was simultaneously determined using control cells that were not infected with the virus.

Reference example l N1-penzoyl-9-[(IR,3S,4R)-3hydroxy-4-(hydroxymethyl)cyclobentyl]
Guanine 9-[(IR,3S,4R)-3-hydroxy-4
mono(hydroxymethyl)cyclobentyl]guanine (1
．． 0g) was suspended in pyridine (30d), penzoyl chloride (3.71g) was added while cooling with ice water, and the mixture was stirred at room temperature for 5 hours and then for 1.5 hours while heating at 45-50°C. Dichloromethane (40d) and ice water were added to the reaction solution, and after stirring, the dichloromethane layer was separated. The dichloromethane layer was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Hexane was added to the residue, and the resulting precipitate was filtered. The obtained precipitate was dissolved in tetrahydrofuran (5 components), and while cooling with ice water, methanol (40 d) and N sodium hydroxide solution (18.8 d) were added, and the mixture was stirred at room temperature for 15 minutes. After adding N-hydrochloric acid (18.8 mQ) and pyridine (1.5 g) to the reaction solution, it was concentrated under reduced pressure. The residue was dissolved in water and methanol (14
・1.7! After heating and dissolving in M), cool with ice water and N! A white powder (1.1 g) of -benzoyl-9-[(IR,3S.4Rl-3-hydroxy-4-(hydroxymethyl)cyclobentyl]guanine) was obtained.

IR (KBr): 3400-3100.
16g5, 1646, 1599, 1548.12
57 cm-' NMR (DMSO-d.) δ: [. 63 (IH,
dt, J=12. 8,9.0Hz). 2.03
(2H, m), 2.17 (III, m), 2J
7 (IH, dt, ?=12.8, 7.8Hz),
3.49 (III, m), 4.10 (it{, m
冫、4.68(LIL t、J=5.2Hz
>, 4. 82(Ill d, J■3. 6}1z
), 5. 02 (III, m). 7. 62 (3
11, m). 8. 05 (21!, d, J=7
．． 0Hz), 8. 18(l}I,s), 11
．． 92 (IH, s), 12. 29(IH, s
). Reference example 2 N! -benzoyl-9-[(IR,3S.4R)-3
Hydroxy-4-[(p-methoxyphenyldiphenylmethoxy)methyl]cyclobenthyrcoguanine 1'J"
-he7zoyl-9-[(tR,3S,4R)-3=hydroxy-4-(hydroxymethyl)cyclobentyrucoguanine (0.85 g) was suspended in N,N-methylformamide (20d), Pyridine (0.436g) and p-anisilk-rodiphenylmethane (0.853g)
After stirring at room temperature for 4 hours, p-anisilk diphenylmethane (0.28.4 g) was added and stirring was continued at room temperature for 15 hours.

Ethyl acetate (50d) was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate, methane-methanol (10:10:1). The eluted fraction was concentrated to dryness under reduced pressure and N! -Penzoyl-9-[(IR,3S,4Rl-3-hydroxy/-4-
II(p-methoxyphenyldiphenylmethoxy)methyl]cyclopentyl 1-guanine (1.45 g) was obtained.

I R (K B r): 3380, 3100,
1663. 1602. 1246cm-'NMR
(CDCIJ3) δ: 2. 30 (5tl, m),
3. 23 (2H, d. J=4.2Hz),
3. 71(3!{, sl 4. 43(l}l,
m>, 4. 98 (01, m), 6.78 (2tf
．． d, J=8.811z). 7.05-7.65 (1
7H, m}, 9.23 (IH, s), 12, 21
(IH, S) Reference row 3 N'-(p-methoxyphenyldiphenylmethyl)-l
-C(IR,3S,4R)-3-hydroxy-4-
[(p-methoxyphenyldiphenylmethoxy)methyl]/clobentyl]guanine 9-[(l R,3 S,4 R)-3-hydroquine-
4-(Hydroxymethyl)/Clobentylcoguanine (
1.0g) in N,N-dimethylformamide (15ml
), added pyridine (1.19g) and p-anisylchlorodiphenylmethane (1.51g), and stirred at room temperature for 30 minutes.
After stirring for an hour, p-anisylchlorodiphenylmethane (1.51 g) was further added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (70d) was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel, and the column was chromatographed with ethyl acetate and methane-methane (10:1 O:1
) and then eluted with ethyl acetate-dichloromethane-methanol (4:4:l). The eluted fraction was concentrated to dryness under reduced pressure to obtain N'-(p-methoxy/phenyldiphenylmethyl)-
9-[(IR,3S,4R)-3-hydroxy-4
- [(p-methoxyphenyldiphenylmethoxy)
White powder of methyl]cyclopentyl]guanine (2.0
5g) was obtained.

I R (K B r): 3350, 1692.
1608. 1565, 1512. 1248cm
'NMR(CDC(23)δ: 1.38(11L+n)
, 1.92 (3H, m)2. 05(11{, m
), 2. 26(lft, d, J=2.21{
z), 2. 99 (IIL tJ=8.6Hz),
3. 23 (LH, dd, J=5. 6, 8.
611 true), 3.69 (311s), 3. 78
(311, s), 3. 97 (IH, m).
4. 40 (ill, m), 6. 71 (2tL d
, J=8. 8Hz), 6. 86(2}1,
d, J=8. 811z) 7.04-7.50 (25
11, n), 10.73 (II, br.s). Reference example 4 N'-(p-methoxyphenyldiphenylmethyl)-9
-r(l R.3S,4 R)-3-(methanesulfonyloki/)-4-[(p-methoxyphenyldiphenylmethoxy)methyl]cyclopentyl]guanine N'-(
p-methoxyphenyldiphenylmethyl)9-[(IR
．． 3S,4 R)-3-Hydroxy-4(p-methoxyphenyldiphenylmethquin)methyl]nclopentyl 1-guanine (2.4 g) in dichloromethane (70d) was added with triethylamine (0.902 g) and Methanesulfonyl chloride (0.476 g) was added, and the mixture was stirred for 40 minutes while cooling with ice water. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give N''-(p-methoxyphenyldiphenylmethyl)-1-1(IR,3S,4R)-3. A crude substance of -(methanesulfonyloxy)-4-[(p-methoxyphenyldiphenylmethoxy/)methyl]cyclopentyl]guanine was obtained.

Reference vAI5 N″-(p-methoxy7phenyldiphenylmethyl)-9
-[(IR,4R)-4-[(p-Methoquinphenyldiphenylmethoxy)methyl]13-oxoneclopentynotetraguanine Chromium dioxide (1.39g) was dissolved in dichloromethane (25d) in pyridine (2.4ml). ) and stirred at room temperature for 20 minutes. Add N'-(p-methoxy/phenyldiphenylmethyl)-9-[(IR,3S4R)-3-hydroxy-4-[(p-methoxyphenyldiphenylmethoxy)methyl]cyclopentyl]guanine (2.8 g
) in dichloromethane (25b=e) was added dropwise, followed by acetic anhydride (1.38-), and the mixture was stirred at room temperature for 20 minutes. The reaction solution was added to a column of linica gel (70d), and the column was eluted with chloropol-methanol (49:1). The eluate overnight was subjected to JHa condensation, and the residue was subjected to silica gel column chromatography. The column was eluted with chloroform methanol (49:1), and the eluted fraction was concentrated to dryness under reduced pressure and N! -(p-methoxyphenyldiphenylmethoxy)-9-[(IR,4R)-4-L: (p-methoxyphenyldiphenylmethoxy/)methyl]-3-oxocyclopentyl-1-guanine (1.69 g) is colorless. I got it as a nronob.

N M R (C D C Q3>δ: 1.83 (2
H, m), 2.08 (IH, m), 2. 35(2[
+, m), 3. 27 (2H, m), 3. 6
8 (3H, s), 3. 81 (3H, s), 4.
25 (18, m), 6.60-7.48 (29H, m
), 7, 58 (ltl, br. s) Reference Example 6 1-[(I R,4 R)-4-(Hydroquine methyl)
3-oxobentylcokuanine N”-(p-methoxy/phenylnophenylmethyl)9-
[(l R,4 R)-4-[(p-methoxyphenyldiphenylmethoxy)methyl]-3-oxonpentyl]guanine (IOOmg) dichloromethane (2-
) 0.367M hydrogen chloride in chloroform (2.7
d) The solution was added and stirred for 1.5 hours while cooling to -20°C. After condensing the reaction solution under reduced pressure at below 10'C, ether (400g) was added to the residue to give 9-[(1R,4R)-4-(
A white powder (27.7 mg) of hydroxymethyl)-131-okine/pentylcoguanine was obtained.

NMR (DMS○-dll) δ: 2, 0-3, O
(5H, m), 3. 61 (211, m), 4
．． 78 (III, m), 4. 90 (IH, m)
, 6. 61 (2tl, br.s), 7. 86
(III, s). 10. 7(ill, m). Reference Example 7 9-[(IR,3S,4R)-3-hydroxy-4-[
(p-methoxyphenyldiphenylmethquin)methyl]
Cyclobentylcoadenine 9-[(l R,3S,4R)-3-hydroxydi-4(hydroxymethyl)cyclopentylcoadenine (
P-anisylchlorodiphenylmethane (1.1 g) was added to a solution of 850 mg) of pyridine (component 10), and the mixture was stirred at room temperature overnight. On the night of the reaction, water (2-) and sodium hydrogen carbonate (400 mg) were added, and the mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was dissolved in chloroform (20
7) and water (20d), and the chloroform layer was dried over 17 um of anhydrous sodium sulfate and concentrated under reduced pressure.

The residue was subjected to column chromatography on 7 silica gel and eluted with chloroform-methanol (4:1). The eluted fraction was concentrated to dryness under reduced pressure to give 9-[(IR, 3S, 4R)
A white powder (1.50 g) of -3-hydroxy-4-[(p-methoxyphenyldiphenylmethoxy)methyl]cyclopentyl-1 adenine was obtained.

Reference Example 8 9-4(]R,4R)-[(p-methoxyphenylphenylmethquin)methyl]-3-oxocyclopentyl]adenine chromium trioxide (1.2 g) was dissolved in pyridine (4. The mixture was added to a solution of 2d) in dichloromethane (24d) and stirred at room temperature for 20 minutes. In this solution, 9-[(l R, 3 S, 4 R)
3-Hydroxy-4-[(p-methoxyphenyldiphenylmethoxy)methyl]cyclopentyl]adenine (1
．． A solution of 56 g) in dichloromethane (I O-) was added dropwise, followed by the addition of acetic anhydride (2.4 d), and then the mixture was heated at room temperature for 20 min.
Stir for a minute. Silica gel column (70d) for reaction branch
In addition, the column was diluted with chloroform-methanol (49.1
) was eluted. The eluate was condensed under reduced pressure TFA, and the residue was subjected to column chromatography on 7 silica gel and eluted with chloroform-methanol (24:1). The eluted fraction was concentrated to dryness under reduced pressure to give 9-[(IR,4R)-4-
[(p-methoxyphenyldiphenylmethoxy)methyl]-3-oxonpentyl]adenine (7 8 8
mg) WofiL Obtained as a syrup.

NMR (CDC(h)δ: 2.07 (31L m)
, 3. 07 (2 [L m), 3. 37 (Ill
．． dd. J=3. 4, 7. 611z),
3. 59 (III, dd, J=5.07, 6
Hz), 3. H(31{, s), 5. 0
8 (IL Q. J=3.5}1z), 5.63 (2
11, br. s), 6.81-7.45 (14tl,
m), 7.87 (IIIs), 8. 35 (18
, s) Example l N”-(p-methoxy/phenyldiphenylmethyl)-9
-[(IR,3R,4R)-3-acetoquine-4-[
(p-methoxyphenyldiphenylmethoxy7)methyl]
cyclopentyl]guanine obtained in Reference Example 4 flJ'[ of phenyldiphenylmethoxy)methyl]cyclobentyl]guanine was dissolved in toluene (2001nl.), and cesium acetate (2.85g) and 18-crown-6 (0.785g) were added to this solution, and the mixture was stirred. 14
The mixture was heated to reflux for an hour. After cooling the reaction mixture to room temperature, insoluble matter was filtered out, and the reactor liquid was concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography, and after washing the column with ethyl acetate, the column was eluted with ethyl acetate, methane-methanol (10:10:l). The eluted fraction was concentrated to dryness under reduced pressure to give N'-(p-methoxyphenyldiphenylmethyl)-9[(IR,3R,4R)-3
A white powder (1.88 g) of -acetoxy4-[(pmethoxyphenyldiphenylmethoxy)methylco7clopentyl]guanine was obtained.

I R (K B r): 3355, 1736.
1688, 1604, 1562, 1510,1
245cn+ NMR (DMS○-d.) δ: 1.23 (IH, II
1), 1.68 (II, m), 1. 76 (3
11, s), 2. 23 (3H, m), 2.
93 (2H, m), 3. 67 (311, s),
3. 75 (3tl, s), 3. 75 (3H,
s), 4. 05 (IIt, s), 5. 25(
IH, m), 6. 84 (2H, d, J=8.
8Hz), 6. 92 (211, d, J=8.81
1z), 7.05-7.50 (2511, m).
7.56(ltl,s), 10. 52 (III
, s). Example 2 N'-(p-methoxyphenyldiphenylmethyl)-9
-[(IR,3R,4R)-3-hydroxy-4[(
p-methoxyphenyldiphenylmethoxy)methyl]cyclopentylcoguanine N'-(p-methoxyphenyldiphenylmethyl)9-
4(IR,3R,4R)-3-acetoki7-4[(p-
methanol (5 4 mg)
-) Soluble; Sodium methox/do (2.7 mg) at night
) was added to the mixture in methanol (0.05d), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel.

The column was heated with ethyl acetate-dichloromethane-meta/l (1
After washing with ethyl acetate (0:10:1), the mixture was eluted with methane-methanol (4:4:1).

The eluted fraction was concentrated to dryness under reduced pressure to give N'-(p-methquinphenyldiphenylmethyl)-1-[(l R,3R,?R
)-3-Hydroquine-4-[(p-methoxyphenyldiphenylmethoxy)methyl]cyclobentyl]guanine white powder (45 mg) was obtained.

I R (K B r): 3360, 1683,
1603, 1560, 1510. 1246cm NMR (DMSO-d.) δ: 1.28 (IH, m)
, 1.54 (IH, m), 1. 88 (2H,
m), 2. 07(lit, m), 2. 92
(IH, m)3. 20(ill, m), 3.
67 (3H, s), 3. 75 (3tl, s).
4. 04 (2If, m), 4.70 (IH, d,
J■3.81Iz), 6.87(211.d, J・9
．． 011z). 6. 91 (2H, d, J=9.
0Hz), 7. 08-7. 46 (24H, m
)7. 56(III, s), 7. 61 (lit.
, s), 10. 51(IH, s) Example 3 9-[(IR,3R,4R)-3-hydroxy-4(hydroxymethyl)cyclopentyl]guanine a
) N”-(p-methoxyphenyldiphenylmethyl)-9-[(IR,3R,4R)-3-hydroxy4-
Dissolve [(p-methoxyphenyldiphenylmethquin)methyl]cyclopentyl]guanine (LOOmg) in acetic acid monohydrate (4:1, jM!) and heat at 45-50°C.
The mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was washed with ether, and Amberlite XADII (601
Column chromatography (manufactured by Rohm & Haas). After washing the column with water, add water to
-L (9:l). The eluted fraction was concentrated under reduced pressure, the residue was dissolved in a small amount of water by heating, and the mixture was left in the refrigerator overnight.
-[(l R.3R,4 R)3-hydroxy-4-(
White crystals (28 mg) of hydroquine methyl)cyclopentyl]guanine were obtained.

b) N2-(p-methoxyphenyl-phenylmethyl)
-9-[(IR,4R)-4-[(p-methquinphenyldiphenylmethquin)methyl]-3-oxocyclopentylcoguanine (LOOMG) in methanol-tetrahydrofuran (2: I, I. Sodium borohydride (lomg) was added to the 5au) solution, and the mixture was stirred for 1 hour while cooling with ice water. A 10% (w/v) solution of hydrogen chloride in methanol (0.5d) was added to the reaction solution, and the mixture was heated at the same temperature for 3
After stirring for 0 minutes, the mixture was neutralized with 0.05N sodium hydrogen carbonate solution and concentrated under reduced pressure. After washing the residue with ester, it was subjected to column chromatography using Amberlite XAD-11 (55Tn1, manufactured by Rohm and Haas). The column was eluted with 1 part water, water methanol (9:1). The eluted fraction was concentrated under reduced pressure, and the residue was dissolved in a small amount of water by heating, and then left in the refrigerator overnight to dissolve 9-[(IR.3R,4R
)-3hydroxy-4-(hydroxymethyl)cyclopentyl]guanine (16 mg) was obtained as white crystals.

24 [α ko 2 5. 7° (c O. 2
15, CH30H) :D NMR (DMS○-dll) δ: 1.71 (LH, m
), 1.96 (IH, m). 2. 18 (IH.
m). 2. 41 (III, m), 3. 48
(ill, m)3. 64 (LH, m). 4.
18(II{, m), 4. 37 (IH, t,
J=5. 4tlz)4. 73(III, n),
4. 94(1) I, d, J=4. 2Hz),
6. 39 (211, br.s), 7.80
(eye 1, s), 10.50 (IH, br.s). Elemental analysis: C,,I-I,5N503・l. 5H,0 calculated value (%): C, 45.20; H, 6.21; N
, 23.96. Experimental value (%): C, 44.79. H
, 6J2; N, 23.6+. Herpes simplex virus! Antiviral activity against type IDso・1.56 μgh
l. tiJJ cytotoxicity: 200 μg/d Example 4 9-[(IR,3R,4R)-3-hydroxy-4-(
hydroxy/methyl)cyclopentyl]adenine9-[
(IR, 4R)-4-[(p-methoxyphenyldiphenylmethoxy)methyl]-3-bentyl]adenine (200 mg) meta/-lutetrahydride furan (2:1.6d) dissolution Sodium borohydride (40 mg) was added to the mixture, and the mixture was stirred for 1 hour while cooling with ice water. A 20% (W/V) hydrogen chloride solution in methanol (0.!M) was added to the reaction mixture, and after stirring at the same temperature for 30 minutes, the mixture was neutralized with 0.05N sodium hydrogen carbonate solution and concentrated under reduced pressure. After washing the residue with ether, Amberlite
It was added to a column of AD-I1 (55d, manufactured by Hum & Haas).

After washing the column with water, it was eluted with water and methanol (17.3). The eluted fractions were concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (4:1). The eluted fraction was concentrated to dryness under reduced pressure to obtain a white powder (25 mg) of 9-[(IR,3R,4R)-3-hydroxy-4-(hydroxymethyl)cyclobentyl]adenine.

N M R (D M S O ds) δ: 1.71
~2. 12 (3FI, m), 2. 27 (IH,
dt, J=7. 6, 7. 6, 10. 0Hz
). 2. 47 (IH, m), 3. 49(lH
．． m), 3. 68 (IH, m), 4. 20
(ill, q, J=4.4Hz), 4. 40(
I}I, L, J=5. 2HZ), 5. 00
(I}I, m), 5. 31(IH, d,''・
5, 2tlz), 7. 25 (2H, br.s)
, 8. 13(ill, s), 8. 22(
IH, s). Effects of the Invention The compounds of the present invention have antiviral activity and low cytotoxicity, and therefore can be used for the treatment and prevention of diseases caused by viral infections.

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, B is a purine base residue with a substituted hand at the 9-position, R
^1 and R^2 each represent a hydroxyl group which may be protected or phosphoric acid esterified) or a salt thereof. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, B is a purine base residue with a bond at the 9-position,
is an organic residue and R^3 is an optionally protected hydroxyl group) is reacted with a carboxylic acid salt to form an acyloxygen, and then subjected to hydrolysis. , chemical formula, table, etc. ▼ (wherein B and R^3 have the same meanings as above). (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, B is a purine base residue with a bond at the 9-position, R
There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by subjecting a compound represented by (^3 represents a hydroxyl group that may be protected) to a reduction reaction. (In the formula, B and R^3 has the same meaning as above).