JPH04360868A - Trifluromethylpyrrole derivative and preventive and therapeutic medicine for liver disease containing the same derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as preventive and theropentic medicines for liver disease. CONSTITUTION:A compound expressed by formula I (R<1> is H, 1-12C alkyl, alkenyl, benzyl, lower alkylcarbonyl, etc.; R<2> is H, lower alkoxycarbonyl, carbamoyl, etc.; R<3> is H, nitro, cyano, phenyl, etc.), e.g. 3-cyano-4- trifluoromethylpyrrole. The compound expressed by formula I is obtained by reacting a 1-position-unsubstituted 4-trifluoromethylpyrrole derivative expressed by formula II with a halide expressed by the formula R<1>-X (X is halogen, carboxyl, sulfuric acid ester, etc.) to introduce a substituent group in 1-position. The compound expressed by formula II is obtained by cyclization reaction between 3,3,3-trifluoropropene derivative expressed by the formula CF3CH =CHR<3> and p-tolylsulfonylmethylisocyanide in the presence of a strong base (e.g. NaH).

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to a novel trifluoromethylpyrrole derivative and a prophylactic or therapeutic agent for liver diseases containing the same as an active ingredient.

0002

BACKGROUND OF THE INVENTION The liver is acutely or chronically damaged by various causes such as viruses, alcohol, nutritional deficiencies, and hepatic circulation disorders, resulting in liver diseases such as fatty liver, jaundice, and cirrhosis. Recently, malotylate and the like have been reported as therapeutic agents for these liver diseases. However, truly effective treatments and therapeutic agents have not yet been found, including symptomatic treatments such as dietary therapy and drug therapy using steroids, immunostimulants, and the like.

0003

[Problems to be Solved by the Invention] As mentioned above, there are still no satisfactory treatments for liver diseases, especially those that are prolonged or chronic. Furthermore, drug therapy using steroids, immunostimulants, etc. has the problem of serious side effects.

0004

[Means for Solving the Problems] As a result of various studies in order to develop a therapeutic agent for liver diseases that solves the above-mentioned problems, the present inventors have developed a novel trifluoromethylpyrrole derivative.
The present invention was completed based on the discovery that the present invention has an excellent suppressive effect on liver damage in an experimental liver damage model.

[0005] The present invention is based on the general formula

[0006]

[Chemical formula 3]

[0007] (In the formula, R1 is a hydrogen atom, and has 1 to 1 carbon atoms.)
2 alkyl or alkenyl group, unsubstituted or substituted benzyl group, lower alkylcarbonyl group, unsubstituted or substituted benzoyl group, lower alkylmethanesulfonyl group, unsubstituted or substituted benzenesulfonyl group,
R2 represents hydrogen, a lower alkoxycarbonyl group, unsubstituted or mono- or di-substituted carbamoyl group with lower alkyl, lower alkenyl, or lower alkynyl, and R3 represents hydrogen, a nitro group, a cyano group, a lower alkoxycarbonyl group, or an unsubstituted carbamoyl group. or substituted phenyl group)
These are 4-trifluoromethylpyrrole derivatives represented by: and drugs for preventing and treating liver diseases containing the same.

Among Rn defined in the present invention, lower alkoxycarbonyl groups include methoxycarbonyl group,
Ethoxycarbonyl group, propyloxycarbonyl group,
Examples include. Substituents for the phenyl group or benzene ring include halogen atoms such as F, Cl, and Br, lower alkyl groups such as methyl, ethyl, propyl, and isopropyl, and lower lower alkyl groups such as methoxy, ethoxy, and isopropoxy. Alkoxy group, nitro group, cyano group,
Examples include trifluoromethyl group. Carbon number 1-1
Examples of alkyl or alkenyl groups up to 2 include methyl, ethyl, propyl, allyl, hexyl, octyl, undecenyl, 11,11,11-trifluoroundecyl, and the like. Lower alkylcarbonyl groups include acetyl group, propionyl group,
Butyryl group and trifluoromethyl group, lower alkylmethanesulfonyl group include methanesulfonyl group,
Examples include ethanesulfonyl group, propanesulfonyl group, trifluoromethanesulfonyl group, and the like.

Further, examples of the lower alkyl-substituted carbamoyl group include N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, and N,N-dimethylcarbamoyl group, and examples of the lower alkenyl-substituted carbamoyl group include N- Examples of the allylcarbamoyl group include an N-methallylcarbamoyl group, and examples of the lower alkynyl-substituted carbamoyl group include an N-propargylcarbamoyl group.

When R2 is hydrogen, the 4-trifluoromethylpyrrole derivative [I] of the present invention can be obtained from the corresponding 3,3,3-trifluoropropene derivative as shown in the following formula by hydrogen at the 1-position. It is produced through two steps: a reaction leading to the atom 4-trifluoromethylpyrrole derivative [I; R1 = H] and introducing a substituent at the 1-position by the action of various reagents.

[0011]

[C4]

(In the formula, X represents a halogen atom such as Cl, Br, or I, a carboxyl group or a sulfonic acid group represented by R1O, and a sulfuric acid ester group represented by R1SO3.) Unsubstituted at the 1-position 4-Trifluoromethylpyrrole derivative [
I; R1 = H] is a 3,3,3-trifluoropropene derivative, such as 1-nitro-3,3,3-trifluoropropene, 4,4,4-trifluoro-2-crotoniryl, 4,4 , ethyl 4-trifluoro-2-crotonate, 2-trifluoromethyl-p-chlorostyrene,
TosM is cyclized by reacting p-tolylsulfonylmethylisocyanide in the presence of a strong base such as sodium hydride.
IC method (Tetrahedoron Lett., 5
337-5340, 1972). In addition, for the production of 3-phenyl-4-trifluoromethylpyrrole derivatives, a separate production method (
JP-A-61-97262) can also be used.

The method for introducing a substituent into the 1-position is to add 1 to 5 equivalents of a halide represented by R1-X to 4-trifluoromethylpyrrole [I; R1=H], toluene,
This can be easily achieved by reaction in an aprotic solvent such as ethyl acetate, THF, or DMF in the presence of a strong base such as NaH, KOtBu, or an organic base such as triethylamine or pyridine. In addition, for lower alkylation,
In acetone or ethyl methyl ketone, add potassium carbonate or sodium carbonate to allow the sulfuric acid dialkyl ester to act. For lower alkyl carbonylation or lower alkyl sulfonylation, use the corresponding carboxylic acid anhydride or sulfonic acid anhydride. It can also be produced without a solvent or by reacting with the addition of an organic base as described above.

When R2 is other than hydrogen, a formyl group is introduced into the corresponding 3-trifluoromethylpyrrole at the 2-position by Vilsmeier reaction, and then oxidized to form a carboxylic acid, followed by a conventional method. can lead to an amide compound via esterification or acid halide.

These novel compounds of the present invention have extremely low toxicity to humans and mammals, and the acute toxicity LD50 value to mice (male) is at a level lower than 1000 mg/kg.

[0016] To treat acute or chronic liver diseases, such as fatty liver, alcoholic hepatitis, toxic liver damage, or liver cirrhosis, the treatment usually depends on the age of the patient, the type and severity of the disease, etc. These compounds are administered orally to adults at a dose of 1 to 100 mg/kg body weight/day in 1 to 3 divided doses per day. The compound of the present invention can be mixed with a solid or liquid excipient carrier to form a form suitable for oral or parenteral administration. The dosage form can be solid preparations such as tablets, pills, capsules, and granules, or solutions, emulsions, suppositories, and the like. In order to prepare each of the above-mentioned formulations, they are manufactured according to conventional formulation techniques, and if necessary, commonly used additives such as auxiliaries, stabilizers, emulsifiers, diluents, etc. can be used. . For example, in the liquid preparation, in addition to distilled water, ethanol, glycerin, propylene glycol, polyethylene glycol, etc., solubilizing agents, buffering agents, preservatives, fragrances, coloring agents, etc. can be used as necessary. The emulsion contains sorbitol syrup, methyl cellulose,
In addition to glycose, sucrose syrup, hydroxypropyl cellulose, edible oil, glycerin, ethanol, water, etc., it may also contain emulsifiers such as gum arabic and lecithin, and surfactants such as Tween and Span. For solid preparations,
Excipients such as lactose, corn starch, and mannitol; lubricants such as calcium phosphate, magnesium stearate, talc, and light silicic anhydride; crystalline cellulose;
A disintegrant such as carboxymethylcellulose calcium can be used.

[0017]

[Examples] The present invention will be specifically explained below with reference to Examples, Prescription Examples, and Test Examples. Example 1 Production of 3-cyano-4-trifluoromethylpyrrole 4
,4,4-trifluorocrotonitrile12. 8g (
0. 106 mol) and p-tolylsulfonylmethylisocyanide 20. 0 g (0.107 mol) in THF
6. Dissolve in a mixed solvent of 90 ml and DMSO 20 ml, and add 60% sodium hydride while stirring under ice cooling. 36g
(0.159 mol) in 60 ml THF suspension, 3
It was added dropwise over 0 minutes. After stirring for another 2 hours at room temperature, 1 liter of cold water was added to stop the reaction, and the organic matter was removed with 100 ml of ethyl acetate.
Extracted twice with ml. After washing with saturated saline, drying (Mg
SO4) and the solvent was distilled off to obtain a yellow solid. Recrystallization from dichloromethane gave 5.31 g (31.3%) of the title compound as white crystals.

[0018] mp 97-98°C IR (KBr) 3260 (NH), 2240 (CN),
1170 (CF3) cm-1 1H-nmr (DMSO-d6) δ7. 56 (1
H, m), 7. 83 (1H, m), 12. 4 (1H
, bs) 19F-nmr(DMSO-d6)-5
5. 9ppm (CFCl3 standard) mass (m/e) 160 (M+), 141

Example 2 Production of 3-nitro-4-trifluoromethylpyrrole 1
-Nitro-3,3,3-trifluoropropene 7.05
g (50 mmol) and p-tolylsulfonylmethylisocyanide9. Dissolve 75 g (50 mmol) in 80 ml of ethyl ether and 40 ml of DMSO, and add 60% sodium hydride while stirring under ice cooling.4. 0g (100
It was added dropwise over 30 minutes to a 50 ml suspension of 1 mmol).

After stirring at room temperature for 30 minutes, add 0.0 ml of cold water. 5 liters were added and ether extraction was performed. After evaporating the solvent, the residue was separated by silica gel column chromatography (dichloromethane elution) and recrystallized from dichloromethane-n-hexane to obtain the title compound as white crystals. 91g (32.
4%) was obtained.

mp 135-137°C IR (KB
r) 3270 (NH), 1260, 1135 (CF3)
cm-1 1H-nmr (DMSO-d6) δ 7. 53
(1H, m), 8. 11 (1H, m), 12.65 (
1H, bs) 19F-nmr(DMSO-d6)-56. 8pp
m (CFCl3 standard) mass (m/e) 180 (M+), 164

0
Example 3 Production of 3-cyano-1-methyl-4-trifluoromethylpyrrole 3-cyano-4-trifluoromethylpyrrole 3. 0
0 g (18.8 mmol) and 3.0 g (18.8 mmol) of dimethyl sulfate. 76
ml (36.9 mmol) in 120 ml of ethyl methyl ketone and 6.93 g (50 mmol) of anhydrous potassium carbonate.
．． 1 mmol) was added thereto, and the mixture was stirred and refluxed for 5 hours. After cooling, the solid was filtered off, 6 ml of 25% aqueous ammonia was added to the filtrate, and the organic matter was extracted with ether. The solvent was distilled off and the residue was separated by column chromatography on silica gel (dichloromethane elution) to yield the title compound as white crystals. 57
g (48.1%) was obtained.

[0023] mp 39-43. 5℃IR(K
Br) 3150, 3120, 2235 (CN), 127
5, 1150, 1115 cm-1 1H-nmr (
CDCl3)δ 3. 69 (3H, s), 6.
97 (1H, m), 7. 15(1H, m)19F-n
mr(CDCl3) -58. 5ppm (CFC
l3 standard) mass (m/e) 174 (M+), 155

0
Example 4 Preparation of 1-methyl-3-nitro-4-trifluoromethylpyrrole Synthesis was performed in the same manner as in Example 3 to obtain white crystals. Yield 68%.

[0025] mp 113-113. 5℃IR
(KBr) 3200, 1270, 1140 (CF3
) cm-1 1H-nmr (CDCl3) δ 3. 71(3
H, s), 6. 93 (3H, m), 7. 51 (2H
, d, J=3Hz) 19F-nmr(CDCl3) -59.1ppm
(CFCl3 standard) mass (m/e) 194 (M+), 178, 164
, 148, 41(B)

Example 5 Production of 1-methyl-3-phenyl-4-trifluoromethylpyrrole The same operation as in Example 3 was carried out to obtain a yellow liquid. Yield: 53%.

IR (Neat) 3175, 3100,
2960, 1205, 1150 cm-1 1H-nmr (CDCl3) δ3. 54 (3H,
s), 6. 62 (1H, m), 6. 91 (1H, m
), 7. 0-7. 7(5H, m) 19F-nmr(CDCl3) -54.8ppm
(CFCl3 standard) mass (m/e) 225 (M+)

[0028]
Example 6 Production of 3-(p-chlorophenyl)-1-methyl-4-trifluoromethyl-pyrrole The same operation as in Example 3 was performed to obtain a yellow liquid. Yield 76%.

IR (Neat) 3160, 2950, 1
200, 1145, 1105 cm-1 1H-nmr (CDCl3) δ3. 54 (3H,
s), 6. 59 (1H, m), 6.90 (1H, m)
, 7.32 (4H, s) 19F-nmr (CDCl3) -54. 8pp
m (CFCl3 standard) mass (m/e) 261, 259 (M+)

0
Example 7 Production of 3-cyano-1-propyl-4-trifluoromethylpyrrole 160 mg (4.0 mmol) of 60% sodium hydride was suspended in 5 ml of THF, and while stirring under ice cooling, 3-cyano-1-propyl-4-trifluoromethylpyrrole was suspended.
Cyano-4-trifluoromethylpyrrole 398mg (
3. 2 mmol) in 5 ml THF was added dropwise. 2
900 mg (7.4 mmol) of propyl bromide after 0 minutes.
was added and stirred at room temperature for 12 hours. After adding 50 ml of water to the reaction solution, the mixture was extracted twice with 50 ml of ethyl acetate. After drying (MgSO4), the solvent was distilled off and the resulting oil was separated by silica gel column chromatography (eluted with n-hexane:ethyl acetate = 5:1) to yield 390 mg (73%) of the title compound as white crystals. Obtained.

mp 41-41. 5℃IR(K
Br) 3150, 3110, 2240 (CN), 127
5, 1160, 1150 cm-1 1H-nmr (
CDCl3)δ 0. 93 (3H, t, J=7.
5Hz), 1. 84 (2H, sep, J=7.5
Hz), 3. 90 (2H, t, J=7.5Hz),
7. 03 (1H, m), 7. 21 (1H, d, J=
3Hz) 19F-nmr (CDCl3) -58. 4pp
m (CFCl3 standard) mass (m/e) 202 (M+), 183 Compounds of Examples 8 to 12 were synthesized according to the method of Example 7.

Example 8 3-(p-chlorophenyl)-4-trifluoromethyl-1-(11,11,11-trifluoroundecyl)
Manufacture of pyrrole. Yellow liquid. Yield 23% IR (Neat) 2930, 2855, 1255, 11
35 cm-1 1H-nmr (CDCl3) δ 1. 2-2.
4 (18H, m), 3. 88 (2H, t, J=7Hz
), 6. 74 (1H, m), 7. 04 (1H, m)
,7. 3-7. 55 (2H, m) 19F-nmr (CDCl3) -54.9, -6
6.8ppm (CFCl3 standard) mass (m/e) 456, 454 (M+ +1), 4
35, 259 (B)

Example 9 Preparation of 1-benzyl-3-cyano-4-trifluoromethylpyrrole White crystals. Yield 93% mp 58. 5-59℃ IR (KBr) 3180, 2230 (CN), 1280
, 1150 cm-1 1H-nmr (CDCl3) δ 5. 07(2)
H, s), 7. 02 (1H, m), 7. 15-7.
5(6H, m) 19F-nmr(CDCl3) -58. 0pp
m (CFCl3 standard) mass (m/e) 250 (M+), 231

003
4] Example 10 Preparation of 1-benzyl-3-nitro-4-trifluoromethylpyrrole White crystals. Yield Quantitative mp 113-113. 5℃ IR (KBr) 3200, 1270, 1140 cm
-1 1H-nmr (CDCl3) δ 3. 71
(3H, s), 6. 93 (3H, m), 7. 51 (
2H, d, J=3Hz) 19F-nmr(CDCl3) -59. 1pp
m (CFCl3 standard) mass (m/e) 194 (M+), 178, 1
64, 148, 41 (B)

Example 11 Preparation of 3-cyano-1-(p-chlorobenzyl)-4-trifluoromethylpyrrole White crystals. Yield 72% mp 94-95°C IR (KBr) 3140, 3105, 2235 (CN)
, 1265, 1160, 1120 cm-1 1H-
nmr(CDCl3)δ 5. 04 (2H, s)
,7. 03 (1H, m), 7. 14 (2H, d, J
=9Hz), 7. 22 (2H, d, J = 3Hz), 7
．． 40 (2H, d, J=9Hz) 19F-nmr (CDCl3) -58. 5pp
m (CFCl3 standard) mass (m/e) 286, 284 (M+), 1
25(B)

Example 12 Preparation of 1-(p-chlorobenzyl)-3-ethoxycarbonyl-4-trifluoro-methylpyrrole White crystals.
Yield 82% mp 79-83°C IR (KBr) 3155, 3025, 1710 (CO)
, 1240, 1140 cm-1 1H-nmr (C
DCl3 ) δ 1. 33 (3H, t, J=6Hz
), 4.28 (2H, q, J=6Hz), 5. 05(
2H, s), 7. 0-7. 5(6H, m)19F-
nmr(CDCl3) -58. 3ppm (CF
Cl3 standard) mass (m/e) 333, 331 (M+), 1
25(B)

Example 13 Preparation of 1-acetyl-3-cyano-4-trifluoromethylpyrrole 3-cyano-4-trifluoromethylpyrrole 410m
g (3.3 mmol) in 10 ml of acetic anhydride; 2. The mixture was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residual brown oil was separated by silica gel column chromatography (eluted with n-hexane:ethyl acetate = 5:1) to give 530 mg (9.5 g) of the title compound as pale yellow crystals.
6%) obtained.

mp 57-60°C IR (KBr)
3140, 2230 (CN), 1755 (CO), 12
70, 1205, 1125 cm-1 1H-nmr
(CDCl3)δ 2. 64 (3H, s), 7.
72 (1H, m), 7. 9 (1H, d, J = 3Hz
) 19F-nmr (CDCl3) -60. 0pp
m (CFCl3 standard) mass (m/e) 264 (M+), 160, 1
05(B)

Example 14 Preparation of 1-benzoyl-3-cyano-4-trifluoromethylpyrrole 3-cyano-4-trofluoromethylpyrrole1. 0
0 g (6.25 mmol) and 1.0 g (6.25 mmol) of benzoyl chloride. 0
In a solution of 5 g (7.5, mmol) in 30 ml of THF,
While stirring under ice-cooling, add 0.0% triethylamine. 76g (
7. 5 mmol) was added dropwise. A white precipitate was immediately formed, but the mixture was stirred at room temperature for 12 hours. The mixture was diluted with 30 ml of ethyl ether, filtered, and the solvent was distilled off to obtain a yellow solid. This was separated by silica gel column chromatography (eluting with dichloromethane:n-hexane=1:1) to obtain the title compound as white crystals. 49g
(90%) obtained.

mp88. 5-91℃IR(K
Br) 3150, 2235 (CN), 1715 (CO)
, 12801160, 1120 cm-1 1H-n
mr(CDCl3)δ 7. 5-7.9 (7H,
m) 19F-nmr(CDCl3) -59. 7
ppm (CFCl3 standard) mass (m/e) 264 (M+), 160, 1
05(B) Compounds of Examples 15 to 20 were synthesized according to the method of Example 14.

Example 15 Preparation of 1-benzoyl-3-nitro-4-trifluoromethylpyrrole White crystals. Yield 54% mp 115. 5-121℃ IR (KBr) 3190, 1730 (CO), 1245
, 1135 cm-1 1H-nmr (CDCl3) δ 7. 5-7.
9 (6H, m), 8. 2 (1H, d, J=3Hz)1
9F-nmr(CDCl3) -59. 6 p.
pm (CFCl3 standard) mass (m/e) 320 (M+), 141 (B
)

Example 16 Preparation of 3-cyano-1-methanesulfonyl-4-trifluoromethylpyrrole Pale yellow crystals. Yield 84% mp 136-137°C IR (KBr) 3180, 3050, 2960, 223
0 (CN), 1380, 1250, 1190, 1125
cm-1 1H-nmr (DMSO-d6) δ 3. 28
(3H, s), 8. 22 (1H, m), 8. 44(
1H, m) 19F-nmr(DMSO-d6) −
57. 3ppm (CFCl3 standard) mass (m/e) 238 (M+), 219, 1
60(B)

Example 17 Preparation of 1-benzenesulfonyl-3-cyano-4-trifluoromethylpyrrole White crystals. Yield 89% mp 131-133°C IR (KBr) 3135, 2130 (CN), 1385
(SO2), 1250, 1190, 1130 cm
-1 1H-nmr (CDCl3) δ 7. 5-
8.1 (7H, m) 19F-nmr (CDCl3) -59. 5
ppm (CFCl3 standard) mass (m/e) 300 (M+), 141 (B
)

Example 18 Preparation of 1-benzenesulfonyl-3-nitro-4-trifluoromethylpyrrole White crystals. Yield 77% mp 149. 5-150. 5℃IR(KB
r) 3195, 3155, 1405 (SO2), 12
55, 1150 cm-1 1H-nmr (CDCl
3) δ 7. 5-8.1 (7H, m), 8. 1
(1H, d, J = 3Hz) 19F-nmr (CDCl3
) -59. 4 ppm (CFCl3 standard) mass (m/e) 320 (M+), 141 (B
)

Example 19 1-benzenesulfonyl-3-ethoxycarbonyl-
Preparation of 4-trifluoro-methylpyrroleColorless liquid
Yield 85% IR (Neat) 3180, 3020, 1750 (CO
), 1405 (SO2), 1205, 1170 c
m-1 1H-nmr (CDCl3) δ 1. 33 (3
H, t, J=6Hz), 4.3(2H, q, J=6Hz
), 7. 5-8. 1(7H, m) 19F-nmr(CDCl3) -59. 3
ppm (CFCl3 standard) mass (m/e) 347 (M+), 319, 3
02, 141 (B)

Example 20 Production of 1-(p-chlorobenzenesulfonyl)-3-ethoxycarbonyl-4-trifluoromethylpyrrole White crystals Yield 73% mp 94-96°C IR (KBr) 3160, 3020, 1710 (CO )
, 1405 (SO2), 1200, 1140 cm-
1 1H-nmr (CDCl3) δ 1. 33 (3
H, t, J=6Hz), 4.3(2H, q, J=6Hz
), 7. 5 (1H, m), 7. 58 (2H, d, J
=9Hz), 7. 82 (1H, d, J = 3Hz), 7
．． 92 (2H, d, J=9Hz) 19F-nmr (CDCl3) -59. 2
ppm (CFCl3 standard) mass (m/e) 383, 381 (M+), 1
11(B)

Example 21 Preparation of 2-N-allylcarbamoyl-4-trifluoromethylpyrrole 4-trifluoromethyl-3-pyrrolecarboxylic acid 16
．． 3-trifluoromethylpyrrole obtained by decarboxylating 9 g of 3-trifluoromethylpyrrole was dissolved in 8 ml of dichloroethane, and a solution of 4.3 g of phosphorus oxychloride and 2.0 g of N,N-dimethylformamide in 10 ml of dichloroethane was added under cooling over 30 minutes. Ta. After heating under reflux for 1.5 hours, the mixture was treated with an aqueous sodium acetate solution to obtain 3-formyl-4-trifluoromethylpyrrole as a yellow liquid. This was placed in 60 ml of acetone, and 6.5 ml of Jones oxidation reagent was added thereto over 3 hours under ice cooling. After further stirring at room temperature for 2 hours, water was added to stop the reaction, and the organic matter was extracted with ethyl acetate. When the solvent was distilled off, the white crystals of 4-trifluoromethyl-2-pyrrolecarboxylic acid were converted into 2
．． 3g (13.6%) was obtained. This carboxylic acid 0.5
To a solution of 0 g (2.8 mmol) in 50 ml of toluene was added 0.5 ml of oxalyl chloride, and the mixture was heated under reflux for 2 hours. After distilling off the solvent under reduced pressure, add 20 ml of dichloromethane.
0.4 ml (5.3 mmol) of allylamine dissolved in
, a solution of 1.0 ml of triethylamine in 10 ml of dichloromethane was added dropwise. After stirring at room temperature for 15 hours, the mixture was treated according to a conventional method to obtain a yellowish brown solid. This was separated and purified by silica gel column chromatography (eluting with dichloromethane:methanol=49:1) to obtain 0.32 g (62%) of the title compound as pale yellow crystals.

mp 135-138°C IR (KBr)
3290, 3230 (NH), 1650 (CO),
1605, 1315, 1135, 1100 cm-1 1H-nmr (CDCl3) δ 4.07 (2H,
d, J=6Hz), 5.15-5.4 (2H, m), 5
．． 7-6.2 (1H, m), 6.78 (1H, m), 7
．． 24 (1H, m) 19F-nmr (CDCl3) -55.2 pp
m (CFCl3 standard) mass (m/e) 218 (M+), 199, 17
5, 57 (B)

Example 22 Production of 2-N-propargylcarbamoyl-4-trifluoromethylpyrrole Produced in the same manner as in Example 21.

Light brown crystals Yield 70%m
p 119.5-121℃ IR (KBr) 3410, 3275, 3220 (N
H), 1650 (CO), 1530, 1350, 114
0,1110 cm-1 1H-nmr (CDCl3) δ 2.29 (1H, t
, J=2.5Hz), 4.0(1H, d, J=2.5H
z), 4.26 (1H, d, J=2.5Hz), 6.0
(1H, bs), 6.9 (1H, m), 7.25 (1H
, m) 19F-nmr(CDCl3) -55.4ppm(
CFCl3 standard) mass (m/e) 217 (M++1), 216 (
M+), 162(B)

Formulation Example 1 Compound of Example 9
100mg crystalline cellulose
490mg cornstarch
390m
gHydroxypropylcellulose
20mg per packet
Granules were prepared at the above mixing ratio of 1000 mg.

Formulation Example 2 Compound of Example 17
100mg cornstarch
810 mg Hydroxypropylcellulose 90 mg 1000 mg per capsule Capsules were prepared at the above blending ratio.

Formulation Example 3 Compound of Example 18
100mg mannitol
400mg low substituted hydroxypropyl cellulose 460mg per package
Granules were prepared at the above mixing ratio of 1000 mg.

Formulation Example 4 Compound of Example 18
100mg white sugar
430mg Low substituted hydroxypropylcellulose 430mg Polyvinylpyrrolidone 40m
per g1 packet
Granules were prepared at the above mixing ratio of 1000 mg.

Formulation Example 5 Compound of Example 18
60mg mannitol
122mg carboxymethylcellulose calcium 100mg polyvinylpyrrolidone 15mg magnesium stearate
3mg per tablet
A tablet of 300 mg was prepared at the above blending ratio.

Formulation Example 6 Compound of Example 1
100mg crystalline cellulose
152mg carboxymethylcellulose calcium 120mg polyvinylpyrrolidone 25mg magnesium stearate
3mg per tablet
A tablet of 300 mg was prepared at the above blending ratio.

Test Example 1 [Effect on carbon tetrachloride-induced acute liver injury] (Samples) Sample 1; Compound sample 2 of Example 1; Compound sample 3 of Example 2; Compound sample 4 of Example 9; Example 14 Compound sample 5 of Example 17; compound sample 6 of Example 18; compound sample 7 of Example 18; compound sample 8 of Example 8; compound sample 9 of Example 21; compound control sample of Example 22; malotinate.

(Test animals) A group of 10 ICR mice (6 weeks old, weight 30 g) was used for the test.

(Test method) A specimen was suspended in a 5% gum arabic solution to prepare specimens at various concentrations, and the 5% gum arabic solution was used as a control group. 10 mg/kg body weight of each of the specimen and 5% gum arabic solution was orally administered to individual animals. 60 minutes later, 0.03 ml/kg of carbon tetrachloride solution diluted with olive oil was orally administered. After leaving the animal for 18 hours, blood was collected from the animal under ether anesthesia, and after centrifugation, the serum GPT value was measured.

[0060] In addition, a group of three ICR mice (6 weeks old, weight 30 g) was used as an untreated group. After the test, blood was collected under ether anesthesia, and after centrifugation, the serum GTP level was measured. The value was measured.

[0061] The test results were expressed as the inhibition rate (%) of increase in serum GTP calculated by the following formula. Serum GTP increase suppression rate (%) = (Serum GTP value of each sample group - normal serum GTP value) / (
Serum GTP value of control group - normal serum GTP value) ×
100 The results are shown in Table 1.

[0062]

[Table 1]

[0063]

EFFECTS OF THE INVENTION The compound of the present invention significantly inhibited the increase in serum GPT and GOT activity in an experimental injury model (rat) induced by carbon tetrachloride, and exhibited a remarkable effect of suppressing liver injury. Therefore, the compounds of the present invention are useful as preventive or therapeutic agents for liver diseases.

Claims (2)

[Claims] Claim 1: General formula [Formula 1] (wherein R1 is a hydrogen atom, an alkyl or alkenyl group having 1 to 12 carbon atoms, an unsubstituted or substituted benzyl group, a lower alkylcarbonyl group, an unsubstituted or substituted benzoyl group, R2 represents a lower alkylmethanesulfonyl group, an unsubstituted or substituted benzenesulfonyl group, R2 represents hydrogen, a lower alkoxycarbonyl group, an unsubstituted or mono- or di-substituted carbamoyl group with lower alkyl, lower alkenyl, or lower alkynyl; R3 is hydrogen, a nitro group, a cyano group, a lower alkoxycarbonyl group, or an unsubstituted or substituted phenyl group). [Claim 2] General formula [Formula 2] (wherein R1 is a hydrogen atom, an alkyl or alkenyl group having 1 to 12 carbon atoms, an unsubstituted or substituted benzyl group, a lower alkylcarbonyl group, an unsubstituted or substituted benzoyl group, R2 represents a lower alkylmethanesulfonyl group, an unsubstituted or substituted benzenesulfonyl group, R2 represents hydrogen, a lower alkoxycarbonyl group, an unsubstituted or mono- or di-substituted carbamoyl group with lower alkyl, lower alkenyl, or lower alkynyl; R3 is a 4-trifluoromethylpyrrole derivative represented by hydrogen, a nitro group, a cyano group, a lower alkoxycarbonyl group, or an unsubstituted or substituted phenyl group.