JPH06345748A - New glycyrrhizic acid derivative having antiviral activity - Google Patents

Abstract

PURPOSE:To obtain a 4-(substituted)piperazin-1-yl derivative of a new 11-deoxo- glycyrrhizic acid useful as a preventive and a therapeutic agent for virus infectious diseases including infectious diseases by a virus showing resistance to an existing antiviral substance. CONSTITUTION:A compound of formula I (R is halogen, lower alkyl, NO2, CN, NH2, lower alkylamino, trifluoroacetylamino, acetyl, carboxyl or carbamoyl) and its salt such as 1-(3beta-hydroxy-18beta-olean-12-en-30-oyl)-4-phenylpiperazine. The compound is obtained by condensing 11-deoxo-glycyrrhizic acid with a phenylpiperazine of formula II by using carbodiimide. The compound is useful as a main component of a preventive and a therapeutic agent for infectious diseases caused by various DNA viruses, RNA viruses and retroviruses.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a preventive and therapeutic agent for viral infections, which comprises a novel 11-deoxoglycyrrhetinic acid derivative as a main component.

[0002]

Glycyrrhetinic acid and certain derivatives thereof are known to have anti-ulcer, anti-inflammatory, anti-allergic and anti-hepatitis effects. Examples of this type of compound include carbenoxolone (US Patent No. 30706).
23), a 30-position ester derivative of glycyrrhetinic acid (US Pat. No. 3,070,624), an amino acid salt of glycyrrhetinic acid (JP-B-44-32798), an amide derivative of glycyrrhetinic acid (Belgian Patent No. 753773).
), An amide derivative of 11-deoxoglycyrrhetinic acid (British Patent No. 1346871) and cycloxolone (Journal of Antimicrobial Chemotherapy, Vol. 18, Su.
ppl.B, 185-200 (1986).), glycyrrhizin and its derivatives (Chem.Pharm, Bull, 39 (1), 112-115 (1991).) and the like are known. The present inventors have also developed a novel synthetic method of 11-deoxoglycyrrhetinic acid (JP-A-59-70638),
Hemiester derivatives (JP-A-58-8044), carboxylic acid derivatives and amide derivatives (JP-A-63-1353)
No. 51) has been provided.

Glycyrrhetinic acid and its derivatives have various useful pharmacological actions as described above. But,
There are few reports on antiviral effects.

[0004] For example, it has been reported that glycyrrhizin is effective against herpes virus, but its efficacy has not increased until it can be said to be sufficient for treatment (Nature, 281 (2
5), (1979).). Also, Carbenoxolone (The Lancet, V
ol.336,813 (1990)) and cycloxolone (Cicloxolon
e, Journal of Antimicrobial Chemotherapy, Vol.18,
Suppl.B, 185-200 (1986)) has been reported to be effective against herpes virus, but there is a problem with its cytotoxic effect at a concentration at which antiviral activity is observed, and its stability in aqueous solution. There are various problems. Furthermore, Chem.Pharm.Bull., 39 (1), 112-115, (1991)
Reports that glycyrrhizin is also effective against human AIDS virus, but its effective concentration is not sufficient for treatment. Furthermore, glycyrrhizin, carbenoxolone, and cycloxolone have a problem of side effects due to pseudo-aldosterone-like action.

As antiviral agents other than glycyrrhetinic acid and its derivatives, various nucleic acid type antiviral agents represented by acyclovir have been developed in recent years, and excellent clinical effects have been recognized particularly in infectious diseases caused by herpesvirus group. There is. However, infectious diseases caused by resistant viruses such as those already lacking thymidine kinase have become a problem (Or
al Surg Oral Med Oral Pathol, Vol.67, 427-432 (198
9).). In addition, these nucleic acid-based antiviral agents are generally ineffective against RNA viruses such as influenza virus.

Phosphonoformates (PFA, Japanese clinical, 47 (2), 390-394 (198) are effective as antiviral agents other than nucleic acid antiviral agents against DNA viruses.
9)), Phosphonoacetate (PAA, Japanese Clinical, Volume 47)
(2), 390-394 (1989)) are known. However, with respect to phosphonoformate and phosphonoacetate, renal dysfunction and anemia have become problems as side effects.

Amantadine (pediatric practice, 54 (4), 988-994 (1991).), Rimantadine (pediatric practice, 54 Volume (4), 988-994 (1991).
), LY253963 (thiadiazole derivative, pediatric practice, 54 (4), 988 to 994 (1991).) And the like. Amantadine and rimantadine are effective against influenza A virus but ineffective against influenza B virus, and side effects on the central nervous system pose a problem. With respect to LY253936, an anti-influenza virus action in animals has been confirmed, but clinical efficacy has not yet been confirmed.

AZT, DDI, and the like (pediatric practice, 54 (4), 981 to 987 (19)) are effective as antiviral agents against retroviruses typified by human AIDS virus (HIV).
91).) Is known. However, although these antiviral agents delay the onset of AIDS, complete cure cannot be expected, and side effects such as myelosuppression are a problem.

In recent years, organ transplantation, cancer chemotherapy or HI
The number of patients with immunodeficiency associated with V infection is on the rise and has become a major medical problem. The viral infections that develop in such patients are extremely diverse and often cannot be treated with existing antiviral agents, and there is great hope for the development of superior antiviral agents. In addition, HIV and H
There are great expectations for the development of antiviral agents effective for CV.

[0010]

Therefore, the main object of the present invention is to treat acyclovir-resistant herpesviruses, various DNA viruses including HIV and HCV, R
It is to provide a novel 11-deoxoglycyrrhetinic acid derivative having an excellent effect on NA virus and retrovirus.

[0011]

DETAILED DESCRIPTION OF THE INVENTION The present inventors have so far developed 1- [3β- (3
Some compounds, including -carboxypropanoyloxy) -18β-olean-12-ene-30-oil] -4- (2-methoxyphenyl) piperazine, have anti-herpes simplex type 1 virus activity. It was reported (JP-A-4-352755). However, since there was little difference between the effective concentration and the concentration showing cytotoxicity,
We have conducted studies on 11-deoxoglycyrrhetinic acid derivatives, which have less cytotoxicity and strong antiviral activity.

The inventors of the present invention, for the purpose of elucidating the significance of phenylpiperazine substituted at the 30-position of 11-deoxoglycyrrhetinic acid or its derivatives, have an antiviral effect and a cytotoxic effect of modified or unmodified phenylpiperazine. I studied about. As a result, surprisingly, a large number of compounds have a wide range of antiviruses against various DNA viruses and RNA viruses such as herpes simplex virus (types 1 and 2), vaccinia virus, herpes zoster virus, cytomegalovirus, influenza virus, etc. It has been discovered and reported that it exerts an action and is effective in both local administration and systemic administration.

Furthermore, the present inventors have clarified the antiviral effect of the above-mentioned modified or unmodified phenylpiperazine, and then known compounds containing these compounds as substituents in their structures and these compounds. The antiviral activity of the novel compound in which was introduced as a substituent was investigated. As a result, we have found and reported that, very interestingly, many compounds have strong antiviral activity.

Based on the above findings, the inventors of the present invention have conducted extensive studies for the purpose of further improving the antiviral activity, and as a result, 30% of 11-deoxoglycyrrhetinic acid was obtained.
It has been reported that a compound in which a phenylpiperazine modified with a chloro group or a trifluoromethyl group at the position is introduced, and a glycoside having the compound as an aglycone has a very excellent antiviral effect (DE 0,518,533). Furthermore, the present inventors have studied the relationship between the activity and the substituent of the phenyl group of the phenylpiperazine introduced at the 30-position of 11-deoxoglycyrrhetinic acid, and found that a compound having a certain kind of substituent introduced was a chloro group. It has an anti-herpes simplex type 1 virus activity superior to that of the compound into which the human AIDS virus (HI
It was discovered that it also has an excellent effect on V), and the present invention has been basically completed.

The 11-deoxoglycyrrhetinic acid derivative represented by the general formula (I) is known per se (JP-A-63-13).
5351) is a compound of formula (II)

[Chemical 2] (II) (A in the above formula means hydrogen or an acetyl group.)
The 11-deoxoglycyrrhetinic acid derivative represented by and modified or unmodified phenylpiperazine that can be produced by a conventional method form an amide bond by the acid chloride method to deprotect the 3-position acetyl group, Alternatively, it can be obtained by condensing the 11-deoxoglycyrrhetinic acid derivative represented by the formula (II) and modified or unmodified phenylpiperazine with carbodiimide.

The modified or unmodified phenylpiperazine reacts the corresponding halogenobenzene derivative with piperazine or cyclizes the amino group of the corresponding aniline derivative into piperazine, as shown in formulas (III, IV). That is, it can be obtained by a general method in organic chemistry.

[Chemical 3] (III) (In the formula, R means hydrogen, halogen, lower alkyl, nitro, cyano, amino, lower alkylamino, trifluoroacetylamino, acetyl, carboxyl, carbamoyl.)

[Chemical 4] (IV) (wherein R has the above meaning and X means halogen.)

[0017]

The present invention will be described in more detail with reference to the production examples and pharmacological test examples of the compounds according to the present invention.

Production Example 1 1- (3β-acetoxy-18β-olean-12-d
3-30-oil) -4- (2-phenyl) piperazine known compound 3β-acetoxy-18β-olean-12-ene-30-oil chloride 3.00 g (5.80 mm)
ol) and 646 mg (6.38 mmol) of triethylamine were dissolved in 30.0 ml of dichloromethane, and 1- (2-phenyl) was added thereto.
1.04 g (6.38 mmol) of piperazine was added, and the mixture was stirred at 10 to 20 ° C for 2 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.70 g, yield 99.2%).

MS spectrum (EI / DI) m / z: 642 (M ⁺ ), 162 (
-Speak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.79,0.86,0.88,0.
95,1.13,1.23 (21H, s × 6, CH ₃ × 7), 1.2〜2.1 (23H, m, C
H and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 3.1 ~ 3.2 (4H, m, C
H ₂ × 2), 3.7 to 3.9 (4H, m, CH ₂ × 2), 4.45 to 4.55 (1
H, m, C ₃ -H), 5.2 ~ 5.3 (1H, m, C ₁₂ -H), 6.85 ~ 6.95
(2H, m, aromatic H), 7.25 to 7.32 (2H, m, aromatic H)

3β-acetoxy-18 was prepared in the same manner as in Production Example 1.
Starting from β-olean-12-ene-30-oil chloride and treated in the same way, the following 3β-acetoxyglycyrrhetinic acid derivative was obtained.

Production Example 2 1- (3β-acetoxy-18β-olean-12-d
-30-oil) -4- (2-fluorophenyl) pi
Perazine MS spectrum (EI / DI) m / z: 660 (M ⁺ ), 189 (Bespeak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.80, 0.86, 0.87, 0.
96,1.13,1.23 (21H, s × 6, CH ₃ × 7), 1.2〜2.2 (23H, m, C
H and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 3.0 ~ 3.1 (4H, m, C
H ₂ × 2), 3.7 to 3.9 (4H, m, CH ₂ × 2), 4.45 to 4.55 (1
H, m, C ₃ -H), 5.3 ~ 5.4 (1H, m, C ₁₂ -H), 6.9 ~ 7.1 (4
H, m, aromatic H)

Production Example 3 1- (3β-acetoxy-18β-olean-12-d
-30-Oil) -4- (2-tolyl) piperazine MS spectrum (EI / DI) m / z: 656 (M ⁺ ), 189 (Bespeak) ¹ H-NMR spectrum (CDCl ₃ ) δppm : 0.81,0.87,0.88,0.
97,1.14,1.24 (21H, s × 6, CH ₃ × 7), 1.2〜2.2 (23H, m, C
H and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 2.33 (3H, s, C
H ₃ ), 3.85 ~ 3.95 (4H, m, CH ₂ × 2), 3.75 ~ 3.85 (4H, m,
CH ₂ × 2), 4.45 ~ 4.55 (1H, m, C ₃ -H), 5.3 ~ 5.4 (1H, m, C
₁₂ -H), 6.95 ~ 7.20 (4H, m, aromatic H)

Production Example 4 1- (3β-acetoxy-18β-olean-12-d
-30-oil) -4- (2-n-propylphenyl)
) Piperazine MS spectrum (EI / DI) m / z: 684 (M ⁺ ), 174 (Bespeak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.82, 0.87, 0.88, 0.
97,1.14,1.24 (21H, s × 7, CH ₃ × 7), 1.2〜2.2 (28H, m, C
H, CH ₂ and CH ₃ ), 2.05 (3H, s, CH ₃ CO), 2.6 ~ 2.7
(2H, m, CH ₂ ), 2.8 ~ 2.9 (4H, m, CH ₂ × 2), 3.75 ~ 3.8
5 (4H, m, CH ₂ × 2), 4.45 ~ 4.55 (1H, m, C ₃ -H), 5.3 ~ 5.4
(1H, m, C ₁₂ -H), 7.0 ~ 7.2 (4H, m, aromatic H)

Production Example 5 1- (3β-acetoxy-18β-olean-12-d
-30-oil) -4- (2-acetylphenyl) pi
Perazine MS spectrum (EI / DI) m / z: 684 (M ⁺ , base peak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.80, 0.87, 0.88, 0.
96,1.13,1.22 (21H, s × 6, CH ₃ × 7), 1.0〜2.1 (23H, m, C
H, and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 2.67 (3H, s, CH ₃ C
O), 2.9 ~ 3.1 (4H, m, CH ₂ × 2), 3.75 ~ 3.85 (4H, m, CH
₂ × 2), 4.45 to 4.55 (1H, m, C ₃ -H), 5.3 to 5.4 (1H, m, C ₁₂
-H), 7.02 ~ 7.23 (2H, m, aromatic H), 7.38 ~ 7.48 (2H, m,
aromatic H)

Production Example 6 1- (3β-acetoxy-18β-olean-12-d
-30-oil) -4- (2-carbamoylphenyi)
) Piperazine MS spectrum (EI / DI) m / z: 685 (M ⁺ ), 44 (base-speak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.81,0.87,0.88,0.
97,1.14,1.24 (21H, s × 6, CH ₃ × 7), 1.0〜2.1 (23H, m, C
H, and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 2.95 ~ 3.05 (4H,
m, CH ₂ × 2), 3.75 ~ 3.85 (4H, m, CH ₂ × 2), 4.45 ~ 4.55
(1H, m, C ₃ -H), 5.3 ~ 5.4 (1H, m, C ₁₂ -H), 5.85 (1H, b
r, NH ₂ ), 7.15 ~ 7.28 (2H, m, aromatic H), 7.44 ~
7.51 (1H, m, aromatic H), 8.13 to 8.17 (1H, m, aromatic H
H), 9.20 (1H, br, NH ₂ )

Production Example 7 1- (3β-acetoxy-18β-olean-12-d
-30-oil) -4- (2-nitrophenyl) pipet
Radine MS spectrum (EI / DI) m / z: 645 (M ⁺ ), 189 (Bespeak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.80, 0.87, 0.88, 0.
96,1.13,1.22 (21H, s × 6, CH ₃ × 7), 1.0〜2.1 (23H, m, C
H, and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 3.0 ~ 3.1 (4H,
m, CH ₂ × 2), 3.75 ~ 3.85 (4H, m, CH ₂ × 2), 4.45 ~ 4.55 (1
H, m, C ₃ -H), 5.3 ~ 5.4 (1H, m, C ₁₂ -H), 7.07 ~ 7.16 (2
H, m, aromatic H), 7.47 to 7.54 (1H, m, aromaticH), 7.77
~ 7.81 (1H, m, aromatic H)

Production Example 8 1- (3β-acetoxy-18β-olean-12-d
-30-oil) -4- (2-dimethylaminophenyl)
) Piperazine MS spectrum (EI / DI) m / z: 685 (M ⁺ , base-speak). ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.80, 0.87, 0.88, 0.
96,1.14,1.23 (21H, s × 6, CH ₃ × 7), 0.8〜2.1 (23H, m, C
H, and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 2.83 (6H, s, CH ₃
× 2), 3.05 to 3.15 (4H, m, CH ₂ × 2), 3.75 to 3.85 (4H, m, CH
₂ × 2), 4.45 ~ 4.55 (1H, m, C ₃ -H), 5.30 ~ 5.35 (1H, m, C
₁₂ -H), 6.87 ~ 6.99 (4H, m, aromatic H).

Production Example 9 1- (3β-acetoxy-18β-olean-12-d
-30-oil) -4- (2-aminophenyl) pipet
Radine MS spectrum (EI / DI) m / z: 657 (M ⁺ , base-speak). ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.81, 0.87, 0.88, 0.
97,1.14,1.24 (21H, s × 6, CH ₃ × 7), 0.8〜2.1 (23H, m, C
H, and CH ₂ ), 2.05 (3H, s, CH ₃ CO), 2.85 ~ 2.95 (4H,
m, CH ₂ × 2), 3.70 to 3.90 (4H, m, CH ₂ × 2), 3.99 (2H, br,
NH ₂ ), 4.45 ~ 4.55 (1H, m, C ₃ -H), 5.30 ~ 5.35 (1H, m, C
₁₂ -H), 6.72 ~ 6.77 (2H, m, aromatic H), 6.92 ~ 6.98 (2
H, m, aromatic H).

Production Example 10 1- (3β-hydroxy-18β-olean-12-d
Emissions -30- oil) 4- (2-phenyl) obtained in piperazine Production Example 1 1-(3.beta .- acetoxy -18β- olean-12-en-30-Oil) -4- (2-phenyl) piperazine 3.68g (5.72 mmol) as 1,4-dioxane
It was dissolved in 37.5 ml, and 10% sodium hydroxide-methanol solution 37.5 ml (66.8 mmol) and dichloromethane 50.0 were added thereto.
ml was added, and the mixture was stirred at 20 ° C. for 5 hours. Reaction mixture 5
The mixture was concentrated to 0.0 ml, added with 50.0 ml of methanol and 50.0 ml of water, and the precipitated crystals were collected by filtration to give 3.49 g of the title compound (yield:
99.7%) obtained. Melting point: 273-275 ° C MS spectrum (EI / DI) m / z: 600 (M ⁺ ), 162 (Bespeak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.79, 0.93, 0.95, 1.
00,1.14,1.23 (21H, s × 6, CH ₃ × 7), 0.7〜2.1 (23H, m, C
H and CH ₂ ), 3.1 ~ 3.2 (4H, m, CH ₂ × 2), 3.15 ~
3.25 (1H, m, C ₃ -H), 3.75 ~ 3.85 (4H, m, CH ₂ × 2), 5.
25 ~ 5.33 (1H, m, C ₁₂ -H), 6.85 ~ 6.95 (2H, m, aromatic
H), 7.25〜7.32 (2H, m, aromatic H)

In the same manner as in Production Example 10, the β-acetoxyglycyrrhetinic acid derivatives obtained in Production Examples 2 to 7 were treated to obtain the following 3β-hydroxyglycyrrhetinic acid derivatives.

Production Example 11 4- (2-fluorophenyl) -1- (3β-hydroxy
Si-18β-olean-12-ene-30-oil) pi
Perazine Melting point: 298-301 ℃ MS spectrum (EI / DI) m / z: 618 (M ⁺ ), 180 (base-speak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.79,0.80,0.94,0 .
96,1.00,1.14,1.23 (21H, s × 7, CH ₃ × 7), 0.7〜2.1 (23
H, m, CH and CH ₂ ), 3.0 ~ 3.1 (4H, m, CH ₂ × 2), 3.15
~ 3.25 (1H, m, C ₃ -H), 3.75 ~ 3.90 (4H, m, CH ₂ × 2),
5.28 ~ 5.35 (1H, m, C ₁₂ -H), 6.90 ~ 7.10 (4H, m, aromati
c H)

Production Example 12 1- (3β-hydroxy-18β-olean-12-d
-30-Oil) -4- (2-tolyl) piperazine Melting point: 238-240 ° C MS spectrum (EI / DI) m / z: 614 (M ⁺ , base-speak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.79,0.80,0.94,0.
97,1.00,1.14,1.24 (21H, s × 7, CH ₃ × 7), 0.7〜2.1 (23
H, m, CH and CH ₂ ), 2.33 (3H, s, CH ₃ ), 3.80 to 3.95
(4H, m, CH ₂ × 2) 3.15 to 3.25 (1H, m, C ₃ -H), 3.75 to 3.85
(4H, m, CH ₂ × 2), 5.3 ~ 5.4 (1H, m, C ₁₂ -H), 6.95 ~ 7.2
0 (4H, m, aromatic H)

Production Example 13 1- (3β-hydroxy-18β-olean-12-d
-30-oil) -4- (2-n-propylphenyl)
) Piperazine Melting point: 251-253 ° C MS spectrum (EI / DI) m / z: 642 (M ⁺ , base-speak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.80, 0.88, 0.95, 0.
98,1.00,1.15,1.24 (21H, s × 7, CH ₃ × 7), 0.7〜2.1 (28
H, m, CH, CH ₂ and CH ₃ ), 2.63 to 2.69 (2H, m, CH ₂ ), 2.
8 to 2.9 (4H, m, CH ₂ × 2), 3.15 to 3.25 (1H, m, C ₃ -H),
3.75 ~ 3.85 (4H, m, CH ₂ × 2), 5.3 ~ 5.4 (1H, m, C ₁₂ -H),
7.03 ~ 7.23 (4H, m, aromatic H)

Production Example 14 4- (2-acetylphenyl) -1- (3β-hydroxy
Si-18β-olean-12-ene-30-oil) pi
Perazine melting point: 211-213 ° C MS spectrum (EI / DI) m / z: 642 (M ⁺ , base peak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.79, 0.80, 0.94, 0.
96,1.00,1.14,1.21 (21H, s × 6, CH ₃ × 7), 0.7〜2.1 (23
H, m, CH, and CH ₂ ), 2.67 (3H, s, CH ₃ CO), 2.91 ~ 3.0
2 (4H, m, CH ₂ × 2), 3.15 ~ 3.25 (1H, m, C ₃ -H), 3.73 ~
3.83 (4H, m, CH ₂ × 2), 5.28 ~ 5.33 (1H, m, C ₁₂ -H), 7.00
~ 7.13 (4H, m, aromatic H), 7.38 ~ 7.48 (2H, m, aromatic H
H)

Production Example 15 4- (2-carbamoylphenyl) -1- (3β-hydr
Roxy-18β-olean-12-ene-30-oy
) Piperazine Melting point: 190-193 ℃ MS spectrum (EI / DI) m / z: 643 (M ⁺ , base-speak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.80, 0.81, 0.94, 0.
97,1.00,1.14,1.23 (21H, s × 7, CH ₃ × 7), 0.7〜2.1 (23
H, m, CH and CH ₂ ), 2.95 ~ 3.05 (4H, m, CH ₂ × 2),
3.15 ~ 3.25 (1H, m, C ₃ -H), 3.75 ~ 3.85 (4H, m, CH ₂ ×
2), 5.30-5.35 (1H, m, C ₁₂ -H), 5.78 (1H, br, NH ₂ ),
7.15 ~ 7.28 (2H, m, aromatic H), 7.44 ~ 7.51 (1H, m, arom
atic H), 8.13 ~ 8.17 (1H, m, aromatic H), 9.19 (1H, b
r, NH ₂ )

Production Example 16 1- (3β-hydroxy-18β-olean-12-d
-30-oil) -4- (2-nitrophenyl) pipet
Rajin mp: 259-261 ° C. MS spectrum (EI / DI) m / z : 645 (M +), 409 ( base - spin - click) ¹ H-NMR spectrum (CDCl ₃₎ δppm: 0.79,0.80,0.94,0 .
96,1.00,1.14,1.22 (21H, s × 7, CH ₃ × 7), 0.7〜2.1 (23
H, m, CH, and CH ₂ ), 3.0 to 3.1 (4H, m, CH ₂ × 2), 3.15
~ 3.25 (1H, m, C ₃ -H), 3.75 ~ 3.85 (4H, m, CH ₂ × 2),
5.30 ~ 5.33 (1H, m, C ₁₂ -H), 7.07 ~ 7.16 (2H, m, aromatic
H), 7.47 ~ 7.54 (1H, m, aromatic H), 7.77 ~ 7.81 (1H,
m, aromatic H)

Production Example 17 4- (2-dimethylaminophenyl) -1- (3β-hi
Droxy-18β-olean-12-en-30-oy
) Piperazine Melting point: 252-254 ℃ MS spectrum (EI / DI) m / z: 643 (M ⁺ , base peak). ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.79, 0.80, 0.94, 0 .
96,1.00,1.14,1.23 (21H, s × 7, CH ₃ × 7), 0.70〜2.15 (23
H, m, CH and CH ₂ ), 2.83 (6H, s, CH ₃ × 2), 3.05 ~
3.15 (4H, m, CH ₂ × 2), 3.15 ~ 3.25 (1H, m, C ₃ -H), 3.
75 〜 3.85 (4H, m, CH ₂ × 2), 5.30〜5.35 (1H, m, C ₁₂ -H),
6.84 ~ 6.99 (4H, m, aromatic H).

Production Example 18 4- (2-aminophenyl) -1- (3β-hydroxy
-18β-olean-12-ene-30-oil) pipette
Rajin mp: 263-266 ° C. MS spectrum (EI / DI) m / z :. 657 (M +, base - spin - click) ¹ H-NMR spectrum (CDCl ₃₎ δppm: 0.79,0.81,0.94,0.
97,1.00,1.14,1.23 (21H, s × 7, CH ₃ × 7), 0.80〜2.10 (23
H, m, CH, and CH ₂ ), 2.85 to 2.95 (4H, m, CH ₂ × 2), 3.1
5〜3.25 (1H, m, C ₃ -H), 3.70〜3.90 (4H, m, CH ₂ × 2),
3.98 (2H, br, NH ₂ ), 5.30 ~ 5.35 (1H, m, C ₁₂ -H), 6.
72 ~ 6.77 (2H, m, aromatic H), 6.93 ~ 6.99 (2H, m, aromat
ic H).

Production Example 19 1- (3β-hydroxy-18β-olean-12-d
-30-oil) 4- (2-trifluoroacetyl)
Minophenyl) piperazine, a known compound, 3β-hydroxy-18β-olean-12-ene-30-oic acid, 4.68 g (10.2 mm)
ol), 1- (2-trifluoroacetylaminophenyl)
Piperazine 4.20 g (15.4 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 2.16
Dissolve g (11.3 mmol) in 300 ml of dichloromethane and
It was stirred for 16 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue is purified by silica gel chromatography (developing solvent: dichloromethane) to give 1.68 g of the title compound.
(Yield 23.1%) was obtained. Melting point: 214-216 ° C MS spectrum (EI / DI) m / z: 711 (M ⁺ ), 189 (base-speak) ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.80,0.82,0.95,0.
97,1.00,1.15,1.25 (21H, s × 7, CH ₃ × 7), 0.7〜2.1 (23
H, m, CH and CH ₂ ), 2.8 to 2.9 (4H, m, CH ₂ × 2), 3.15
~ 3.25 (1H, m, C ₃ -H), 3.70 ~ 3.90 (4H, br, CH ₂ × 2),
5.30 ~ 5.40 (1H, m, C ₁₂ -H), 7.15 ~ 7.30 (2H, m, aromati
c H), 8.31 ~ 8.34 (2H, m, aromatic H), 9.53 (1H, br, N
H)

Drug efficacy test example 1 In vitro anti-herpes simplex type 1 virus action and
Cytotoxic effect GMK cells (derived from green monkey kidney) were cultured in a monolayer in a 96-well plate, and herpes simplex virus type 1 (Miyayama strain) and a test compound were added, and after culturing, cytopathic effect by virus (CPE), test compound The inhibitory effect of CPE by C. and the cytotoxic effect of the test compound were observed under a microscope. Calculating the TCID ₅₀ of the CPE by the virus as an indicator, delta from TCID ₅₀ of the test compound treated group and untreated group
The TCID ₅₀ (log ₁₀ ) was determined and the antiviral action of the test compound was evaluated. The test compound was adjusted to 10 mg / ml with DMSO or ethanol, diluted with MEM medium containing 1% fetal bovine serum, and added to the culture system.

Table 1 In vitro herpes simplex virus 1 (Miyama strain) action Test compound Antiviral activity (ΔTCID ₅₀ (log ₁₀ )) Action concentration (μg / ml) 0.5 1 5 Compound 0.33 (-) 1.17 of Production Example 10 (−) 2.00 (−) Compound of Production Example 11 2.00 (−)> 3.00 (−)> 3.17 (−) Compound of Production Example 14 1.86 (−) 2.50 (±)> 3.10 (+) Compound of Production Example 19 1.00 (-) 1.97 (-) 2.00 (-) (): Indicates the strength of cytotoxicity [(-): No cytotoxicity, (±) (+): Mild cytotoxicity, (++): Strong cytotoxicity] . -: Undecidable

 ─────────────────────────────────────────────────── ─── Continued front page (72) Inventor Hiroki Kimura 35, Higashi Sotobori-cho, Higashi-ku, Nagoya City Sanwa Chemical Research Institute Co., Ltd. (72) Inventor Hideaki Inagaki, 35, Higashi Sotobori-cho, Higashi-ku, Nagoya City, Sanwa Chemical Research Institute Co., Ltd.

Claims (5)

[Claims] 1. A compound represented by the formula (I): (I) A novel glycyrrhetinic acid derivative represented by the formula (wherein R means hydrogen, halogen, lower alkyl, nitro, cyano, amino, lower alkylamino, trifluoroacetylamino, acetyl, carboxyl, carbamoyl) and a salt thereof. . 2. The compound according to claim 1 is 1- (3β-hydroxy-18β-olean-12-en-30-oil) -4-phenylpiperazine, 1- (3β-hydroxy-18β-olean-12. -En-30-Oil)-
4- (2-fluorophenyl) piperazine, 1- (3β
-Hydroxy-18β-olean-12-ene-30-
Oil) -4- (2-chlorophenyl) piperazine, 1
-(3β-hydroxy-18β-olean-12-ene-30-oil) -4- (2-methylphenyl) piperazine, 1- (3β-hydroxy-18β-olean-1
2-ene-30-oil) -4- (2-n-propylphenyl) piperazine, 1- (3β-hydroxy-18β
-Olean-12-ene-30-oil) -4- (2-
Acetylphenyl) piperazine, 1- (3β-hydroxy-18β-olean-12-ene-30-oil)-
4- (2-carbamoylphenyl) piperazine, 1-
(3β-hydroxy-18β-olean-12-ene-
30-oil) -4- (2-trifluoroacetylaminophenyl) piperazine, 1- (3β-hydroxy-1)
8β-olean-12-ene-30-oil) -4-
(2-Dimethylaminophenyl) piperazine, 1- (3
β-hydroxy-18β-olean-12-ene-30
-Oil) -4- (2-aminophenyl) piperazine,
A novel glycyrrhetinic acid derivative and a salt thereof, which is 1- (3β-hydroxy-18β-olean-12-ene-30-oil) -4- (2-nitrophenyl) piperazine. 3. An antiviral agent comprising the compound according to claim 1 or 2 as a main component, which is used as a preventive or therapeutic agent for infectious diseases caused by various DNA viruses, RNA viruses and retroviruses. 4. An antiviral agent comprising the compound according to claim 1 or 2 as a main component, which is used as a prophylactic or therapeutic agent for viral infections of the Herpesviridae. 5. An antiviral agent comprising the compound according to claim 1 or 2 as a main component, which is used as a prophylactic or therapeutic agent for human AIDS virus infection.