JP3010502B2 - Pyrrole aldehyde derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pyrrolealdehyde derivative having an excellent lipid-lowering effect and useful as a therapeutic agent for hyperlipidemia.

[0002]

2. Description of the Related Art Conventionally, abnormal lipid metabolism such as blood lipids such as triglyceride and cholesterol causes abnormal increase and imbalance of blood lipids, causing arteriosclerosis, angina pectoris and myocardial infarction. Is considered to be a large risk factor for causing ischemic heart disease or cerebral infarction.

Hitherto, as a drug for hyperlipidemia, clofibrate drugs, nicotinic acid and derivatives thereof have been mainly used, but these drugs lower blood triglycerides but have a weak effect on cholesterol. In recent years, probucol having a new structure and cholestyramine, an anion exchange resin, have been used as agents for lowering blood cholesterol, but these have no effect on triglycerides.

[0004] The abnormal increase of triglyceride and cholesterol in blood alone is a major cause of arteriosclerosis, especially atherosclerosis, but the risk of the onset is marked if both lipids are increased simultaneously. It is known to increase. As described above, drugs that lower blood triglyceride and cholesterol have already been used in clinical settings, but development of drugs that are more powerful and have fewer side effects is desired in terms of dose, safety, and application range. In particular, the development of drugs that simultaneously lower blood triglyceride and cholesterol strongly attracts particular attention from the perspective of treatment and prevention of diseases such as ischemic heart disease and cerebral infarction caused by arteriosclerosis. There is no drug to make.

[0005]

The inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, it has been found that a specific pyrrole aldehyde derivative can simultaneously enhance blood triglyceride and cholesterol more than conventional drugs. The present inventors have found that they have an excellent lipid lowering effect of lowering the concentration, and have completed the present invention.

[0006]

That is, the gist of the present invention is as follows.
The following general formula (I)

[0007]

Embedded image

Wherein R is halogen, hydroxy, amino, carbamoyl, C ₁ -C ₅ alkylamino, C ₂
Dialkylamino -C _6, acylamino C ₂ -C _6, alkylthio C ₁ -C _5, mercapto, C ₂ -C
₆ acyloxy, carbamoyloxy, C ₆ -C ₁₂ aryl and C ₃ -C ₇ 1 or more C ₁₀ optionally substituted by a substituent of -C selected from cycloalkyl of
C ₁₀ -C ₁₆ having one or more ₁₆ alkyl groups or vinyl groups
Represents an alkenyl group of )).

Hereinafter, the present invention will be described. The pyrrolealdehyde derivative of the present invention is represented by the above general formula (I).
In the formula, the alkyl group which may have a substituent represented by R includes a decyl group, an undecyl group, a 2,2-dimethylundecyl group, a 11,11′-dimethyldodecyl group, a dodecyl group, a 12-decyl group. Examples thereof include an alkyl group having 10 to 16 carbon atoms such as a methyltridecyl group, a tridecyl group, a 12,12-dimethyltridecyl group, a tetradecyl group, a 6,6-dimethyltetradecyl group, a pentadecyl group, and a hexadecyl group. Examples of the substituent which can be substituted on the group include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a hydroxyl group; an amino group; a carbamoyl group, a methylamino group, an ethylamino group, an n-propylamino group, and an i- Alkyl having 1 to 5 carbon atoms, such as propylamino group, n-butylamino group, t-butylamino group, n-pentylamino group, etc. Diamino group having 2 to 6 carbon atoms such as dimethylamino group, methylethylamino group, diethylamino group, dipropylamino group; acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group; An acylamino group having 2 to 6 carbon atoms such as a valerylamino group, a pivaloylamino group, a hexanoylamino group; a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group,
an alkylthio group having 1 to 5 carbon atoms such as an n-butylthio group, a t-butylthio group, an n-pentylthio group; a mercapto group; an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group;
An acyloxy group having 2 to 6 carbon atoms such as a pivaloyloxy group and a hexanoyloxy group; a carbamoyloxy group;
Aryl groups having 6 to 12 carbon atoms such as phenyl group, tolyl group, xylyl group and naphthyl group; cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group And the like. Further, in the present invention, a compound having 12 to 14 carbon atoms in the alkyl group serving as a base is preferable.

The alkenyl group includes 1-decenyl group, 4,7-decadienyl group, 10-methyl-9-undecenyl group, 2-undecenyl group, 4,8-dimethyl-
3,7-nonadienyl group, 1-dodecenyl group, 2-tridecenyl group, 6-tridecenyl group, 1-tetradecenyl group, 3,7,11-trimethyl-2,6-10-dodecatrienyl group, 1-pentadecenyl group Having 10 or more carbon atoms having one or more vinyl groups such as 1-hexadecenyl group
Alkenyl group, preferably an alkenyl group having 12 to 14 carbon atoms.

Specific examples of the pyrrolealdehyde derivative of the present invention include the compounds shown in Tables 1, 2 and 3 below.

[0012]

[Table 1]

[0013]

[Table 2]

[0014]

[Table 3]

The compound of the present invention can be produced, for example, by the following method. Method 1:

[0016]

Embedded image

Wherein R ¹ represents an alkyl group or an alkenyl group. That is, pyrrole-2-carboxylic acid methyl ester (II) and a suitable acyl chloride (III) are mixed with benzene, methylene chloride in the presence of a Lewis acid such as aluminum chloride, stannic chloride or boron trifluoride diethyl ether complex. If the Friedel-Crafts reaction is carried out in a solvent such as carbon disulfide and a temperature range from -10 ° C to the boiling point of the solvent, methyl 4-acylpyrrole-2-carboxylate (IV) can be obtained. The keto group is then subjected to a suitable reduction reaction, such as diborane reduction, Raney nickel reduction of dithioketal, or catalytic hydrogenation of acetate synthesized via alcohol, for example, to give 4-alkylpyrrole-2.
Carboxylic acid methyl ester (V). From the obtained compound (V), a description in the literature (Organi
c Reactions, 8, 232, 1954
The compound of the present invention represented by the general formula (VI) can be obtained through three steps according to the McFaddine-Stevens method of the present invention. Method 2:

[0018]

Embedded image

[0019]

Embedded image

Wherein R ¹ is as described above. ]
That is, when 4-methylpyrrole-2-carboxylic acid methyl ester (V) is heated at a high temperature in the presence of a base such as sodium hydroxide or potassium hydroxide in an alcohol-based solvent such as ethylene glycol or diethylene glycol containing water, the ester is obtained. Decarboxylation occurs simultaneously with hydrolysis of the group, and 3-alkylpyrrole (VII) can be obtained in almost quantitative yield. By subjecting the obtained compound (VII) to a Vils-Meier reaction using a combination of dimethylformamide and phosphorus oxychloride, or N-methylformanilide and phosphorus oxychloride, the compound of the present invention represented by the general formula (VI) can be obtained. Can be Method 3:

[0021]

Embedded image

[0022]

Embedded image

Wherein R ¹ is as described above, and n
Represents the number of repetitions in the reaction (B), and represents an integer of 2 or more. That is, methyl 4-formylpyrrole-2-carboxylate represented by the above formula (VIII) (Bulletin de la Society C)
hemique de France, p. 283 (19
72) and methoxymethyltriphenylphosphonium chloride in a Wittig reaction in the presence of a base to give the compound (IX). Then, the compound (IX)
Is subjected to hydrolysis in an alcoholic solvent containing water using an acid catalyst such as sulfuric acid and paratoluenesulfonic acid,
(2-methoxycarbonylpyrrole) -4-acetaldehyde (X). In the reaction route (A), when the obtained compound (X) is further reacted with an alkyltriphenylphosphonium bromide under the conditions of the Wittig reaction, the cis- and / or trans-forms represented by the above formula (XI) are obtained. -Alkenylpyrrole-2-carboxylic acid methyl ester (XI) is obtained from this compound (X
In the method I), the compound of the present invention represented by the general formula (XII) can be derived by the McFaddin-Stevens method in the same manner as in the method 1. In the reaction route (B), the compound represented by the formula (X) is converted into the compound represented by the formula (VIII) →
By repeating the Wittig reaction and acid decomposition an arbitrary number of times in the same manner as in the reactions (IX), (IX) → (X), (X ′)
A compound represented by the formula was obtained, and the compound having a double bond at any position (XI
The compound of the present invention represented by the formula I ') can be obtained. Method 4:

[0024]

Embedded image

Wherein R ¹ is as described above. ]
By reacting 4-formylpyrrole-2-carboxylic acid methyl ester with an alkyl (or alkenyl) triphenylphosphonium bromide under the same Wittig reaction conditions as in Method 3, the cis isomer represented by the above formula (XIII) And / or trans 4-alkenylpyrrole-2-carboxylic acid methyl ester is obtained. The obtained compound (XIII) can be led to the compound of the present invention represented by the general formula (XIV) in the same manner as in Method 1.

The compound of the present invention is administered to humans as a therapeutic agent for hyperlipidemia, preferably by oral administration. As dosage forms for oral administration, forms such as tablets, granules, powders, capsules and the like are used. These are the usual additives to the compound of the present invention, for example, excipients such as glucose, lactose, corn starch or mannitol. , Hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC)
And disintegrants such as starch and gelatin powder, and lubricants such as talc and magnesium stearate.

The dose of the compound of the present invention is 10 mg to 10 g, more preferably 100 mg to 5 g per day for an adult in the case of oral administration, which is administered once or in two or three divided doses. be able to.

[0028]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Synthesis Example 1 Synthesis of methyl 4-tridecanoylpyrrole-2-carboxylate 102.9 g (0.48 mol) of tridecanoic acid was dissolved in 480 ml of methylene chloride, and 52.6 ml of thionyl chloride was added thereto.
(0.72 mol) and N, N-dimethylformamide 0.1.
2 ml were added and left overnight. This was concentrated under reduced pressure, and the remaining oil was added to 400 ml of methylene chloride containing 106.6 g (0.8 mol) of anhydrous aluminum chloride. To this, pyrrole-2-carboxylic acid methyl ester, 50.05 g
(0.4 mol) of a solution of 200 ml of methylene chloride in 3-9.
The solution was added dropwise at about 40 minutes over about 40 minutes. After completion of the dropwise addition, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours.
Added. To this, methylene chloride (1000 ml) was added to dissolve all the crystals, the layers were separated, and the organic layer was washed three times with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from 400 ml of ethyl acetate and 400 ml of hexane.
7.2 g of 4-tridecanoylpyrrole-2-carboxylic acid methyl ester were obtained as almost white crystals. Yield 8
3% m. p. 92-93 ° C

IR (KBr) cm ^-1 : 3270, 2920, 2855, 1690, 1660,
1565, 1455, 1385, 1290, 1215 NMR (CDCl ₃ ) δ: 0.88 (t, 3H), 1.15, 1.38 (each m, 18H), 1.65, 1.75 (each m, 2H), 2.75 (t, 2H), 3.89 (s, 3H), 7.28, 7.30 (each m, 1H), 7.53, 7.55 (each m, 1H), 9 .52 (broad s, 1H)

Synthesis Example 2 Synthesis of methyl 4-tridecanoylpyrrole-2-carboxylate dithioethylene ketal 4-tridecanoylpyrrole-2- obtained in Synthesis Example 1
18.29 g (56.9 mmol) of carboxylic acid methyl ester was dissolved in 140 ml of acetic acid, and 14.0 ml (167 mmol) of 1,2-ethanedithiol and 14 ml of boron trifluoride / diethyl ether complex were added thereto, and the mixture was cooled on ice. And stirred overnight. This was concentrated under reduced pressure, 100 ml of water was added to the residue, and the mixture was extracted with 200 ml of ethyl acetate (100 ml × 2). The extracts were combined, washed with a 5% aqueous sodium hydroxide solution and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain methyl 4-tridecanoylpyrrole-2-carboxylate dithioethylene ketal. The mother liquor is subjected to silica gel column chromatography (eluent:
Ethyl acetate / hexane = 1/6) to obtain the target compound remaining in the recrystallization solvent. 15.44 g total yield, 68 yield
% M. p. 77-78 ° C

IR (KBr) cm ^-1 : 3360, 2940, 2860, 1705, 1440,
1385, 1265, 1210, 1120 NMR (CDCl ₃ ) δ: 0.88 (t, 3H), 1.20, 1.40 (each m, 20H), 2.22, 2.28 (each m, 2H) , 3.25, 3.41 (each m, 4H), 3.84 (s, 3H), 6.92 (s, 1H), 7.05, 7.07 (each m, 1H), 9.08. (Broad s, 1H)

Synthesis Example 3 Synthesis of 4-tridecylpyrrole-2-carboxylic acid methyl ester 4-tridecanoylpyrrole-2- obtained in Synthesis Example 2
Carboxylic acid methyl ester dithioethylene ketal 1
5.06 g (37.9 mmol) was added to a mixed solution of 150 ml of Raney nickel (activated type, manufactured by Aldrich) washed with water and then ethanol and 750 ml of ethanol, and the mixture was heated under reflux for 30 minutes. After cooling to about 30 ° C,
Raney nickel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 10.70 g of 4-tridecylpyrrole-2-carboxylic acid methyl ester as white crystals. Yield 91.8% m. p. 80-8
2 ℃

IR (KBr) cm ^-1 : 3340, 2920, 2850, 1690, 1445,
1390, 1265, 1205, 1130 NMR (CDCl ₃ ) δ: 0.88 (t, 3H), 1.2, 1.4 (each m, 20H), 1.49, 1.62 (each m, 2H) , 2.45 (t, 2H), 3.83 (s, 3H), 6.72, 6.75 (each m, 2H), 8.88 (broad s, 1H).

Synthesis Example 4 Synthesis of 3-tridecylpyrrole 9.50 g (30.9 mmol) of methyl 4-tridecylpyrrole-2-carboxylate obtained in Synthesis Example 3, 200 ml of ethylene glycol and 10 ml of water The solution is added with 20 g of potassium hydroxide and heated at 190 ° C. for 5 hours with stirring. After cooling, water was added and the mixture was extracted with ethyl acetate.The organic layer was washed with water and dried over anhydrous magnesium sulfate.
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/5) to obtain 7.50 g of 3-tridecylpyrrole. Yield 97% m.p. p. 32.5-33.5 ° C

IR (KBr) cm ^-1 : 3420, 2950, 2860, 765 ¹ H NMR (CDCl ₃ , 250 MHz) δ: 0.88 (3H, t), 1.25 (20H, m), 1.57 ( 2H, m), 2.48 (2H, t), 6.09 (1H, m), 6.57 (1H, m), 6.72 (1H, m), 7.97 (1H, broads)

Example 1 Synthesis of 4-tridecylpyrrole-2-aldehyde (Table 1)
Compound No. in the 4) 2.49 g of 3-tridecylpyrrole obtained in Synthesis Example 4
(10 mmol) and 1.62 N-methylformanilide
To a solution of g (12 mmol) of ethylene chloride (25 ml), 1.01 ml (11 mmol) of phosphorus oxychloride was added dropwise with ice cooling and stirring. After heating under reflux for 30 minutes, the temperature was returned to room temperature, and an aqueous solution (1 g) of sodium acetate (6.0 g) was added.
0 ml) and heated to reflux again for 15 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was dispersed.
After washing with saturated saline in this order, the extract was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 1/10).
To give 0.32 g of 4-tridecylpyrrole-2-aldehyde. Yield 12% m. p. 61-6
4 ℃

IR (KBr) cm ^-1 : 3220, 2940, 2860, 1690, 1645,
5. 1400, 1390, 765 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (20H, m), 1.54 (2H, m), 2.47 (2H, t), 80 (1H, m), 6.90 (1H, m), 9.20 (1H, broad s), 9.44 (1H, s)

Synthesis Example 5 Synthesis of methyl 4-dodecanoylpyrrole-2-carboxylate 213 g of lauric acid (1.0 g) in the same manner as in Synthesis Example 1.
6 mol) as the starting material for 4-dodecanoylpyrrole-2-
245.5 g of carboxylic acid methyl ester were obtained. Yield 9
0% m. p. 102-103 ° C IR (KBr) cm ^-1 : 3270, 2920, 2850, 1690, 1660 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (16H, m), 1.70 ( 2H, m), 2.75 (2H, t), 3.88 (3H, s), 7.30 (1H, m), 7.53 (1H, m), 9.50 (1H, broad s)

Synthesis Example 6 Synthesis of methyl 4- (1-hydroxydodecyl) pyrrole-2-carboxylate 245.5 g (0.80 mol) of methyl 4-dodecanoylpyrrole-2-carboxylate obtained in Synthesis Example 5 ) To 1.5 liters of tetrahydrofuran and 0.15 of methanol
One liter is added, and 15.1 g (0.40 mol) of sodium borohydride is added little by little under stirring at a temperature of 10 to 21 ° C. The mixture was stirred at 20 ° C., and 1 hour later, 7.5 g (0.20 mol) of sodium borohydride was further added. After stirring at 20 ° C. for 1 hour, the solvent was distilled off under reduced pressure and 700 ml of water was added to the residue.
And 2.4 liters of ethyl acetate. The organic layer is separated, washed successively with 700 ml of water and then with 700 ml of saturated saline, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 247.0 g of pale brown crystals. 99% yield

IR (KBr) cm ^-1 : 3450, 3240, 2930, 1680 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (18H, m), 1.73 (2H, m ), 3.85 (3H, s), 4.63 (1H, m), 6.88 (1H, m), 6.92 (1H, m), 9.05 (1H, broads).

Synthesis Example 7 Synthesis of methyl 4- (1-acetoxydodecyl) pyrrole-2-carboxylate 247.0 g of methyl 4- (1-hydroxydodecyl) pyrrole-2-carboxylate obtained in Synthesis Example 6 ( 0.
(80 moles) in a solution of 1.6 liters of toluene in 180 ml (1.91 moles) of acetic anhydride and 180 ml (2.2
3 mol) and heated at 105 ° C. for 2.5 hours. After cooling to room temperature, the mixture was washed twice with 700 ml of a 2N hydrochloric acid solution, 1.2 liter of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 30 minutes, and the organic layer was extracted. The extracted organic layer is sequentially washed with a saturated aqueous solution of sodium hydrogencarbonate and 700 ml of saturated saline, and dried over anhydrous magnesium sulfate. The crystals obtained by distilling off the solvent were evaporated with hexane 7
Recrystallization from 00 ml gave 258.0 g of very pale brown crystals. Yield 92% m.p. p. 69-70 ° C

IR (KBr) cm ^-1 : 3300, 2920, 1705 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (18H, m), 1.86 (2H, m), 2.03 (3H, s), 3.85 (3H, s), 5.73 (1H, t), 6.89 (1H, m), 6.95 (1H, m), 9.08 (1H) , Broad s)

Synthesis Example 8 Synthesis of methyl 4-dodecylpyrrole-2-carboxylate 258.0 g of methyl 4- (1-acetoxydodecyl) pyrrole-2-carboxylate obtained in Synthesis Example 7 (0.
10% in a solution of 2.0 liters of ethanol
16 g of palladium-carbon was added, and catalytic hydrogen reduction was performed at 50 ° C. in a hydrogen atmosphere. It took 5.5 hours to complete the reaction, 1.5 liters of chloroform was added, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain crystals. Ethanol 9
Recrystallization from 50 ml gave 179.6 g of 4-dodecylpyrrole-2-carboxylic acid methyl ester as white crystals. Yield 83% m. p. 68-69 ° C

IR (KBr) cm ^-1 : 3340, 2920, 1690 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (18H, m), 1.54 (2H, m), 2.44 (2H, t), 3.83 (3H, s), 6.74 (2H, m), 8.88 (1H, broad s)

Synthesis Example 9 Synthesis of 4-dodecylpyrrole-2-carboxylic acid hydrazide 3.57 g (12 mmol) of methyl 4-dodecylpyrrole-2-carboxylate obtained in Synthesis Example 8 was hydrated with hydrazine in 75 ml of ethanol. After reacting with 15 ml of the product (100%) under heating and reflux for 36 hours, the crystals precipitated after cooling were filtered to obtain 3.30 g of 4-dodecylpyrrole-2-carboxylic acid hydrazide as white crystals. 92% yield
m. p. 137-139.5 ° C IR (KBr) cm ^-1 : 3320, 2940, 2860, 1645, 1540 NMR (DMSO-d ₆ ) δ: 0.84 (3H, t), 1.22 (18H, m), 1.45 (2H, m), 2.33 (2H, t), 4.25 (2H, broads), 6.55 (1H, m), 6.59 (1H, m), 8.60 ( 1H, s), 9.11 (1H, s)

Synthesis Example 10 Synthesis of 4-dodecylpyrrole-2-carboxylic acid p-toluenesulfonylhydrazide 3.29 g (11 mmol) of 4-dodecylpyrrole-2-carboxylic acid hydrazide obtained in Synthesis Example 9 was treated with pyridine 35.
Then, 2.23 g (12 mmol) of paratoluenesulfonyl chloride was added little by little under ice-cooling and stirring. After reacting at room temperature for 1.5 hours, the reaction solution was treated with 6N hydrochloric acid (70 ml).
The precipitate was filtered, washed with water, and then recrystallized from a mixed solvent of ethanol / water (10/1) to give 4-dodecylpyrrole-2-carboxylic acid p-toluenesulfonylhydrazide 4. .55 g were obtained as white crystals. Yield 91% m. p. 134.5-135.
5 ℃

IR (KBr) cm ^-1 : 3420, 3330, 2940, 2860, 1650,
1540, 1335, 1165 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (18H, m), 1.53 (2H, m), 2.38 (3H, s), 43 (2H, t), 6.54 (1H, m), 6.71 (1H, m), 7.23 (2H, d), 7.38 (1H, d), 7.78 (2H, d) ), 7.86 (1H, d), 8.95 (1H, broads)

Example 2 Synthesis of 4-dodecylpyrrole-2-aldehyde (Compound No. 3 in Table 1) 2.27 g of 4-dodecylpyrrole-2-carboxylic acid paratoluenesulfonylhydrazide obtained in Synthesis Example 10 (5 .
(1 mmol) of ethylene glycol solution was heated to 160 ° C., and 1.35 g (13 mmol) of sodium carbonate was added at once, and then heated for 1.5 minutes. After the temperature of the reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The reaction was carried out again using exactly the same scale and operation as the above reaction, and the crude product was combined and purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/10). Recrystallization from the solvent gave 1.12 g of the desired 4-dodecylpyrrole-2-aldehyde as pale yellow crystals. Yield 42% m. p. 64-65 ° C

IR (KBr) cm ^-1 : 3200, 2940, 2860, 1690, 1650,
1405,775 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (18H, m), 1.57 (2H, m), 2.48 (2H, t), 6.80 ( 1H, m), 6.91 (1H, m), 9.38 (1H, broads), 9.44 (1H, s)

Example 3 Synthesis of 4-tetradecylpyrrole-2-aldehyde (Compound No. 5 in Table 1) 4-Tetradecylpyrrole-2-aldehyde was obtained in the same manner as in Example 2 with a yield of 43%. Synthesized. m. p. 7
0-71 ° C IR (KBr) cm ^-1 : 3320, 2940, 2860, 1685, 1650,
1400,770 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (22H, m), 1.57 (2H, m), 2.48 (2H, t), 6.80 ( 1H, m), 6.91 (1H, m), 9.40 (1H, broad s), 9.44 (1H, s)

Synthesis Example 11 Synthesis of 4-methoxyvinylpyrrole-2-carboxylic acid methyl ester Methoxymethyltriphenylphosphonium chloride 20
A solution of lithium diisopropylamide in tetrahydrofuran (2.01 molar concentration) was added to a solution of 0 g (0.58 mol) in 1.5 liter of tetrahydrofuran under ice-cooling and stirring.
20 ml (0.44 mol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Then, 400 ml of a tetrahydrofuran solution of 57.6 g (0.38 mol) of 4-formylpyrrole-2-carboxylic acid methyl ester was added again under ice cooling. It was added dropwise at a temperature of ８8 ° C. After reacting at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/4), and 34.4 g of 4-methoxyvinylpyrrole-2-carboxylic acid methyl ester was obtained as E-form. Obtained as a mixture of Z isomers. Yield 50%

NMR (CDCl ₃ ) δ: 3.63 (s, E form), 3.76 (s, Z form), 3.85 (3H, s), 5.20 (d, Z form, J = 6.5 Hz), 5.68 (d, E form, J = 13 Hz), 6.01 (d, Z form), 6.82 (2H, m), 7.00 (1H, m), 7.17 (1H, m), 9.10 (1H, broad s)

Synthesis Example 12 Synthesis of (2-methoxycarbonylpyrrole) -4-acetaldehyde 13.0 g (72 mmol) of 4-methoxyvinylpyrrole-2-carboxylic acid methyl ester obtained in Synthesis Example 11 in 280 ml of isopropyl alcohol and water 1.13 g of paratoluenesulfonic acid was added to 280 ml of the mixed solution to give 3.5.
Heated to reflux for an hour. After cooling, a saturated saline solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saline solution containing a small amount of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 2 /
Purification in 5) gave 7.50 g of the desired (2-methoxycarbonylpyrrole) -4-acetaldehyde as an oil. 62% yield

IR (Neat) cm ^-1 : 3340, 1720, 1695, 1220, 770 NMR (CDCl ₃ ) δ: 3.57 (2H, t), 3.85 (3H, s), 6.81 (1H) , M), 6.88 (1H, m), 9.26 (1H, broads), 9.72 (1H, d)

Synthesis Example 13 Synthesis of methyl methyl 4- (2-tridecenyl) pyrrole-2-carboxylate 14.1 g (60 mmol) of undecyl bromide and 15.7 g (60 mmol) of triphenylphosphine in xylene for 15 hours After heating under reflux, xylene was distilled off under reduced pressure, ether was added, and the mixture was decanted to remove the supernatant. This operation was repeated three times to obtain 19.3 g of undecyltriphenylphosphonium bromide. This bromide was dissolved in 200 ml of tetrahydrofuran, and 15% n-butyllithium in hexane (1.
20 ml (32 mmol) were added dropwise. After 10 minutes of stirring, 2.17 g of (2-methoxycarbonylpyrrole) 4-acetaldehyde obtained in Synthesis Example 12 under ice cooling.
(13 mmol) in tetrahydrofuran (6 ml) was added dropwise, and the mixture was further reacted for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/10) to give the desired 4-
3.41 g of (2-tridecenyl) pyrrole-2-carboxylic acid methyl ester was obtained in the form of an oil. 86% yield

IR (Neat) cm ^-1 : 3340, 2940, 2860, 1690, 770 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (16H, m), 2.00, 2 .20 (each 2H, m), 3.17, 3.22 (each 2H, d), 3.83 (3H, s), 5.50 (2H, m), 6.74 (2H, m), 8.95 (1H, broads)

Synthesis Example 14 Synthesis of 4- (2-tridecenyl) pyrrole-2-carboxylic acid hydrazide 4- (2-tridecenyl) pyrrole obtained in Synthesis Example 13
Using 3.69 g (12 mmol) of 2-carboxylic acid methyl ester, 4- (2-tridecenyl) pyrrole-2-carboxylic acid hydrazide was obtained in the same manner as in Synthesis Example 9.
39 g were obtained as white crystals. Yield 92% m.p. p. 1
29.5-131.5 ° C IR (KBr) cm ^-1 : 3310, 2930, 2860, 1640, 1620,
1530 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (16H, m), 2.08 (2H, m), 3.15, 3.22 (each 2H, d), 4 .02 (2H, s), 5.49 (2H, m), 6.43 (1H, m), 6.73 (1H, m), 7.30 (1H, s), 9.40 (1H, m) broad s)

Synthesis Example 15 Synthesis of 4- (2-tridecenyl) pyrrole-2-carboxylic acid p-toluenesulfonylhydrazide 4- (2-tridecenyl) pyrrole obtained in Synthesis Example 14
3.38 g (11 mmol) of 2-carboxylic acid hydrazide
And 4.81 g of 4- (2-tridecenyl) pyrrole-2-carboxylic acid p-toluenesulfonylhydrazide was obtained as white crystals in the same manner as in Synthesis Example 10. Yield 94% m.p. p. 131.5-133 ° C IR (KBr) cm ^-1 : 3320, 2930, 2860, 1645, 1540,
1160 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (16H, m), 2.10 (2H, m), 3.15, 3.21 (each 2H, d), 5 .50 (2H, m), 6.54 (1H, m), 6.72 (1H, m), 7.24 (2H, d), 7.35 (1H, d), 7.78 (2H, m) d), 7.85 (1H, d), 8.96 (1H, broads)

Example 4 Synthesis of 4- (2-tridecenyl) pyrrole-2-aldehyde (Compound No. 33 in Table 1) 4- (2-tridecenyl) pyrrole obtained in Synthesis Example 15
3. 2-carboxylic acid paratoluenesulfonyl hydrazide
Using 80 g, 4- (2-
1.45 g of (tridecenyl) pyrrole-2-aldehyde were obtained as pale yellow crystals. Yield 50% m. p. 29-3
2 ° C IR (KBr) cm ^-1 : 3300, 2940, 2860, 1650, 1400,
785 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (16H, m), 2.00, 2.10 (each 2H, m), 3.19, 3.25 (each 2H , D), 5.50 (2H, m), 6.80 (1H, m), 6.93 (1H, m), 9.44 (1H, s), 9.60 (1H, broads)

Test Example 1 The lipid lowering effect of the compound of the present invention was measured by the following method. Six male Wistar rats weighing 140 to 150 g were treated as a group, and 5 mg, 10 mg, or 20 mg / day of the test compound suspended in 0.05% Tween 80 was used.
It was orally administered once a day for 8 days in kg. Blood was collected 3 hours after the final administration of the test compound, and triglyceride (T
G) was determined by an enzymatic method using a neutral fat measurement kit manufactured by Diatron and New Clintech TG, and cholesterol (Chol) was determined by an enzymatic method using a cholesterol determination kit manufactured by Kyowa Medex and Determiner TC5. The amount was measured.

The results were determined by the percentage (%) of the decrease in the TG amount and the Chol amount with respect to the control group not receiving the test compound. The results are shown in Table 4 below.

[0062]

[Table 4]

[0063]

The compound of the present invention exhibits an effective lowering effect on triglyceride and cholesterol in serum even at a low dose, and thus is useful as a therapeutic drug for hyperlipidemia and further as an anti-atherosclerotic drug.

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mayumi Hirata 1000 Kamoshita-cho, Midori-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Research Institute (56) References JP-A-3-47165 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 207/00-207/50 A61K 31/40 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound represented by the following general formula (I) Wherein R is halogen, hydroxy, amino, carbamoyl, C ₁ -C ₅ alkylamino, C ₂ -C ₆ dialkylamino, C ₂ -C ₆ acylamino, C ₁ -C ₅
Alkylthio, mercapto, C ₂ -C ₆ acyloxy, carbamoyloxy, C ₆ -C ₁₂ aryl and C
Represents a C ₁₀ -C ₁₆ alkyl group or a C ₁₀ -C ₁₆ alkenyl group having at least one vinyl group which may be substituted by one or more substituents selected from _3- C ₇ cycloalkyl. ).