JPH07188231A - Cyclopropane derivative and antiviral agent containing the derivative - Google Patents

Abstract

PURPOSE:To obtain a new cyclopropane derivative useful as an antiviral agent having excellent solubility in water, oral absorbability and therapeutic effect. CONSTITUTION:This cyclopropane derivative is a compound of formula I [R<1> and R<2> each is H or a group of formula II (R<3> is a 1-6C alkyl); R<1> and R<2> are not H at the same time; X is H, OH, NH2 or a halogen; Y is H, OH or NH2] or its pharmacologically permissible salt, e.g. 9-[1'S,2'R-bis(O-L-alanyloxymethyl) cyclopropan-1'beta-yl]methylguanine. The compound of formula I wherein both R<1> and R<2> are group of formula II can be produced by carrying out dehydrative condensation of a cyclopropane derivative of formula III with an N-protected amino acid of formula IV (Z is amino-protecting group) in a polar solvent using a condensation agent and deprotecting the protecting group of the amino group of the obtained ester.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cyclopropane derivative, more specifically, it has antiviral activity,
The present invention relates to a cyclopropane derivative useful as a therapeutic agent for various viral diseases and an antiviral agent containing the same.

[0002]

Many nucleic acid-related compounds have antiviral activity, such as acyclovir, ganciclovir,
Azidothymidine and the like are actually used as antiviral agents. However, these nucleic acid-related compounds generally have low water solubility, and when used as injections, it is necessary to dissolve them in a large amount of water for intravenous infusion, or it is difficult to use them as eye drops. Further, when used as an oral preparation, there were problems such as poor absorbability. JP-A-59-105
Japanese Unexamined Patent Publication No. 87 describes an amino acid ester of acyclovir, particularly an ester of glycine and alanine, as a compound having improved water solubility as compared with acyclovir. Further, JP-A-64-68373 describes that valine and isoleucine esters of acyclovir are superior in bioavailability (oral absorption) after oral administration as compared with glycine and alanine esters. There is. JP-A-2-218667 describes an amino acid ester of ganciclovir, but does not show data on oral absorbability, and it is clear what kind of amino acid ester improves oral absorbability. is not.

[0003]

On the other hand, Japanese Patent Laid-Open No. 5-78
Japanese Patent No. 357 describes that the compound represented by the following general formula (II) has a strong antiviral activity.

[Chemical 3] (In the formula, X represents a hydrogen atom, a hydroxyl group, an amino group, and a halogen atom, and Y represents a hydrogen atom, a hydroxyl group, and an amino group.) However, this compound, like the conventional nucleic acid antiviral agents, There were problems such as low water solubility, poor oral absorption and skin permeability.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to improve the water solubility and the oral absorbability of the compound represented by the general formula (II), and as a result, the hydroxyl group of the compound is changed to a specific amino acid. It was found that the esterification improves the oral absorbability and actually enhances the therapeutic effect, and has completed the present invention.

That is, the present invention relates to a cyclopropane derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof and an antiviral agent containing the same.

[0006]

[Chemical 4] [Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom or a group represented by the following general formula (1) (provided that both are not hydrogen atoms),
X represents a hydrogen atom, a hydroxyl group, an amino group or a halogen atom, and Y represents a hydrogen atom, a hydroxyl group or an amino group. ]

[0007]

[Chemical 5] (In the group, R ³ represents an alkyl group having 1 to 6 carbon atoms.)

The number of carbon atoms in the general formula (1) is 1 to
Examples of the alkyl group of 6 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a 2-butyl group, an n-pentyl group, an n-hexyl group, and a methyl group. , Ethyl group, isopropyl group, isobutyl group and 2-butyl group are preferable, and methyl group and ethyl group are particularly preferable. The configuration of the asymmetric carbon atom in the general formula (1) is S configuration.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

Examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, acetic acid,
Examples thereof include organic acid salts such as lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, succinic acid and methanesulfonic acid.

Preferred cyclopropane derivatives are shown below. 9- [1'α, 2'α-bis (OL-alanyloxymethyl) cyclopropan-1'β-yl] methylguanine 9- [1'α, 2'α-bis (OL- 2-Aminobutyroyloxymethyl) cyclopropan-1′β-yl]
Methylguanine 9- [1′α, 2′α-bis (OL-valyloxymethyl) cyclopropan-1′β-yl] methylguanine 9- [1′α, 2′α-bis (OL -Leucyloxymethyl) cyclopropane-1'β-yl] methylguanine 9- [1'α, 2'α-bis (OL-isoleucyloxymethyl) cyclopropane-1'β-yl] methyl Guanine 9- [1'α, 2'α-bis (OL-alanyloxymethyl) cyclopropane-1'β-yl] methyl-2-
Aminopurine 9- [1'α, 2'α-bis (OL-2-aminobutyroyloxymethyl) cyclopropan-1'β-yl]
Methyl-2-aminopurine 9- [1′α, 2′α-bis (OL-valyloxymethyl) cyclopropan-1′β-yl] methyl-2-aminopurine 9- [1′α, 2 'α-bis (OL-leucyloxymethyl) cyclopropan-1'β-yl] methyl-2-
Aminopurine 9- [1′α, 2′α-bis (OL-isoleucylmethyl) cyclopropan-1′β-yl] methyl-2-aminopurine 9- [1′α, 2′α- Bis (OL-alanyloxymethyl) cyclopropane-1'β-yl] methyl-2-
Amino-6-chloropurine 9- [1'α, 2'α-bis (OL-2-aminobutyroyloxymethyl) cyclopropan-1'β-yl]
Methyl-2-amino-6-chloropurine 9- [1'α, 2'α-bis (OL-valyloxymethyl) cyclopropan-1'β-yl] methyl-2-amino-6-chloropurine 9- [1'α, 2'α-bis (OL-leucyloxymethyl) cyclopropan-1'β-yl] methyl-2-
Amino-6-chloropurine 9- [1'α, 2'α-bis (OL-isoleucylmethyl) cyclopropan-1'β-yl] methyl-2-amino-6-chloropurine

The cyclopropane derivative of the present invention includes both a racemic body and each optically active body.
Regarding the relative configuration of each compound, when cyclopropane is considered to be a plane, the substituents located below the plane are α,
Substituents located above the plane are represented by β.

The compound of the present invention can be produced, for example, as follows.

[0014]

[Chemical 6] (In the formula, X, Y and R ³ have the same meanings as described above, and Z represents an amino-group protecting group.)

First, a cyclopropane derivative (formula (1)) and an N-protected amino acid (formula (2)) obtained by the method described in JP-A-5-78357 and the like are treated with dimethylformamide, pyridine, acetonitrile and tetrahydrofuran. In a polar solvent as described above, a condensation agent such as carbodiimides such as N, N'-dicyclohexylcarbodiimide or 2-chloro-1-methylpyridinium tosylate is used for dehydration condensation to obtain the ester of formula (3). The target compound (formula (4)) can be obtained by deprotecting the amino-protecting group of the obtained ester by a suitable method.

As the amino-protecting group in the formula (2), those usually used in peptide synthesis can be used, and examples thereof include t-butoxycarbonyl group and benzyloxycarbonyl group. In the former case, the deprotection method may be carried out under acidic conditions such as trifluoroacetic acid and hydrochloric acid, and in the latter case, catalytic reduction in the presence of palladium-carbon may be used. An azido group may be used as a protecting group, but in this case, it can be converted into an amino group by reduction.

Instead of the above-mentioned condensing agent, an active ester of an N-protected amino acid such as N-hydroxysuccinimide or 2,4-dinitrophenol, or an acid anhydride may be used.

Of the compounds represented by the general formula (I), R ¹
Alternatively, when either one of R ² is a hydrogen atom, it can be produced, for example, as follows.

[0019]

[Chemical 7] (In the formula, Z and R ³ have the same meanings as described above, and DMTr
Represents a dimethoxytrityl group. )

That is, in the compound of the formula (8) included in the present invention, one hydroxyl group of the cyclopropane derivative represented by the formula (1 ') is protected by a dimethoxytrityl group, and the compound is separated and purified by, for example, column chromatography. After doing, N
It can be obtained by dehydration condensation with a protected amino acid and deprotection. Separation and purification may be performed after deprotection.

The compounds of the invention have antiviral activity,
Expected as an antiviral agent. Examples of viruses include herpes simplex virus, cytomegalovirus, V
ZV (Varicella Zoster Virus), EBV (Epstein-Ba
rr Virus), hepatitis virus, etc.

When the compound of the present invention is used as an antiviral agent, it can be administered intravenously, orally, transdermally, or by instillation. The dose varies depending on the patient's symptoms, age, and administration method, but is usually 0.1 to 500 m.
g / kg / day. The compound of the present invention is administered as an antiviral agent composition prepared by mixing with a suitable pharmaceutical carrier.

The formulation forms include injections, tablets, granules,
Fine granules, powders, capsules, creams, suppositories and the like, and examples of the carrier for the formulation include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropyl cellulose, Hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium salt, magnesium stearate, talc, acetylcellulose, sucrose, titanium oxide, benzoic acid, paraoxybenzoic acid ester, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, Egg yolk, surfactant, simple syrup, citric acid, distilled water, glycerin, propylene glycol, macrogol, sodium monohydrogen phosphate, sodium dihydrogen phosphate Sodium phosphate, sodium chloride, phenol, Saromechiru, there are sodium hydrogen sulfite, depending on the form of the preparation, is used in admixture with the compounds of the present invention.

The content of the active ingredient of the present invention in the preparation varies greatly depending on the form of the preparation, and is not particularly limited, but usually 0.01 to the total amount of the composition.
It is 80% by weight, preferably 1 to 70% by weight.

Next, the contents of the present invention will be specifically described by way of examples.

【Example】

Example 1 9- [1'S, 2'R-bis (OL-alanyloxymethyl) cyclopropane-
Production of 1'-yl] methylguanine trihydrochloride

Step 19- [1'S, 2'R-bis [O]
Production of-(Nt-butoxycarbonyl) -L-alanyloxymethyl] cyclopropan-1'-yl] methylguanine 9- [1'S, obtained by the method described in JP-A-5-78357. 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine 99.2 mg
(0.374 mmol) was dissolved in 3 ml of N, N-dimethylformamide at 60 ° C., 195 mg (1.03 mmol) of Nt-butoxycarbonyl-L-alanine,
N, N'-dicyclohexylcarbodiimide 259 mg
(1.26 mmol) and 13 mg (0.106 mmol) of 4-dimethylaminopyridine were added. After stirring the reaction solution at room temperature for 80 hours, the temperature was raised to 60 ° C. and the temperature was changed to Nt.
-Butoxycarbonyl-L-alanine 195 mg (1.
03 mmol) and 259 mg (1.26 mmol) of N, N'-dicyclohexylcarbodiimide were added. The reaction solution was cooled to room temperature and further stirred for 90 hours, then the insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane:
162.6 mg (0.2
(67 mmol, 70%) of the title compound was obtained.

White solid ¹ H-NMR (CD ₃ OD) δ: 0.85 (t, J = 5.4 Hz, 1 H), 1.22-1.32 (m, 1
H), 1.27 (d, J = 7.5Hz, 3H), 1.37 (d, J = 7.2Hz, 3H), 1.47
(s, 9H), 1.48 (s, 9H), 1.78-1.90 (m, 1H), 3.97 (d, J = 14.4
Hz, 1H), 4.04-4.28 (m, 6H), 4.36 (dd, J = 6.5,11.9Hz, 1H),
7.84 (s, 1H) mass spectrum (FAB): 607 (MH ⁺ )

Step 2 9- [1'S, 2'R-bis (O
-L-alanyloxymethyl) cyclopropane-1'-
Production of 9- [1 ′S, 2′R-bis [O- (Nt-butoxycarbonyl) -L-alanyloxymethyl] cyclopropan-1′-yl] methylguanine 144.8 mg
(0.238 mmol) was dissolved in 2 ml of 1,4-dioxane, and 2 ml of 4N hydrochloric acid-dioxane was added. After stirring for 1 hour, the precipitated white solid was collected by filtration and dried under reduced pressure to quantitatively obtain 114.3 mg (0.238 mmol) of the title compound.

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.88 (t, J = 5.6Hz, 1H), 1.29 (dd, J =
5.6,9.2Hz, 1H), 1.34 (d, J = 6.9Hz, 3H), 1.39 (d, J = 7.2Hz,
3H), 1.73-1.84 (m, 1H), 3.95-4.27 (m, 8H), 7.14 (brs, 2
H), 8.60 (brs, 3H), 8.68 (brs, 3H), 9.00 (s, 1H), 11.63
(brs, 1H) High-resolution mass spectrum (C ₁₇ H ₂₆ N ₇ O ₅ , MH ⁺ ): calculated 408.1995, measured 408.1993

The following compounds were produced in the same manner as in Example 1.

Example 2 9- [1'S, 2'R-bis (OL-valyloxymethyl) cyclopropane-1 '
-Yl] Methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.86-0.92 (m, 7H), 0.98 (d, J = 7.2Hz,
6H), 1.22-1.32 (m, 1H), 1.76-1.82 (m, 1H), 2.00-2.18 (m,
2H), 3.98-4.40 (m, 8H), 6.77 (brs, 2H), 8.42 (s, 1H), 8.
46 (brs, 3H), 8.58 (brs, 3H) high resolution mass spectrum (C ₂₁ H ₃₄ N ₇ O ₅ , MH ⁺ ): calculated value 464.2621, measured value 464.2630

Example 3 9- [1'S, 2'R-bis (OL-leucyloxymethyl) cyclopropane-
Production of 1'-yl] methylguanine trihydrochloride

White solid ¹ H-NMR (D ₂ O) δ: 0.90-0.96 (m, 12H), 1.02 (t, J = 6.0Hz, 1
H), 1.40 (dd, J = 5.7Hz, 9.0Hz, 1H), 1.50-1.80 (m, 6H), 4.
00-4.23 (m, 6H), 4.40 (s, 2H), 4.48-4.60 (m, 2H), 8.65
(s, 1H) High resolution mass spectrum (C ₂₃ H ₃₈ N ₇ O ₅ , MH ⁺ ): Calculated value 492.2934, Measured value 492.2941

Example 4 Preparation of 9- [1'S, 2'R-bis (OL-isoleucyloxymethyl) cyclopropan-1'-yl] methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.79-0.86 (m, 7H), 0.91 (t, J = 6.9H
z), 1.12-1.48 (m, 5H), 1.74-1.94 (m, 3H), 3.70-3.94
(m, 2H), 4.00-4.30 (m, 6H), 6.98 (brs, 2H), 8.57 (brs, 3
H), 8.70 (brs, 3H), 8.84 (s, 1H), 11.48 (brs, 1H) High-resolution mass spectrum (C ₂₃ H ₃₈ N ₇ O ₅ , MH ⁺ ): calculated 492.2934, found 492.2913

Example 5 Preparation of 9- [1'S, 2'R-bis (O-α-L-2-aminobutyroyloxymethyl) cyclopropan-1'-yl] methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.82-0.95 (m, 1H), 0.88 (t, J = 7.2Hz,
3H), 0.93 (t, J = 7.2Hz, 3H), 1.28 (dd, J = 5.7Hz, 9.0Hz, 1
H), 1.70-1.83 (m, 5H), 3.85-4.00 (m, 2H), 4.00-4.35 (m,
6H), 6.99 (brs, 2H), 8.60 (brs, 3H), 8.67 (brs, 3H), 8.8
0 (s, 1H), 11.48 (brs, 1H) High-resolution mass spectrum (C ₁₉ H ₃₀ N ₇ O ₅ , MH ⁺ ): Calculated value 436.2308, Measured value 436.2309

Comparative Example The following compounds were produced in the same manner as in Example 1.

Comparative Example 1 9- [1'S, 2'R-bis (O-glycyloxymethyl) cyclopropane-1'-
[Ill] production of methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.83 (t, J = 5.4Hz, 1H), 1.34 (dd, J =
5.1,8.7Hz, 1H), 1.64-1.76 (m, 1H), 3.72-3.86 (m, 4H),
3.91-4.33 (m, 6H), 7.13 (brs, 2H), 8.50 (brs, 3H), 8.57
(brs, 3H), 8.89 (s, 1H), 11.58 (brs, 1H) High-resolution mass spectrum (C ₁₅ H ₂₂ N ₇ O ₅ , MH ⁺ ): calculated value 380.1680, measured value 380.1682

Comparative Example 2 9- [1'S, 2'R-bis (OL-prolyloxymethyl) cyclopropane-
Production of 1'-yl] methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (t, J = 5.7Hz, 1H), 1.28 (dd, J =
5.1Hz, 9.0Hz, 1H), 1.74-2.00 (m, 9H), 2.14-2.30 (m, 4H),
4.00-4.40 (m, 8H), 7.04 (brs, 2H), 8.83 (s, 1H), 9.08-9.
30 (m, 3H), 10.26-10.50 (m, 3H), 11.53 (brs, 1H) High resolution mass spectrum (C ₂₁ H ₃₀ N ₇ O ₅ , MH ⁺ ): Calculated value 460.2308, Measured value 460.2290

Comparative Example 3 Preparation of 9- [1'S, 2'R-bis (OL-phenylalanyloxymethyl) cyclopropan-1'-yl] methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.65 (t, J = 5.7Hz, 1H), 1.14 (dd, J =
5.7Hz, 9.0Hz, 1H), 1.49-1.61 (m, 1H), 3.00-3.24 (m, 4H),
3.85-4.32 (m, 8H), 6.98 (brs, 2H), 7.16-7.35 (m, 10H),
8.72 (brs, 3H), 8.87 (s, 1H), 8.82 (brs, 3H), 11.49 (brs,
1H) High resolution mass spectrum (C ₂₉ H ₃₄ N ₇ O ₅ , MH ⁺ ): calculated value 560.2621, measured value 560.2605.

Comparative Example 4 9- [1'S, 2'R-bis (O-α-L-asparatyl) cyclopropane-1'-
[Ill] production of methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.76-0.83 (m, 1H),
1.20-1.28 (m, 1H), 1.58-1.68 (m, 1H), 2.90 (d, J = 5.1Hz, 2
H), 3.66 (d, J = 9.6Hz, 2H), 3.92-4.40 (m, 6H), 6.84 (brs,
2H), 8.50-8.80 (m, 7H), 11.34 (brs, 1H) High-resolution mass spectrum (C ₁₉ H ₂₆ N ₇ O ₉ , MH ⁺ ): calculated 496.1792, found 496.1793

Comparative Example 5 9- [1'S, 2'R-bis (O-β-L-asparatyl) cyclopropane-1'-
[Ill] production of methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-0.82 (m, 1H), 1.21-1.30 (m, 1
H), 1.58-1.68 (m, 1H), 2.80-3.02 (m, 4H), 3.73-3.76 (m,
2H), 3.92-4.38 (m, 6H), 6.85 (brs, 2H), 8.42-8.82 (m, 7
H), 11.34 (brs, 1H) high-resolution mass spectrum (C ₁₉ H ₂₆ N ₇ O ₉ , MH ⁺ ): calculated 496.1792, found 496.1790

Comparative Example 6 9- [1'S, 2'R-bis (O-β-alanyloxymethyl) cyclopropane-
Production of 1'-yl] methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.90 (m, 1H), 1.26-1.44 (m, 5
H), 1.65-1.80 (m, 1H), 2.68-2.80 (m, 2H), 2.95-3.03 (m,
2H), 3.82-4.44 (m, 6H), 7.30 (bs, 2H), 8.31 (bs, 3H), 8.
73 (bs, 3H), 9.06 (d, J = 7.8Hz, 1H), 11.78 (bs, 1H) High resolution mass spectrum _{(C 17 H 26 N 7 O} 5, MH +): calcd 408.1995, found 408.2010

Comparative Example 7 9- [1'S, 2'R-bis (OD-alanyloxymethyl) cyclopropane-
Production of 1'-yl] methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.86 (t, J = 5.7Hz, 1H), 1.29 (dd, J =
5.7Hz, 9.0Hz, 1H), 1.35 (d, J = 7.2Hz, 3H), 1.41 (d, J = 6.9H
z, 3H), 1.67-1.78 (m, 1H), 3.90-4.38 (m, 8H), 6.94 (brs,
2H), 8.57 (brs, 3H), 8.64 (brs, 3H), 8.70 (s, 1H), 11.18
(brs, 1H) High-resolution mass spectrum (C ₁₇ H ₂₆ N ₇ O ₅ , MH ⁺ ): calculated 408.1995, measured 408.1997

Comparative Example 8 9- [1'S, 2'R-bis (OD-valyloxymethyl) cyclopropane-1 '
-Yl] Methylguanine trihydrochloride

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.85 (t, J = 5.6Hz, 1H), 0.93 (d, J = 6.
9Hz, 3H), 0.95 (d, J = 6.9Hz, 3H), 0.96 (d, J = 7.2Hz, 3H),
0.97 (d, J = 6.6Hz, 3H), 1.30 (dd, J = 5.6,8.4Hz, 1H), 1.71-
1.81 (m, 1H), 2.06-2.22 (m, 2H), 3.99-4.34 (m, 8H), 6.94
(bs, 2H), 8.52 (bs, 2H), 8.69 (bs, 2H), 11.36 (bs, 1H) High-resolution mass spectrum (C ₂₁ H ₃₄ N ₇ O ₅ , MH ⁺ ): calculated value 464.2621, measured value 464.2642

Comparative Example 9 9- [1'S, 2'R-bis (OL-lysyloxymethyl) cyclopropane-1 '
-Yl] Methylguanine pentahydrochloride production

Step 19- [1'S, 2'R-bis [O]
Preparation of-(α-Nt-butoxycarbonyl) -ω-N-benzyloxycarbonyl-L-lysyloxymethyl] cyclopropan-1'-yl] methylguanine 9- [1'S, 2'R-bis (Hydroxymethyl) cyclopropan-1′-yl] methylguanine 200 mg
(0.74 mmol) was dissolved in 20 ml of N, N-dimethylformamide, and α-Nt-butoxycarbonyl-
ω-N-benzyloxycarbonyl-L-lysine 769
mg (2.02 mmol), N, N′-dicyclohexylcarbodiimide 507 mg (2.46 mmol) and 4-dimethylaminopyridine 26 mg (0.21 mm
ol) was added and the mixture was stirred at room temperature for 28 hours. Furthermore α-N
-T-butoxycarbonyl-ω-N-benzyloxycarbonyl-L-lysine 769 mg (2.02 mmo
l), N, N'-dicyclohexylcarbodiimide 50
7 mg (2.46 mmol) and 4-dimethylaminopyridine 26 mg (0.21 mmol) were added, the mixture was stirred at room temperature for 110 hours, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100:
5) over 440 mg (0.444 mmol, 58.9)
%) Of the title compound was obtained.

White solid ¹ H-NMR (CDCl ₃ ) δ: 0.68-0.72 (m, 1H), 1.02-1.15 (m, 1H),
1.38 (s, 9H), 1.42 (s, 9H), 1.22-1.80 (m, 13H), 3.10-3.2
0 (m, 4H), 3.70-4.35 (m, 8H), 5.07 (s, 4H), 5.24-5.32 (m,
1H), 5.36-5.44 (m, 1H), 7.26-7.34 (m, 10H), 7.63 (s, 1H) Mass spectrum (FAB): 990 (MH ⁺ )

Step 2 9- [1'S, 2'R-bis (O
Preparation of -L-lysyloxymethyl) cyclopropan-1'-yl] methylguanine pentahydrochloride 9- [1'S, 2'R-bis [O- (α-Nt-butoxycarbonyl) -ω- Benzyloxycarbonyl-L
-Lysyloxymethyl] cyclopropan-1'-yl]
365 mg (0.369 mmol) of methylguanine was dissolved in 5 ml of methanol, and 5% palladium carbon (52.
4% wet) 150 mg was added, and under hydrogen atmosphere, at room temperature
Stir for hours. This was filtered and the solvent was distilled off under reduced pressure, then dissolved in 4 ml of methanol and 4 ml of 4N hydrochloric acid-dioxane.
Was added and stirred at room temperature for 6 hours, and then the solvent was distilled off under reduced pressure. The obtained residue is reprecipitated from methanol-ethyl acetate, and the deposited precipitate is collected by filtration and dried under reduced pressure.
Obtained 1.7 mg (0.343 mmol, 93.3%) of the title compound.

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.92 (t, J = 5.7Hz, 1H), 1.29 (dd, J =
5.7Hz, 9.0Hz, 1H), 1.32-1.83 (m, 13H), 2.70-2.83 (m, 4
H), 3.85-4.30 (m, 8H), 7.04 (brs, 2H), 8.12 (brs, 6H),
8.62-8.84 (m, 7H), 11.52 (brs, 1H) High-resolution mass spectrum (C ₂₃ H ₄₀ N ₉ O ₅ , MH ⁺ ): calculated 522.3152, found 522.3178

Comparative Example 10 9- [1'S, 2'R-bis (OL-seryloxymethyl) cyclopropane-1 '
-Yl] Methylguanine trihydrochloride

Step 1 9- [1'S, 2'R-bis [O
-(Nt-butoxycarbonyl) O-benzyl-L-
Preparation of ceryloxymethyl] cyclopropan-1′-yl] methylguanine 9- [1 ′S, 2′R-bis (hydroxymethyl) cyclopropan-1′-yl] methylguanine 200 mg
(0.754 mmol) was dissolved in 20 ml of N, N-dimethylformamide, and Nt-butoxycarbonyl-O was added.
-Benzyl-L-serine 597 mg (2.02 mmo
l), N, N'-dicyclohexylcarbodiimide 50
7 mg (2.46 mmol) and 4-dimethylaminopyridine 26 mg (0.21 mmol) were added and the mixture was stirred at room temperature for 2
Stir for 8 hours. Furthermore, Nt-butoxycarbonyl-
597 mg of O-benzyl-L-serine (2.02 mmo
l), N, N'-dicyclohexylcarbodiimide 50
7 mg (2.46 mmol) and 4-dimethylaminopyridine 26 mg (0.21 mmol) were added, and after stirring at room temperature for 110 hours, the insoluble material was filtered off and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol = 100: 5).
427.7 mg (0.522 mmol, 69.2)
%) Of the title compound was obtained.

White solid ¹ H-NMR (CDCl ₃ ) δ: 0.60-0.68 (m, 1H), 1.00-1.10 (m, 1H),
1.39 (s, 9H), 1.41 (s, 1H), 1.52-1.65 (m, 1H), 3.60-3.94
(m, 6H), 4.02-4.30 (m, 4H), 4.36-4.58 (m, 2H), 4.46 (s, 2
H), 4.50 (s, 2H), 5.42 (d, J = 8.1Hz, 1H), 5.61 (d, J = 8.1H
z, 1H), 6.00 (brs, 2H), 7.20-7.32 (m, 10H), 7.59 (s, 1H) Mass spectrum (FAB): 820 (MH ⁺ )

Step 2 9- [1'S, 2'R-bis (O
Preparation of -L-seryloxymethyl) cyclopropan-1'-yl] methylguanine trihydrochloride 9- [1'S, 2'R-bis [O- (Nt-butoxycarbonyl) O-benzylseryloxy Methyl] cyclopropan-1′-yl] methylguanine 300 mg
(0.366 mmol) was dissolved in 5 ml of methanol,
150 mg of 5% palladium carbon (52.4% wet) was added, and the mixture was stirred at 40 ° C for 10 hours under a hydrogen atmosphere of 3 kgf / cm ² . This was filtered and the solvent was distilled off under reduced pressure. To the residue was added 4 ml of 4N hydrochloric acid-dioxane and the mixture was stirred at room temperature for 1 hour, then the solvent was distilled off under reduced pressure. The obtained residue was reprecipitated from methanol-diethyl ether, and the deposited precipitate was collected by filtration and dried under reduced pressure to give 180.5 mg (0.3
29 mmol, 89.9%) of the title compound was obtained.

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (t, J = 5.7Hz, 1H), 1.28 (dd, J =
5.1Hz, 8.7Hz, 1H), 1.62-1.72 (m, 1H), 3.70-3.92 (m, 6H),
3.94-4.28 (m, 6H), 6.80 (brs, 2H), 8.38 (s, 1H), 8.54 (br
s, 3H), 8.60 (brs, 3H), 11.18 (brs, 1H) high resolution mass spectrum (C ₁₇ H ₂₆ N ₇ O ₇ , MH ⁺ ): calculated value 440.1894, measured value 440.1894

Example 6 9- [1'S, 2'R-bis (OL-alanyloxymethyl) cyclopropane-
Production of 1'-yl] methylguanine dihydrochloride

Step 1 9- [1'S, 2'R-bis [O
Preparation of-(N-benzyloxycarbonyl) -L-alanyloxymethyl] cyclopropan-1'-yl] methylguanine 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropane-1'- Il] methylguanine 200mg
(0.754 mmol) was dissolved in 50 ml of N, N-dimethylformamide, and N-benzyloxycarbonyl-
L-alanine 451 mg (2.02 mmol), N,
N'-dicyclohexylcarbodiimide 507 mg
(2.46 mmol) and 4-dimethylaminopyridine 26 mg (0.21 mmol) were added, and the mixture was stirred at room temperature for 48 hours. Furthermore, N-benzyloxycarbonyl-L-
Alanine 451 mg (2.02 mmol), N, N'-
507 mg of dicyclohexylcarbodiimide (2.46
mmol) and 4-dimethylaminopyridine 26 mg
(0.21 mmol) was added and the mixture was stirred at room temperature for 96 hours, then the insoluble material was filtered off and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 5) to give 429 mg.
(0.635 mmol, 84.3%) of the title compound was obtained.

White solid ¹ H-NMR (DMSO-d6) δ: 0.72 (m, 1H), 1.13 (m, 1H), 1.17 (d, J
= 7.5Hz, 3H), 1.26 (d, J = 7.5Hz, 3H), 1.59 (m, 1H), 3.8-4.
2 (m, 8H), 5.03 (s, 4H), 6.27 (bs, 2H), 7.2-7.4 (m, 10H),
7.63 (s, 1H), 7.68 (d, J = 7.5Hz, 1H), 7.75 (d, J = 7.5Hz, 1
H), 10.51 (bs, 1H) Mass spectrum (FAB): 676 (MH ⁺ )

Step 2 9- [1'S, 2'R-bis (O
-Α-L-alanyloxymethyl) cyclopropane-
Preparation of 1'-yl] methylguanine dihydrochloride 9- [1'S, 2'R-bis [O- (Nt-butoxycarbonyl) -α-L-alanyloxymethyl] cyclopropane-1 ' -Yl] methylguanine 2.042 g
(3.02 mmol) was dissolved in 30.2 ml of methanol, 408 mg of 10% palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere for 24 hours. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give 1.61 g of the title compound quantitatively.

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (t, J = 5.4Hz, 1H), 1.19 (dd, J =
5.4,8.7Hz, 1H), 1.30 (d, J = 7.2Hz, 3H), 1.39 (d, J = 7.2Hz,
3H), 1.67-1.75 (m, 1H), 3.90-4.26 (m, 8H), 6.49 (bs, 2
H), 7.78 (s, 1H), 8.50 (bs, 6H), 10.72 (bs, 1H) Mass spectrum (FAB): 408 (MH ⁺ ) High resolution mass spectrum (C ₁₇ H ₂₆ N ₇ O ₅ , MH ⁺ ): Calculated 408.1995, measured 408.1984

Example 7 9- [1'S, 2'R-bis (OL-valyloxymethyl) cyclopropane-1 '
-Yl] Methylguanine dihydrochloride production

Step 1 9- [1'S, 2'R-bis [O
Preparation of-(N-benzyloxycarbonyl) -L-valyloxymethyl] cyclopropan-1'-yl] methylguanine 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl ] Methylguanine 5.305 g
(20 mmol) as N, N-dimethylformamide 15
It was dissolved in 0 ml and N-benzyloxycarbonyl-L-
Valine 13.468 g (53.6 mmol), N, N '
-Dicyclohexylcarbodiimide 13.453 g (6
5.2 mmol) and 4-dimethylaminopyridine 6
84 mg (5.6 mmol) was added, and the mixture was stirred at room temperature for 78 hours. Furthermore, 13.468 g (53.6 mmol) of N-benzyloxycarbonyl-L-valine, N, N'-
Dicyclohexylcarbodiimide 13.453 g (6
5.2 mmol) and 4-dimethylaminopyridine 6
After adding 84 mg (5.6 mmol) and stirring at room temperature for 98 hours, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 5), which was 9.8.
2 g (13.4 mmol, 67.1%) of the title compound was obtained.

White solid ¹ H-NMR (CDCl ₃ ) δ: 0.64 (t, J = 5.4H
z, 1H), 0.80-1.00 (m, 12H), 1.10-1.20 (m, 1H), 1.58-1.70 (m, 1H), 2.00-2.20 (m, 2H), 3.80-4.37 (m, 8H ),
5.00-5.15 (m, 4H), 5.44 (d, J = 9.0Hz, 1H), 5.70 (d, J = 9.0H
z, 1H), 6.29 (brs, 2H), 7.17-7.40 (m, 10H), 8.02 (s, 1H) Mass spectrum (FAB): 732 (MH ⁺ )

Step 2 9- [1'S, 2'R-bis (O
Preparation of -L-valyloxymethyl) cyclopropan-1'-yl] methylguanine dihydrochloride 9- [1'S, 2'R-bis [O- (N-benzyloxycarbonyl) -L-valyloxymethyl ] Cyclopropan-1′-yl] methylguanine 290 mg (0.4
37 mmol) was dissolved in 4 ml of methanol, 0.96 ml of 1N hydrochloric acid and 5% palladium carbon (52.4% we).
t) 200 mg was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. This was filtered and the solvent was distilled off under reduced pressure. The obtained residue was reprecipitated from ethanol-ethyl acetate, and the deposited precipitate was collected by filtration and dried under reduced pressure to give 250 mg (0.437).
(mmol, 100%) of the title compound was obtained.

White solid ¹ H-NMR (DMSO-d ₆ ) δ: 0.86-0.92 (m, 7H), 0.98 (d, J = 7.2Hz,
6H), 1.22-1.32 (m, 1H), 1.76-1.82 (m, 1H), 2.00-2.18 (m,
2H), 3.98-4.40 (m, 8H), 6.77 (brs, 2H), 8.42 (s, 1H), 8.
46 (brs, 3H), 8.58 (brs, 3H) High resolution mass spectrum (C ₂₁ H ₃₄ N ₇ O ₅ , MH ⁺ ): Calculated value 464.2621, Measured value 464.26443

Test Example 1 Oral Absorption Measurement Each test compound was dissolved in 0.2 ml of physiological saline so that the dose was 0.1 mmol / kg, and male IC at 5 weeks of age was used.
R mouse was orally administered. 15 minutes, 30 minutes, 1 after administration
Blood was collected from 3 mice each at 3 hours, 2 hours, and 4 hours, and centrifuged at 3000 rpm for 10 minutes to obtain plasma. 20% trichloroacetic acid aqueous solution (100 μl) was added to plasma (100 μl) and shaken to obtain 8000 r
The supernatant was obtained by centrifugation at pm for 1 minute. The concentration of 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine in this supernatant was measured by HPLC, and the area under the plasma concentration curve (AUC) was measured. I asked. The results are shown in Table 1.

[0078]

[Table 1]

As is clear from this result, the compound of the present invention was 9- [1'S, 2'R-bis (hydroxymethyl)
It excels in oral absorbability compared to cyclopropan-1′-yl] methylguanine, and has oral absorbability equal to or higher than that of 9- (2-OL-valyloxyethoxy) methylguanine. You can see that

Test Example 2 Oral Administration Drug Efficacy Test HSV-1 (Tom) was added to 4-week-old male CDF-1 mice.
(ioka strain) was intraperitoneally infected with a virus amount of 2.4 × 10 ⁵ pfu / head. Administration of each test compound was started 3 hours after infection. 0.625, 1.25, 2.5 μmol of each test compound was administered once a day for 5 consecutive days.
/ Ml / kg / day of distilled water for injection 0.2ml
It was dissolved in and was administered into the stomach with a catheter. Each administration group consisted of 10 animals, and the survival rate and the average number of death days were calculated 21 days after infection. The results are shown in Table 2.

[0081]

[Table 2]

As is clear from these results, 9-[[1'S, 2'R-bis (O- which is one of the compounds of the present invention.
L-alanyloxymethyl) cyclopropan-1'-yl] methylguanine has a medicinal effect as compared with 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine. It can be seen that the above is also excellent.

Example 8 Preparation of preparation for injection and drip 9 g of 1 g of 9-[[1'S, 2'R-bis (OL-alanyloxymethyl) cyclopropan-1'-yl] methylguanine was added to 600 ml of 600 ml. Dissolve in purified water, and filter by sterilization using a Millipore filter. 20 ml of this filtrate 15 g
25 lyophilized in vials
A lyophilized formulation containing mg was obtained.

Example 9 Preparation of tablets 9-[[1'S, 2'R-bis (OL-alanyloxymethyl) cyclopropan-1'-yl] methylguanine 10 g and 40 g lactose, 49 g Crystalline cellulose, 1
g of magnesium stearate was thoroughly mixed and compressed with a tableting machine to give tablets containing 250 mg per tablet.

Example 10 Preparation of granules 9-[[1'S, 2'R-bis (OL-alanyloxymethyl) cyclopropan-1'-yl] methylguanine 10 g and 90 g lactose, 100 g The crystalline cellulose of 1 was well mixed, compressed by a roll type compressor, pulverized, and sieved to obtain granules of 20-80 mesh.

Example 11 Preparation of ointment 9-[[1'S, 2'R-bis (OL-alanyloxymethyl) cyclopropan-1'-yl] methylguanine 1 g, propylene glycol 6 g, carboxy About 60 g of a mixed solution of 4 g of methyl cellulose and 89 g of white petrolatum
The mixture was heated to ℃, mixed and dissolved to obtain a 1 wt% ointment.

Example 12 Preparation of Eye Drops 9-[[1'S, 2'R-bis (OL-alanyloxymethyl) cyclopropan-1'-yl] methylguanine 1 g and sodium chloride 1 g were pure. It was dissolved in 100 ml of water and the pH was adjusted to 7.5 with sodium monohydrogen phosphate to obtain an eye drop of about 1% by weight.

[0088]

According to the present invention, it is excellent in water solubility and
It is possible to provide an antiviral agent having excellent oral absorbability and therapeutic effect.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location C07D 473/32 473/34 321 473/40 (72) Inventor Naoshi Tsuji Suzuki, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture 1-1 Ajinomoto Co., Inc. Central Research Institute (72) Inventor Satoshi Iwayama 1-1 Suzuki Town, Kawasaki-ku, Kawasaki City, Kanagawa Ajinomoto Co., Inc. Central Research Center (72) Inventor Katsuya Suzuki Kawasaki, Kawasaki, Kanagawa Prefecture 1-1, Suzuki-cho, Ajinomoto Co., Inc. Central Research Laboratory (72) Inventor Yuko Omura 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa Ajinomoto Co., Ltd. Central Research Center (72) Inventor Masahiko Okunishi Kawasaki, Kanagawa 1-1, Suzuki-cho, Kawasaki-ku, Ichi Ajinomoto Co., Inc. Central Research Laboratory

Claims (6)

[Claims] 1. A cyclopropane derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. [Chemical 1] [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a group represented by the following general formula (1) (provided that both are not hydrogen atoms),
X represents a hydrogen atom, a hydroxyl group, an amino group or a halogen atom, and Y represents a hydrogen atom, a hydroxyl group or an amino group. ] [Chemical 2] (In the group, R ³ represents an alkyl group having 1 to 6 carbon atoms.) 2. X is a hydroxyl group and Y is an amino group.
The described cyclopropane derivative or a pharmaceutically acceptable salt thereof. 3. The cyclopropane derivative or the pharmaceutically acceptable salt thereof according to claim ^1, wherein R ¹ and R ² are both groups represented by the general formula (1). 4. A cyclopropane derivative or a pharmaceutically acceptable salt thereof according to claim ³ , wherein R ³ is a methyl group, an ethyl group, an isopropyl group, an isobutyl group or a 2-butyl group. 5. 9- [1 ′S, 2′R-bis (OL-alanyloxymethyl) cyclopropan-1′β-yl]
Methylguanine or a pharmaceutically acceptable salt thereof. 6. An antiviral agent containing the cyclopropane derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.