JPH06104658B2 - Pyrrolecarboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention has a pyrrolecarboxylic acid derivative or a pharmaceutically acceptable salt thereof which has an excellent lipid-lowering effect and is useful as a therapeutic drug for hyperlipidemia and the like. Regarding

[Problems to be Solved by Prior Art and Invention]

Conventionally, blood lipids, for example, abnormal lipid metabolism such as triglyceride and cholesterol, causes an abnormal increase or imbalance in blood lipids, causing arteriosclerosis,
Consequently, it is considered to be a large risk factor for causing ischemic heart disease such as angina and myocardial infarction, or cerebral infarction.

Conventionally, as drugs for hyperlipidemia, clofibrate drugs, nicotinic acid and its derivatives have been mainly used, but these reduce blood triglyceride but have a weak effect on cholesterol. In recent years, probucol having a new structure and cholestyramine which is an anion exchange resin have been used as agents for lowering blood cholesterol, but they have no effect on triglyceride.

Blood triglyceride and cholesterol are the major causes of arteriosclerosis, especially atherosclerosis, due to the abnormal increase of each of them, but when both lipids are increased at the same time, the risk of their development is significantly increased. It is known.

As mentioned above, drugs that lower blood triglyceride and cholesterol are already used in clinical settings.
It is desired to develop a more potent drug with less side effects in terms of dose, safety and application range. In particular, the development of a drug that strongly reduces blood triglyceride and cholesterol at the same time attracts particular attention from the viewpoint of treatment and prevention of diseases such as ischemic heart disease and cerebral infarction caused by arteriosclerosis, but these are still satisfied. There is no drug to let you.

[Means for solving problems]

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, a specific pyrrolecarboxylic acid derivative or a pharmaceutically acceptable salt thereof has a stronger effect on blood triglyceride and cholesterol at the same time than conventional drugs. It has been found that it has an excellent lipid-lowering effect of reducing the amount of the compound to the above-mentioned level, and completed the present invention.

That is, the gist of the present invention is the general formula (I) (In the formula, R ¹ represents a hydrogen atom, an alkyl group or an alkenyl group having 5 to 25 carbon atoms, and R ² represents a hydrogen atom, a phenyl group,
Alternatively, it represents an alkyl group having 1 to 10 carbon atoms which may have a substituent, and R ³ represents a hydrogen atom or an alkyl group or alkenyl group having 10 to 16 carbon atoms. However, R ¹ and R ³ are not simultaneously hydrogen, and when R ¹ represents 5 to 25 alkyl or alkenyl group having a carbon number, R ¹ and CO ₂ R ²
And are not adjacent to each other. ) The pyrrolecarboxylic acid derivative represented by: or a pharmaceutically acceptable salt thereof.

The present invention will be described below. The pyrrolecarboxylic acid derivative of the present invention is represented by the above general formula (I).

In the formula, the alkyl group represented by R ¹ has 5 to 5 carbon atoms.
25 linear, branched or cyclic alkyl groups, preferably an alkyl group having 10 to 16 carbon atoms can be mentioned. Examples of the alkenyl group include an alkenyl group having 5 to 25 carbon atoms, preferably one having at least one vinyl group in the molecule, and preferably an alkenyl group having 10 to 16 carbon atoms.

In the formula, the alkyl group represented by R ² has 1 to 1 carbon atoms.
Mention may be made of 10 alkyl groups, in particular alkyl groups having 1 to 4 carbon atoms. Examples of the substituent that may be substituted on the alkyl group include a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylamino group having 1 to 5 carbon atoms, a dialkylamino group having 2 to 6 carbon atoms, and carbon. Number 1
Examples include an alkylcarbonylamino group having 5 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a mercapto group, an alkylcarbonyloxy group having 1 to 5 carbon atoms, and an aminocarbonyloxy group.

In the formula, the alkyl group represented by R ³ has 10 to 16 carbon atoms.
There may be mentioned straight-chain, branched-chain or cyclic alkyl groups. Examples of the alkenyl group include alkenyl groups having 10 to 16 carbon atoms and having at least one vinyl group in the molecule. In the present invention, the substituents R ¹ and -CO ₂ R ² are
Substitutions are made on positions that are not adjacent to each other on the pyrrole ring.
Specifically, at the 3-position of the pyrrole ring, —CO ₂ R ² (in that case, R ²
Is more preferably a hydrogen atom. ) Replaces 5
Position in the compound R ¹ is substituted, or -CO ₂ R ² (at that time, R ² is are hydrogen atoms is more preferable.) At the 2-position of the pyrrole ring is substituted, R ¹ in the 4-position or 5-position Compounds in which are substituted are preferred.

Further, a compound in which any one of R ¹ , R ^{2 and} R ³ is a hydrogen atom is preferable. However, R ¹ and R ³ do not represent a hydrogen atom at the same time.

Specific examples of the compound of the present invention include the compounds shown in Table 1 below.

Examples of the pharmaceutically acceptable salt of the derivative of pyrrolecarboxylic acid include salts of inorganic metals such as sodium, potassium, calcium and magnesium, ammonium salts or triethylammonium salts, cyclohexylammonium salts, organic amines such as lysine salts. Examples include salt.
When R ² in the general formula (I) contains an amino group, inorganic acid salts such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acid salts such as maleic acid, succinic acid and citric acid are mentioned. be able to.

The compound of the present invention can be produced, for example, by the method described below.

Method 1: [In the formula, R ⁴ represents an alkyl group having ⁴ to 24 carbon atoms, and X represents a halogen atom. That is, when the compound (II) obtained by reacting pyrrole with methyl or ethyl magnesium halide is reacted with a suitable acyl chloride (III) in an inert solvent such as diethyl ether or tetrahydrofuran, 2
An acylpyrrole (IV) is obtained. This compound (IV)
If the usual Wolff-Kishner reduction is applied to the 2-alkylpyrrole (V) having a reduced ketone group, a high yield can be obtained. When the Grignard reagent is allowed to act on the above compound (V) again in an inert solvent such as diethyl ether or tetrahydrofuran and ethyl chlorocarbonate (VI) is added and the reaction is carried out at a temperature of 0 ° C to the boiling point of the solvent, 5-alkylpyrrole-2 is obtained. -Carboxylic acid ethyl ester (VII) is obtained. Further, the compound of the present invention represented by the above general formula (VIII) can be obtained by hydrolysis in the usual way.

Method 2: [In the formula, R ⁴ represents an alkyl group having ⁴ to 24 carbon atoms. ] That is, pyrrole-3-carboxylic acid ethyl ester (IX) and a suitable acyl chloride (III) are combined with benzene and carbon disulfide in the presence of a Lewis acid such as aluminum chloride, stannic chloride or boron trifluoride diethyl ether complex. When the reaction is carried out in a solvent usually used for Friedel-Crafts reaction such as -10 ° C to the boiling point of the solvent, 5-acyl-pyrrole-3-carboxylic acid ethyl ester (X) is obtained. Next, the ketone group is converted to a dithioketal (XI) by a commonly used method, and then heated to reflux with excess Raney nickel in a solvent, preferably ethanol, to give 5-alkylpyrrole-3-carboxylic acid ethyl ester ( XII). Further, the compound (XII) is hydrolyzed by a conventional method to obtain the compound of the present invention represented by the above general formula (XIII).

The compound (IX) can be obtained by a known method described in the literature (eg, Canadian Journal of Chemistry Volume 58, page 2527, 1980).
Year) can be manufactured.

Method 3: [In the formula, R ⁴ represents an alkyl group having ⁴ to 24 carbon atoms, and R ⁵ represents an alkyl group having 3 to 23 carbon atoms. That is, 5-acylpyrrole-3-carboxylic acid ethyl ester (X) obtained as described in the above-mentioned Method 2 is treated with a suitable reducing agent, preferably sodium borohydride, in an alcohol solvent such as methanol or ethanol. To reduce the alcoholic compound (XIV). If this alcohol form (XIV) is heated and refluxed with an excess of a base such as caustic soda or caustica and an alcoholic solvent such as ethanol or ethylene glycol containing water for an appropriate time, the carboxylic acid ethyl ester is hydrolyzed at the same time. A dehydration reaction occurs to obtain the compound of the present invention represented by the above general formula (XV).

Method 4: [In the formula, R ⁵ represents an alkyl group having 3 to 23 carbon atoms. That is, the compound (XV) having an alkenyl group having a double bond in conjugation with the pyrrole ring obtained in the above Method 3 is treated with palladium-in a suitable solvent (for example, alcohol system such as ethanol, organic acid such as acetic acid). The compound of the present invention represented by the general formula (XVI) can be easily obtained by catalytic hydrogenation using black, palladium-carbon, platinum or the like as a catalyst.

Method 5: [In the formula, R represents an alkyl group having 5 to 25 carbon atoms. That is, the ketone group of the γ-keto ester (XVII) is protected with an ethylene ketal group according to a conventional method, and the obtained compound (XVIII) is treated with sodium hydride or ethyl formate in an inert solvent such as ether or tetrahydrofuran. The above compound (XIX) is obtained by performing the so-called Claisen condensation in the presence of a base such as sodium ethoxide.
And Next, after deprotecting the ethylene ketal group, the obtained compound (XX) is treated with ammonia or ammonium acetate in an alcohol solvent to form a pyrrole ring, and 5-alkylpyrrole-3-carboxylic acid ethyl ester (XXI ) Get. Further, the compound of the present invention represented by the above general formula (XXII) can be obtained by hydrolysis in the usual way. The starting material γ-ketoester (XVII) was prepared by a known method (for example, Chemical Abs
tract, 81, 63104e; Ion (Madrid), 34, 397, 557, 1
974).

Method 6: [In the formula, R ⁴ represents an alkyl group having ⁴ to 24 carbon atoms. ] That is, pyrrole-2-carboxylic acid methyl ester (XXIII) and an appropriate acyl chloride (III) are treated with benzene and disulfide in the presence of a Lewis acid such as aluminum chloride, stannic chloride, or boron trifluoride diethyl ether complex. 4-Acylpyrrole-2-carboxylic acid methyl ester (XXIV) is obtained by carrying out the Friedel-Crafts reaction in a temperature range of -10 ° C to the boiling point of the solvent in a solvent such as carbon. Then, the keto group is converted to 4-alkylpyrrole-2-carboxylic acid methyl ester (XXV) by an appropriate reduction reaction, for example, diborane reduction, Raney nickel reduction of dithioketal described in Method 2 or catalytic hydrogenation of an acetate synthesized via alcohol. I can guide you.

Further, 4-alkylpyrrole-2 represented by the general formula (XXVI) can be obtained by hydrolyzing the above compound (XXV) by a conventional method.
A carboxylic acid is obtained.

Method 7: [In the formula, R ⁵ represents an alkyl group having 3 to 23 carbon atoms. ] 4-Formylpyrrole-2 represented by the above formula (XXVII)
-Carboxylic acid methyl ester (Bulletin de la Societe
Chemique de France, page 283 (1972)] and dodecyltriphenylphosphonium bromide represented by the above formula (XXVIII) [Chemistry and Industry (London), page 1086 (1958)] subjected to the Wittig reaction A cis- and / or trans-form 4-alkenylpyrrole-2-carboxylic acid methyl ester represented by (XXIX) is obtained.

When this is hydrolyzed in a conventional manner, the cis- and / or trans-form 4-alkenylpyrrole-2-carboxylic acid represented by the above formula (XXX), which is the compound of the present invention, is obtained.

Method 8 (Synthesis of Pyrrolecarboxylic Acid Ester) Pyrrolecarboxylic acid is esterified by any of the following methods.

[Wherein R ¹ and R ² are as defined above (however,
R ² is a phenyl group), and X represents a halogen atom. ] The pyrrole carboxylic acid represented by the above formula (XXXI) with a halide compound represented by the above formula (XXXII) in the presence of a base such as sodium hydride or triethylamine in an inert solvent such as tetrahydrofuran or dimethylformamide; When the reaction is carried out at 10 ° C to the boiling point of the solvent, the above formula (XXXII
An ester form of pyrrolecarboxylic acid represented by I) is obtained.

[R ¹ and R ² in the formula are as defined above. A method which is usually used in a dehydration condensation reaction of pyrrolecarboxylic acid (XXXI), for example, after introducing it into a mixed acid anhydride with an organic base such as ethyl chlorocarbonate and triethylamine or in the presence of a condensing agent such as dicyclohexylcarbodiimide, By reacting with alcohol or phenol, the pyrrolecarboxylic acid ester represented by the above formula (XXXIII) is obtained.

Method 9: [In the formula, R ¹ and R ³ are as defined above, and X represents a halogen atom. ] Pyrrolecarboxylic acid (XXXI) and a suitable halide compound (XXXIV) in the presence of a base such as sodium hydride, potassium metal, sodium ethoxide, etc. in an inert solvent such as ether, tetrahydrofuran, dimethylformamide, etc. The compound (XXXV) obtained by reacting in the temperature range of the boiling point of the solvent is heated to reflux and hydrolyzed in an alkaline aqueous solution containing an alcohol solvent such as ethanol to be represented by the above formula (XXXVI). Pyrrolecarboxylic acid is obtained. Incidentally, as the starting material, an ester of pyrrolecarboxylic acid can be used instead of the compound (XXXI).

The compound of the present invention is administered to humans as a therapeutic drug for hyperlipidemia, preferably by oral administration. As the dosage form for oral administration, tablets, granules, powders, capsules, and other forms are used, and these are the usual additives for the compound of the present invention, such as buttohose, lactose, corn starch, and mannitol. Agent, hydroxypropyl cellulose (HP
C), a binder such as carboxymethyl cellulose (CMC),
It can be produced by adding disintegrating agents such as starch and gelatin powder, lubricants such as talc and magnesium stearate, and the like.

In the case of oral administration, 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, which may be administered once or in 2 to 3 divided doses. it can.

〔Example〕

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Incidentally, Synthesis Examples 1 to 11 show the synthesis of raw materials and intermediates in the process of synthesizing the compound of the present invention, and Examples 1 to 86 show the synthesis of the compound of the present invention.

Synthesis Example 1 Synthesis of 2-tetradecanoylpyrrole 30 ml of 3M methylmagnesium bromide in ether (90
6.04 g (90 mmol) of pyrrole was added to (mmol) under stirring at room temperature, and the mixture was heated under reflux for 30 minutes. The reaction mixture was ice-cooled, and myristoyl chloride obtained from 9.14 g (40 mmol) of myristic acid by a conventional method was gradually added. After completion of the dropwise addition, the mixture was heated under reflux for 1 hour, then returned to room temperature, poured into an ice water solution containing ammonium chloride and extracted with ethyl acetate,
After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is purified by column chromatography (developed with ethyl acetate: hexane = 1: 5) to be 2-
7.31 g of tetradecanoylpyrrole (yield 66%) was obtained.

IR (KBr) cm ^-1 : 3310,2940,1645 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (20H, m), 1.71 (2H,
m), 2.75 (2H, t), 6.28 (1H, m), 6.90 (1H, m), 7.01 (1
H, m) Synthesis Example 2 Synthesis of 2-tetradecylpyrrole 7.31 g (2 of 2-tetradecanoylpyrrole obtained in Synthesis Example 1
(6 mmol), 30% (610 mmol) of 100% hydrazine hydrate and 20 g (350 mmol) of caustic potash were heated in 200 ml of diethylene glycol at 200 ° C. for 3 hours, then returned to room temperature and water was added for ether extraction. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a residue, which was purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 10) to give 2-tetradecylpyrrole 6.14. g (yield 88%) was obtained.

IR (KBr) cm ^-1 : 3380,2940 NMR (CDCl ₃ ) δ: 0.89 (3H, t), 1.27 (22H, m), 1.63 (2H,
m), 2.61 (2H, t), 5.92 (1H, m), 6.14 (1H, m), 6.68 (1
H, m), 7.90 (1H, broad S) Example 1 Synthesis of 5-tetradecylpyrrole-2-carboxylic acid ethyl ester (Compound No. 41 in Table 1) 2-Tetradecylpyrrole obtained in Synthesis Example 2 4.00 g (15 mmol) was dissolved in 20 ml of anhydrous ether, 7 ml (21 mmol) of an ether solution of methylmagnesium bromide (about 3M) was added at room temperature, and the mixture was heated under reflux for 30 minutes. While cooling the reaction solution with ice water, 2 ml (21 mmol) of ethyl chlorocarbonate was added and heated under reflux for 10 hours, then returned to room temperature, poured into ice water containing ammonium chloride, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:
Purification with hexane = 1: 10) gave 1.89 g (yield 37%) of 5-tetradecylpyrrole-2-carboxylic acid ethyl ester.

Melting point (mp): 60-63 ° C IR (KBr) cm ^-1 : 3310,2930,1675 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (22H, m), 1.34 (3H,
t), 1.59 (2H, m), 2.60 (2H, t), 4.28 (2H, q), 5.97 (1
H, m), 6.83 (1H, m), 8.75 (1H, broad S) Example 2 Synthesis of 5-tetradecylpyrrole-2-carboxylic acid (Compound No. 40 in Table 1) Obtained in Example 1 Ethyl 5-tetradecylpyrrole-2-carboxylic acid ethyl ester 0.50 g (1.5 mmol)
Dissolve in 20 ml, and add 3 ml of N-caustic soda aqueous solution (3
(Mmol) and heated to reflux for 6 hours. After cooling, the precipitate is filtered, washed well with ether, suspended in aqueous hydrochloric acid and extracted with ether. Further, after washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
0.34 g of tetradecylpyrrole-2-carboxylic acid (yield 74
%) Was obtained.

mp: 68-69 ° C IR (KBr) cm ^-1 : 3340,3255,2930,1660,1500 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (22H, m), 1.64 (2H,
m), 2.62 (2H, t), 6.02 (1H, m), 6.97 (1H, m), 8.90 (1
H, broad S) Synthetic Example 3 Synthesis of γ-keto octadecanoic acid ethyl ester ethylene ketal 9.25 g (28 mmol) of γ-keto octadecanoic acid ethyl ester and 9.00 g (145 mmol) of ethylene glycol were added as a small amount of a p-toluenesulfonic acid catalyst. In the presence, toluene 300m
The mixture was refluxed for 5 hours while being dehydrated in a Dean-Stark apparatus. After washing successively with saturated aqueous sodium hydrogen carbonate and saturated brine, the solvent was evaporated under reduced pressure and the resulting oil was purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 10) to give ethyl γ-ketooctadecanoate. 7.42 g (yield 71%) of ester ethylene ketal was obtained.

IR (Neat) cm ^-1 : 2920,1740 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (24H, m), 1.25 (3H,
t) 1.60 (2H, m), 1.98 (2H, t), 2.36 (2H, t), 3.93 (4
H, S), 4.10 (2H, q) Example 3 Synthesis of 5-tetradecylpyrrole-3-carboxylic acid ethyl ester (Compound No. 42 in Table 1) Ethyl γ-ketooctadecanoate obtained in Synthesis Example 3 A solution of 7.42 g (20 mmol) of ester ethylene ketal and 1.93 g (26 mmol) of ethyl formate in 20 ml of ether was added to 60%.
20 ml of sodium hydride 1.20 g (30 mmol) ether
The suspension was added dropwise to the suspension under stirring at room temperature, and then reacted at room temperature for 18 hours. Further, 0.70 g (17 mmol) of 60% sodium hydride and 1.00 g (13 mmol) of formic acid ethyl ester were added to the reaction solution, and the mixture was stirred at room temperature for 50 hours. The reaction was terminated by adding dilute hydrochloric acid, the ether extract was distilled off under reduced pressure, 30 ml of concentrated hydrochloric acid was added to the obtained residue, and the mixture was vigorously stirred for 1.5 hours. After extraction with ether, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (developing with ethyl acetate: hexane = 1: 10), γ-keto-α- Formyl octadecanoic acid ethyl ester (3.63 g, yield 51%) was obtained.

To 4.13 g (12 mmol) of oil (γ-keto-α-formyl octadecanoic acid ethyl ester) obtained here, 150 ml of ammonia saturated ethanol solution was added and heated under reflux for 14 hours, then the solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column. Purification by chromatography (developed with ethyl acetate: hexane = 1: 10) gave 3.53 g (yield 90%) of 5-tetradecylpyrrole-3-carboxylic acid ethyl ester.

mp: 59-62 ℃ IR (KBr) cm ^-1 : 3320,2940,1680 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.23 (22H, m), 1.33 (3H,
t), 1.60 (2H, m), 2.56 (2H, t), 4.26 (2H, q), 6.30 (1
H, m), 7.29 (1H, m), 8.20 (1H, broad s) Example 4 Synthesis of 5-tetradecylpyrrole-3-carboxylic acid (Compound No. 38 in Table 1) Obtained in Example 3. 5-Tetradecylpyrrole-3-carboxylic acid ethyl ester 3.53 g (11 mmol) ethanol 1
To 20 ml solution, 25 ml of N-caustic soda aqueous solution was added, and the mixture was heated under reflux for 16 hours, ethanol was distilled off, acidified with aqueous hydrochloric acid solution and extracted with ethyl acetate. After washing with water, drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 4) to give 5-tetradecylpyrrole-3-carboxylic acid. 2.19 g (68% yield) was obtained.

mp: 83-85 ° C IR (KBr) cm ^-1 : 3470,2950,1670 NMR (CDCl ₃ ) δ: 0.88 (3H, m), 1.25 (22H, m), 1.61 (2H,
m), 2.57 (2H, t), 6.36 (1H, m), 7.38 (1H, m), 8.20 (1
H, broad s) Synthesis Example 4 Synthesis of 5-tridecanoylpyrrole-3-carboxylic acid ethyl ester Pyrrole-3-carboxylic acid ethyl ester 2.78 g (20 mmol) in 20 ml of benzene under ice-cooling tridecanoic acid 4.
Tridecanoyl chloride synthesized by a conventional method from 28 g (20 mmol) was added, and then 3.5 ml of stannic chloride (3
0 mmol) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 15 hours, diluted hydrochloric acid was added, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 5-Tridecanoyl-purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 7)
Obtained 4.85 g (yield 72%) of 3-carboxylic acid ethyl ester.

IR (KBr) cm ^-1 : 3290,2920,1700,1660 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (18H, m), 1.25 (3H,
t), 1.71 (2H, m), 2.78 (2H, t), 4.25 (2H, q), 7.31 (1
H, m), 7.59 (1H, m), 9.60 (1H, broad s) Synthesis Example 5 Synthesis of 5-tridecanoylpyrrole-3-carboxylic acid ethyl ester dithioethylene ketal 5-Trideca obtained in Synthesis Example 4 Noylpyrrole-3-carboxylic acid ethyl ester 4.85 g (1.45 mmol) and ethanedithiol 5 ml acetic acid 40 ml were added to a solution of boron trifluoride / diethyl ether complex 5 ml and reacted at room temperature for 2.5 hours. The mixture was extracted with ethyl, washed with an aqueous solution of sodium carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 7) to give 5-tridecanoylpyrrole-3-carboxylic acid ethyl ester dithioethylene ketal 3.74 g
(Yield 63%) was obtained.

IR (KBr) cm ^-1 : 3350,2910,1680 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (18H, m), 1.61 (2H,
m), 2.56 (2H, t), 3.40 (4H, m), 4.23 (2H, q), 6.36 (1
H, m), 7.39 (1H, m), 8.28 (1H, broad s) Example 5 Synthesis of 5-tridecylpyrrole-3-carboxylic acid ethyl ester (Compound No. 32 in Table 1) Synthesis Example 5 Obtained 5-tridecanoylpyrrole-3-carboxylic acid ethyl ester dithioethylene ketal 3.74 g
(9.1 mmol) and Raney nickel 30 ml ethanol 200
Heated to reflux in ml for 2 hours. Raney nickel was filtered using Celite, washed well with ethanol, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 7) to give ethyl 5-tridecylpyrrole-3-carboxylate. 2.60 g of ester (89% yield)
Got

mp: 59.5-60.5 ° C IR (KBr) cm ^-1 : 3320,2930,1680 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (20H, m), 1.60 (2H,
m), 2.56 (2H, t), 4.28 (2H, q), 6.31 (1H, m), 7.30 (1
H, m), 8.30 (1H, broad m) Example 6 Synthesis of 5-tridecylpyrrole-3-carboxylic acid (Table 1
Compound No. 30 in) 5-tridecylpyrrole-3-carboxylic acid ethyl ester obtained in Example 5 2.60 g (8.1 mmol) of ethanol 40
10 ml of an aqueous solution containing 1.40 g (33 mmol) of caustic soda was added to the ml solution, and the mixture was heated under reflux for 36 hours. Ethanol was distilled off, acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crystals. Purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 2), pure 5-tridecylpyrrole-3-carboxylic acid 2.04 g (yield 8
6%). mp: 82-84 ° C IR (KBr) cm ^-1 : 3450,2920,1665 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (20H, m), 1.61 (2H,
m), 2.57 (2H, t), 6.36 (1H, m), 7.39 (1H, m), 8.24 (1
H, broad m) Example 7 Synthesis of 5- (1-pentadecenyl) pyrrole-3-carboxylic acid (Compound No. 76 in Table 1) 5-pentadecanoylpyrrole-obtained by the same method as in Synthesis Example 4 To a solution of 4.59 g (13 mmol) of ethyl 3-carboxylic acid in 100 ml of ethanol was added sodium borohydride 5
After adding 00 mg (13 mmol) and reacting at room temperature for 16 hours,
Ethanol was distilled off under reduced pressure, water was added, the mixture was extracted with ether, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the product obtained was mixed with 35 ml of ethanol, 12 ml of water and potassium hydroxide.
3.53 g (63 mmol) was added, and the mixture was heated under reflux for 5 days. Acidify with hydrochloric acid, extract with ethyl acetate, wash with water, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and purify the product by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 2) to give 5- ( 2.33 g of 1-pentadecenyl) pyrrole-3-carboxylic acid (60% yield)
Got mp: 90-96 ℃ IR (KBr) cm ^-1 : 3450,2940,1670 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.28 (22H, m), 2.17 (2H,
m), 5.88 (1H, m), 6.20 (1H, m), 6.53 (1H, m), 7.42 (1
H, m), 8.49 (1H, broad s) Example 8 Synthesis of 5-tetradecylpyrrole-3-carboxylic acid (Compound No. 38 in Table 1) 5- () obtained in the same manner as in Example 7 To a solution of 3.05 g (10 mmol) of 1-tetradecenyl) pyrrole-3-carboxylic acid in 20 ml of ethanol, 300 mg of 10% palladium-black was added, and catalytic reduction was carried out for 2 hours. After removing the catalyst, the product was crystallized from heptane to obtain the same product as in Example 4. 2.50 g (yield 82%) The melting point, IR and NMR are almost the same as those of the compound of Example 4.

Synthesis Example 6 Synthesis of 4-tetradecanoylpyrrole-2-carboxylic acid methyl ester Tetradecanoyl chloride 2.71 g (11 mmol) in a solution of 1.25 g (10 mmol) of pyrrole-2-carboxylic acid methyl ester in 5 ml of benzene under ice cooling. Was added, and then 1.73 ml (15 mmol) of stannic chloride was added dropwise. After reacting at room temperature for 2 hours, diluted hydrochloric acid was added, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The product was subjected to silica gel column chromatography (ethyl acetate:
(Development with hexane = 1: 7) to give 4-tetradecanoylpyrrole-2-carboxylic acid methyl ester 1.80 g
(Yield 54%) was obtained.

IR (KBr) cm ^-1 : 3290,2920,1705,1665 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.30 (20H, m), 1.70 (2H,
m), 2.75 (2H, t), 3.88 (3H, s), 7.29 (1H, m), 7.53 (1
H, m), 9.30 (1H, broad s) Example 9 Synthesis of 4-tetradecylpyrrole-2-carboxylic acid methyl ester (Compound No. 39 in Table 1) 4-Tetradecanoyl obtained in Synthesis Example 6 To 1.80 g (5.4 mmol) of pyrrole-2-carboxylic acid methyl ester was added 30 ml (90 mmol) of a tetrahydrofuran solution of diborane (about 3 M), 1 ml of boron trifluoride / diethyl ether complex was further added, and the mixture was left at room temperature overnight. . Methanol was added, water was added, and the mixture was extracted with ethyl acetate, washed with water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 3) to give 4-tetradecylpyrrole-2-carboxylic acid methyl ester 0.22 g.
(Yield 13%) was obtained. mp: 80-82 ℃ IR (KBr) cm ^-1 : 3360,2950,1695 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (22H, m), 1.56 (2H,
m), 2.45 (2H, t), 3.83 (3H, s), 6.74 (2H, m), 8.85 (1
H, broad s) Example 10 Synthesis of 4-tetradecylpyrrole-2-carboxylic acid (Compound No. 37 in Table 1) 0.22 g of 4-tetradecylpyrrole-2-carboxylic acid methyl ester obtained in Example 9 To 0.6 ml of ethanol (0.69 mmol), add 1 ml of 2N caustic soda solution and heat to reflux.
I went there for 13 hours. After adding water and washing with ether, the aqueous layer was acidified with hydrochloric acid and extracted with ether, washed with water and dried over anhydrous magnesium sulfate, and 0.19 g of 4-tetradecylpyrrole-2-carboxylic acid (yield 95%) was obtained by distilling off the solvent. Obtained. mp: 148-
150 ℃ IR (KBr) cm ^-1 : 3400,2930,1690 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (22H, m), 1.53 (2H,
t), 6.94 (1H, m), 6.97 (1H, m), 9.10 (1H, broad s) Example 11 Synthesis of 5-tridecylpyrrole-3-carboxylic acid propyl ester 5-tridecylpyrrole-3-carboxylic acid Acid 1.50g (5.11
Mmol) and dicyclohexylcarbodiimide 1.27 g
(6.15 mmol) is added to 25 ml of tetrahydrofuran, 3.8 ml of n-propyl alcohol and 62 mg of dimethylaminopyridine are added, and the mixture is heated at 60 ° C. for 10 hours with stirring. After cooling, the precipitate is removed, and the mixture is thoroughly washed with ether, and the washing solution and the washing solution are combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developed with ethyl acetate: hexane = 1: 20) to obtain 1.26 g (yield 73%) of 5-tridecylpyrrole-3-carboxylic acid propyl ester.

mp 51-52 ° C IR (KBr) cm ^-1 : 3280, 2930, 1675 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 0.97 (3H, t), 1.25 (20
H, m), 1.65 (4H, m), 2.54 (2H, t), 4.17 (2H, t),
6.31 (1H, m), 7.28 (1H, m), 9.04 (1H, broad s) Example 12 Synthesis of 5-tridecylpyrrole-3-carboxylic acid 2-bromoethyl ester 5-tridecylpyrrole-3-carboxylic To 20 ml of tetrahydrofuran solution containing 1.47 g (5.0 mmol) of acid, 0.60 g (5.53 mmol) of ethyl chlorocarbonate and 0.60 g of triethylamine
(5.94 mmol) was added and the mixture was stirred at room temperature for 10 minutes, and then 2-
Add 1.88 g (15 mmol) of bromoethanol and heat to reflux for 1.5 hours. Further, 0.94 g (7.5 mmol) of 2-bromoethanol was added, and the mixture was heated under reflux for 9 hours, cooled, acidified with aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oily substance was purified by silica gel column chromatography (developed with ethyl acetate: exane = 1: 10) to give 5-tridecylpyrrole-3-carboxylic acid 2-bromoethyl ester 1.05. g (yield 53%) was obtained. mp67-69.5 ° C IR (KBr) cm ^-1 : 3340, 2930, 1690 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.33 (20H, m), 1.60 (2
H, m), 2.56 (2H, t), 3.59 (1H, t), 3.76 (1H, t),
4.49 (2H, m), 6.34 (1H, m), 7.34 (1H, m), 8.20 (1
H, broad s) Examples 13 to 32 The compounds shown in Table 2 below were synthesized according to the methods described in the above Examples.

Synthesis Example 7 Synthesis of 4-tridecanoylpyrrole-2-carboxylic acid methyl ester Tridecanoic acid 102.9 g (0.48 mol) was added to methylene chloride 480 ml.
Dissolved in 52.6 ml (0.72 mol) of thionyl chloride and N,
0.2 ml of N-dimethylformamide was 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. Pyrrole-2-carboxylic acid methyl ester,
A solution of 50.05 g (0.4 mol) of methylene chloride in 200 ml of 3-9
The solution was added dropwise at 40 ° C. for about 40 minutes. After the dropping was completed, the temperature was gradually raised to room temperature and stirred for 2 hours, and this was added to 800 ml of ice-water. To this, 1000 ml of methylene chloride was added to dissolve all the crystals, the layers were separated, the organic layer was washed 3 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 to obtain 107.2 g of 4-tridecanoylpyrrole-2-carboxylic acid methyl ester as almost white crystals.

Yield 83% mp: 92-93 ℃ IR (KBr) cm ^-1 : 3270,2920,2855,1690,1660,1565,1455,1
385,1290,1215 ¹ HNMR (CDCl ₃ , 250MHz) δ: 0.88 (3H, t, J = 6.6Hz) 1.15-1.38 (18H, m) 1.65-1.75 (2H, m) 2.75 (2H, t, J = 7.5Hz) 3.89 (3H, s) 7.28-7.30 (1H, m) 7.53-7.55 (1H, m) 9.52 (1H, broad s) Synthesis Example 8 4-Tridecanoylpyrrole-2-carboxylic acid methyl ester dithioethylene Synthesis of ketal 4-tridecanoylpyrrole-2-obtained in Synthesis Example 7
18.29 g (56.9 mmol) of carboxylic acid methyl ester was dissolved in 140 ml of acetic acid, and 14.0 ml of 1,2-ethanedithiol was added thereto.
(167 mmol) and 14 ml of boron trifluoride / diethyl ether complex were added, and the mixture was stirred overnight under water cooling. This was concentrated under reduced pressure, 100 ml of water was added to the residue, and 200 ml of ethyl acetate (100 ml x
Extracted in 2). The extracts were combined, washed with a 5% aqueous sodium hydroxide solution and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of acetic acid and hexane to give 4-tridecanoylpyrrole-
2-Carboxylic acid methyl ester dithioethylene ketal was obtained. The mother liquor was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 1/6) to obtain the desired product remaining in the recrystallization solvent. Total yield 15.44g, yield 68% mp: 77-78 ℃ IR (KBr) cm ^-1 : 3360,2940,2860,1705,1440,1385,1265,1
210,1120 ¹ HNMR (CDCl ₃ , 250MHz) δ: 0.88 (3H, t, J = 6.6Hz) 1.20-1.40 (20H, m) 2.22-2.28 (2H, m) 3.25-3.41 (4H, m) 3.84 ( 3H, s), 6.92 (1H, s) 7.05-7.07 (1H, m) 9.08 (1H, broad s) Example 33 Synthesis of 4-tridecylpyrrole-2-carboxylic acid methyl ester (Compound No. in Table 1) .15) 4-Tridecanoylpyrrole-2-obtained in Synthesis Example 8
Carboxylic acid methyl ester dithioethylene ketal 15.0
Raney nickel (activated type, manufactured by Aldrich), 6 g (37.9 mmol) of which was washed with water and then with ethanol 15
The mixture was added to a mixed solution of 0 ml 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 and the liquid was concentrated under reduced pressure. Recrystallization of the residue from ethanol gave 10.70 g of 4-tridecylpyrrole-2-carboxylic acid methyl ester as white crystals. Yield 91.8
% Mp: 80-82 ℃ IR (KBr) cm ^-1 : 3340,2920,2850,1690,1445,1390,1265,1
205,1130 ¹ HNMR (CDCl ₃ , 250MHz) δ: 0.88 (3H, t, J = 6.6Hz) 1.2-1.4 (20H, m) 1.49-1.62 (2H, m) 2.45 (2H, t, J = 7.6Hz) ) 3.83 (3H, s) 6.72-6.75 (2H, m) 8.88 (1H, broad s) Example 34 Synthesis of 4-tridecylpyrrole-2-carboxylic acid (Table 1
Compound No. 14 in) To 4-tridecylpyrrole-2-carboxylic acid methyl ester 10.01 g (32.6 mmol) obtained in Example 33, ethanol 200 ml, water 80 ml and 95% sodium hydroxide 5.5 g (1
(31 mmol) was added and the mixture was heated under reflux for 1 hr. After cooling water 10
0 ml was added, acidified with hydrochloric acid and extracted with a mixed solvent of 400 ml of ethyl ether, 100 ml of ethyl acetate and 300 ml of tetrahydrofuran. Extract the water bath again with 100 ml of ethyl acetate,
The extracts were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. This was concentrated under reduced pressure and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain 7.55 g of 4-tridecylpyrrole-2-carboxylic acid as white crystals.

mp: 150-151 ℃ IR (KBr) cm ^-1 : 3390,2960,2925,2860,1685,1495,1440,1
280,1130,1120 ¹ HNMR (DMSO-d ₆ , 250MHz) δ: 0.84 (3H, t, J = 6.5Hz) 1.22 (20H, broad s) 1.40-1.52 (2H, m) 2.35 (2H, t, J = 7.4 Hz) 6.53 (1H, s), 6.71 (1H, s) Synthesis Example 9 Synthesis of 4-dodecanoylpyrrole-2-carboxylic acid methyl ester Lauric acid 213 g (1.06 mol) in exactly the same manner as in Synthesis Example 7.
As a raw material, 245.5 g of 4-dodecanoylpyrrole-2-carboxylic acid methyl ester was obtained. Yield 90% mp: 102-103
℃ 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 (1
H, m), 9.50 (1H, broad s) Synthesis Example 10 Synthesis of 4- (1-hydroxydodecyl) pyrrole-2-carboxylic acid methyl ester Methyl 4-dodecanoylpyrrole-2-carboxylate obtained in Synthesis Example 9 To 245.5 g (0.80 mol) of ester, 1.5 l of tetrahydrofuran and 0.15 l of methanol were added, and under stirring at a temperature of 10 to 21 ° C, 15.1 g (0.40 mol) of sodium borohydride
Add little by little. After stirring at 20 ° C for 1 hour, 7.5 g (0.20 mol) of sodium borohydride was further added, and after stirring at 20 ° C for 1 hour, the solvent was distilled off under reduced pressure and 700 ml of water and 2.4 l of ethyl acetate were added to the residue. . The organic layer was separated, washed successively with 700 ml of water and then 700 ml of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 247.0 g of pale brown crystals. Yield 99% 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 (1
H, m), 9.05 (1H, broad s) Synthesis Example 11 Synthesis of 4- (1-acetoxydodecyl) pyrrole-2-carboxylic acid methyl ester 4- (1-hydroxydodecyl) pyrrole-2 obtained in Synthesis Example 10 -Carboxylic acid methyl ester 247.0 g (0.80 mol)
180 ml (1.91 mol) of acetic anhydride and 180 ml (2.23 mol) of pyridine were added to a solution of 1.6 l of toluene in (1) and heated at 105 ° C. for 2.5 hours. After cooling to room temperature, wash twice with 700 ml of 2N hydrochloric acid solution, add 1.2 l of saturated aqueous sodium hydrogen carbonate solution, and add at room temperature.
After stirring for 30 minutes, the organic layer is extracted. The extracted organic layer is washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated saline (700 ml) and dried over anhydrous magnesium sulfate. The crystal obtained by distilling off the solvent was recrystallized from 700 ml of hexane to obtain 258.0 g of an extremely light brown crystal. Yield 92% mp: 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 (1
H, m), 6.95 (1H, m), 9.08 (1H, broad s) Example 35 Synthesis of 4-dodecylpyrrole-2-carboxylic acid methyl ester (Compound No. 11 in Table 1) Obtained in Synthesis Example 11 4- (1-hydroxydodecyl) pyrrole-2-carboxylic acid methyl ester 258.0 g (0.73 mol) in ethanol 2.0 l solution was added 10% palladium-carbon 16 g, and catalytic hydrogen reduction was performed at 50 ° C. under hydrogen atmosphere. It was 5.5
The reaction was completed over a period of time, 1.5 l of chloroform was added to remove the catalyst, and the solvent was evaporated under reduced pressure to give crystals. Recrystallized from 950 ml of ethanol to give 4-dodecylpyrrole.
179.6 g of 2-carboxylic acid methyl ester was obtained as white crystals.

Yield 83% mp: 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 (1
H, broad s) Example 36 Synthesis of 4-dodecylpyrrole-2-carboxylic acid (Compound No. 10 in Table 1) 112.0 g (0.38 of 4-dodecylpyrrole-2-carboxylic acid methyl ester obtained in Example 35) Ethanol 1.45 to mol)
1, water 1.45 l and 95% sodium hydroxide 31.0 g (0.74 mol) were added, and the mixture was heated under reflux for 2 hours. Hot water (1.45 L) was added at 80 ° C, and 6N sulfuric acid was added little by little at the same temperature to adjust the reaction solution to pH2. Cool to 45 ° C and filter the precipitated crystals with water. The crystals are dissolved in 4 liters of tetrahydrofuran, washed twice with 1 liter of saturated saline and dried over anhydrous magnesium sulfate. The crystals obtained by concentrating the solvent under reduced pressure were recrystallized from a mixed solvent of 600 ml of tetrahydrofuran and 600 ml of hexane to obtain 4 crystals.
92.6 g of dodecylpyrrole-2-carboxylic acid were obtained as white crystals. Yield 87% mp: 152-153 ° C IR (KBr) cm ^-1 : 3380,2920,1685 NMR (DMSO-d ₆ ) δ: 0.88 (3H, t) 1.22 (18H, m), 1.44 (2H, m ), 2,34 (2H, t), 6.52 (1H,
m), 6.71 (1H, m), Examples 37 to 46 The compounds shown in Table 3 below were synthesized according to the methods described in Examples 35 and 36 above.

Example 47 Synthesis of 4- (1-cis-tridecenyl) pyrrole-2-carboxylic acid methyl ester (Compound No. 73 in Table 1) Document (Chemistry and Industry (London), page 1086 (1958)) Dodecyltriphenylphosphonium bromide 16.0 g (31.4 mmol) of tetrahydrofuran 95 m
18.5 ml of a hexane solution of n-butyllithium (about 15% concentration) was added dropwise to the suspension at −50 ° C., the temperature was raised to room temperature, the mixture was stirred for 30 minutes, and then the temperature was returned to −50 ° C. to the literature (Bulletin de la Societ
e Chimique de France, page 283 (1972) 4
-Formylpyrrole-2-carboxylic acid methyl ester 2.
A solution of 4 g (15.7 mmol) in 50 ml of tetrahydrofuran was added dropwise. After stirring for 1 hour, water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 7) to give 4- (1-cis-tridecenyl) pyrrole-2-carboxylic acid methyl ester. 3.11g (yield 65
%) Was obtained. mp: 51-52 ° C IR (KBr) cm ^-1 : 3300,2930,1685 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.29 (18H, m), 2.29 (2H,
m), 3.86 (3H, s), 5.50 (1H, m), 6.17 (1H, m), 6.93 (2
H, m) Example 48 Synthesis of 4- (1-cis-tridecenyl) pyrrole-2-carboxylic acid (Compound No. 72 in Table 1) 4- (1-cis-Tridecenyl) obtained in Example 47 A solution of 3.10 g (10.2 mmol) of pyrrole-2-carboxylic acid methyl ester in 50 ml of ethanol was mixed with 86% of 95% sodium hydroxide.
25 ml of an aqueous solution containing 0 mg (20.4 mmol) was added, and the mixture was heated under reflux for 1 hour. The reaction mixture was acidified by adding 6N sulfuric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, treated with activated carbon, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized with a mixed solvent of hexane and tetrahydrofuran to give 1.33 g of 4- (1-cis-tridecenyl) pyrrole-2-carboxylic acid (yield 45%).
Got

mp: 157-158 ℃ IR (KBr) cm ^-1 : 3390,2940,1680 NMR (DMSO-d ₆ ) δ: 0.86 (3H, t) 1.22 (18H, m), 2.21 (2H, m), 5.33 ( 1H, m), 6.18 (1H,
d), 6.72 (1H, m), 6.94 (1H, m) Example 49 Synthesis of 4- (1-trans-tridecenyl) pyrrole-2-carboxylic acid methyl ester (Compound No. 73 in Table 1) Bromide To a suspension of 32 g (62.7 mmol) of dodecyltriphenylphosphonium in 200 ml of tetrahydrofuran, 40 ml of a hexane solution of n-butyllithium (about 15% concentration) was added dropwise under ice cooling. After stirring the reaction mixture for 30 minutes, lower it to -78 ° C and
-Formylpyrrole-2-carboxylic acid methyl ester 4.
A solution of 8 g (31.4 mmol) of tetrahydrofuran in 100 ml was dropped, and after stirring for 1 hour, 190 ml of ethanol was further dropped. The reaction solution was stirred at −78 ° C. for 1.5 hours, and then stirred further for 12 hours while gradually raising the temperature to room temperature. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline,
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by column chromatography (developing solvent; ethyl acetate: hexane = 1: 10), and the residue was washed with hexane.
By recrystallizing once, 4- (1-trans-tridecenyl) pyrrole-2-carboxylic acid methyl ester 1.30 g
(14% yield) was obtained. mp: 65-67 ° C IR (KBr) cm ^-1 : 3350,2940,1690 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.32 (18H, m), 2.12 (2H,
m), 3.85 (3H, t), 5.95 (1H, s), 6.18 (1H, d), 6.83 (1
H, m), 6.95 (1H, m) Example 50 Synthesis of 4- (1-trans-tridecenyl) pyrrole-2-carboxylic acid (Compound No. 72 in Table 1) 4-obtained in Example 49 A solution of 1.30 g (4.3 mmol) of (1-trans-tredecenyl) pyrrole-2-carboxylic acid methyl ester in 20 ml of ethanol contained 95% sodium hydroxide (340 m).
8 ml of an aqueous solution containing g (8.0 mmol) was added, and the mixture was heated under reflux for 1 hour. After adding 6N sulfuric acid to the reaction solution to make it acidic,
The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, treated with activated carbon, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized with a mixed solvent of hexane and tetrahydrofuran to obtain 940 mg of 4- (1-trans-tridecenyl) pyrrole-2-carboxylic acid (yield 72%).

mp: 161-163 ° C IR (KBr) cm ^-1 : 3400,2920,1690 NMR (DMSO-d ₆ ) δ: 0.84 (3H, t) 1.22 (18H, m), 2.07 (2H, m) 5.89 (1H , m), 6.13 (1H, d), 6.81 (1H, m), 6.84 (1H,
m) Example 51 Synthesis of 4-tridecylpyrrole-2-carboxylic acid ethyl ester (Compound No. 16 in Table 1) 140 mg (3.50 mmol) of 60% sodium hydride was washed with hexane and added to 20 ml of dimethylformamide. While stirring at room temperature, 990 mg (3.38 mmol) of 4-tridecylpyrrole-2-carboxylic acid obtained in Example 2 was added little by little.
After stirring for 10 minutes in the reaction solution, 5.0 g (31.8 mmol) of ethyl iodide
Is added and heated at 55 ° C for 22 hours. After cooling, an aqueous hydrochloric acid solution was added to acidify the mixture, the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 10) to give 4-tridecylpyrrole-2-carboxylic acid ethyl ester 600 m.
g was obtained as white crystals. Yield 55% mp: 59-60 ° C IR (KBr) cm ^-1 : 3340,2920,1690 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.26 (20H, m), 1.34 (3H,
t), 1.55 (2H, m), 2.45 (2H, m), 4.29 (2H, q), 6.72 (1
H, m), 6.75 (1H, m) 8.85 (1H, broad s) Example 52 Synthesis of 4-tridecylpyrrole-2-carboxylic acid dimethylaminoethyl ester hydrochloride (Compound No. 3 in Table 1)
3) 4-Tridecyl-pyrrole-2-carboxylic acid dimethylaminoethyl ester synthesized by the same method as in Example 51 was dissolved in a mixed solution of ethanol and ether, and hydrogen oxide-containing ethanol was added to precipitate crystals. To take. The obtained crystals are recrystallized with a mixed solution of ethanol and ether to obtain the above-mentioned desired product. Yield 41% mp: 109-111 ° C IR (KBr) cm ^-1 : 3200,2930,2600,1710 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (20H, m), 1.53 (2H,
m), 2.44 (2H, t), 2.92 (6H, s), 3.38 (2H, t), 4.49 (2
H, m), 6.85 (2H, m) Example 53 Synthesis of 4-tridecylpyrrole-2-carboxylic acid N-butylcarbamoylmethyl ester (Compound No. 3 in Table 1)
4) The desired product was synthesized in the same manner as in Example 51. Yield 36% mp: 101-102 ° C IR (KBr) cm ^-1 : 3350,2920,1670,1650 NMR (CDCl ₃ ) δ: 0.90 (6H, m), 1.26 (22H, m), 1.55 (4H,
m), 2.45 (2H, t), 3.33 (2H, t), 4.73 (2H, s), 6.82 (2
H, m) Example 54 Synthesis of 4-tridecylpyrrole-2-carboxylic acid N, N-diethylcarbamoylmethyl ester (Compounds in Table 1
No. 35) The target product was synthesized in the same manner as in Example 51. Yield 46% mp: 107-108 ° C IR (KBr) cm ^-1 : 3310,2950,1710,1640 NMR (CDCl ₃ ) δ: 0.85 (3H, t), 1.12 (3H, t), 1.18 (23H,
m), 1.69 (2H, m), 2.42 (2H, t), 3.26 (2H, q), 3.40 (2
H, q) 4.84 (2H, s), 6.84 (1H, m), 7.24 (1H, m) Example 55 4-tridecylpyrrole-2-carboxylic acid N, N-bis (2-hydroxyethyl) carbamoylmethyl Synthesis of ester (Compound No. 36 in Table 1) In the same manner as in Example 51, the desired product was synthesized. Yield 14% mp: 99.5-101 ° C IR (KBr) cm ^-1 : 3330,2940,1710,1640 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (20H, m), 1.69 (2H,
m), 2.43 (2H, t), 3.47 (2H, t), 3.56 (2H, t), 3.84 (4
H, m), 6.71 (1H, m), 6.85 (1H, m) Example 56 Synthesis of 1-tetradecylpyrrole-3-carboxylic acid ethyl ester (Compound No. 89 in Table 1) Sodium hydride (60 % Oil dispersion) 0.84
g (21 mmol) of dry dimethylformamide (DMF) 15
To this, 2.78 g (20 mmol) of pyrrole-3-carboxylic acid ethyl ester was added little by little under ice cooling.
After stirring at room temperature for 10 minutes, 6.65 g of bromotetradecane (24
(Mmol) under ice cooling. After stirring for 3.5 hours at room temperature,
30 ml of water is added and the mixture is extracted with 70 ml of ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the remaining oil was purified by silica gel column chromatography (eluent, ethyl acetate /
Hexane = 1/20 to 1/10), 1-tetradecylpyrrole-
6.33 g of 3-carboxylic acid ethyl ester was obtained as white crystals. Yield 89.0% mp: 32-33 ° C IR (KBr) cm ^-1 : 2940,2860,1700,1540 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (22H, m), 1.35 (3H,
t), 1.77 (2H, m), 3.85 (2H, t), 4.26 (2H, q), 6.55 (2
H, m), 7.27 (1H, m) Example 57 Synthesis of 1-tetradecylpyrrole-3-carboxylic acid (Compound No. 88 in Table 1) 1-Tetradecylpyrrole-3-obtained in Example 56 5.43 g (15.3 mmol) of carboxylic acid ethyl ester was added to a mixed solution of 95% sodium hydroxide (2.58 g, 61.3 mmol) in 100 ml of ethanol and 40 ml of water, and the mixture was heated under reflux for 5 hours. After distilling off ethanol under reduced pressure and adding 100 ml of water,
70 ml of ethyl acetate was added to the crystals, which were acidified with concentrated hydrochloric acid.
And extract with 50 ml. Wash this extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from hexane to obtain 1.76 g of 1-tetradecylpyrrole-3-carboxylic acid as white crystals. Yield 79.9% mp: 66-67 ° C IR (KBr) cm ^-1 : 2930,2860,1650,1545 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 (22H, m), 1.74 (2H,
m), 3.86 (2H, t), 6.60 (2H, m), 7.36 (1H, m) Examples 58 to 73 According to the above Examples 55, 56 or 57, the compounds shown in Table 4 below were synthesized.

Reference Example 1 Synthesis of 1-hexyl-5-tridecylpyrrole-3-carboxylic acid 60% Sodium hydride in oil (360 mg, 9.0 mmol) was washed with hexane and added to a mixed solution of 8 ml of dimethylformamide and 2 ml of dimethyl sulfoxide. Further, 1.20 g (4.1 mmol) of 5-tridecylpyrrole-3-carboxylic acid was added, and the mixture was stirred at room temperature for 1 hour. Hexyl bromide (1.50 g, 9.1 mmol) was added to this reaction solution, and the mixture was stirred at room temperature for 48 hours, acidified with aqueous hydrochloric acid and extracted with ethyl acetate, washed with water, and the solvent was distilled off under reduced pressure to give a residue. Add 20 ml of ethanol, 10 ml of water and 1.0 g of causticum. The mixture is heated under reflux for 24 hours, cooled, acidified with aqueous hydrochloric acid and extracted with ethyl acetate.

The organic layer is separated from this extract, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (developed with chloroform containing 5% methanol) to give the pure target product.
1.20 g (78% yield) was obtained.

mp: 44-46 ° C IR (KBr) cm ^-1 : 2940,1660, NMR (CDCl ₃ ) δ: 0.88 (6H, m), 1.29 (26H, m), 1.66 (4H,
m), 2.47 (2H, t), 3.78 (2H, t), 6.34 (1H, d), 7.29 (1
H, d) Example 74 According to the method of Reference Example 1, the compounds shown in Table 5 below were synthesized.

Test Example 1 The lipid-lowering effect of the compound of the present invention was measured by the following method.

A group of 5 to 6 male Wistar rats weighing 140 to 150 g was treated with a test compound suspended in a 0.5% carboxymethylcellulose (CMC) solution at 10 mg, 30 mg or 40 mg / k.
Oral administration was once a day for 5 days or 8 days. Blood was collected 3 hours after the final administration of the test compound, and triglyceride (TG) in serum was measured by an enzyme method using Neutrintech TG, a kit for measuring neutral fat manufactured by Diayatron, and cholesterol (Cho1) was Kyowa Medex. The amount was measured by an enzymatic method using a cholesterol quantification kit, Determiner TC5 manufactured by the same company.

Results are TG vs control group without test compound
Amount, the percentage of decrease in Cho1 amount (%). The results are shown in Table 6 below. (Compound No. corresponds to Table 1).

[Effect of the Invention] The compound of the present invention shows an effective lowering effect on serum triglyceride and cholesterol, and is expected to be used as a therapeutic agent for hyperlipidemia and further as an anti-atherogenic agent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinya Inoue, 1000 Kamoshida-cho, Midori-ku, Yokohama, Kanagawa Sanryo Kasei Co., Ltd. (72) Inventor Tetsuro Shinfuku 1000 Kamoshida-cho, Midori-ku, Yokohama, Kanagawa Sanryo Kasei Co., Ltd., Research Institute (72) Inventor Masayuki Mitsuya, 1000 Kamoshida-cho, Midori-ku, Yokohama, Kanagawa Sanryo Kasei Co., Ltd. (72) Inventor Mayumi Hirata, 1000, Kamoshida-cho, Midori-ku, Yokohama, Kanagawa (56) References JP-A-61-44815 (JP, A) JP-A-61-183222 (JP, A)

Claims (6)

[Claims] 1. The following general formula (I): (In the formula, R ¹ represents a hydrogen atom, an alkyl group or an alkenyl group having 5 to 25 carbon atoms, and R ² represents a hydrogen atom, a phenyl group,
Alternatively, it represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and R ³ represents a hydrogen atom, an alkyl group having 10 to 16 carbon atoms, or an alkenyl group. However, R ¹ and R ³ do not represent a hydrogen atom at the same time, and R ¹ has 5 to 25 carbon atoms.
R ¹ and CO when represented by a ^single alkyl or alkenyl group
It is not located adjacent to ₂ R ² . ) A pyrrolecarboxylic acid derivative represented by: or a pharmaceutically acceptable salt thereof. ^2. A substituent in the alkyl group of R ² is a halogen atom, a hydroxyl group, an amino group, an alkylamino group having 1 to 5 carbon atoms, a dialkylamino group having 2 to 6 carbon atoms, a carbamoyl group, or a carbon atom 1. A pyrrolecarboxylic acid derivative according to claim 1, which is an alkylcarbonylamino group having 5 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a mercapto group, an alkylcarbonyloxy group having 1 to 5 carbon atoms or an aminocarbonyloxy group. A pharmaceutically acceptable salt thereof. 3. A pyrrole carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is an alkyl group or an alkenyl group having 10 to 16 carbon atoms. 4. A pyrrolecarboxylic acid derivative according to claim 1, wherein R ² is a hydrogen atom, a phenyl group or an optionally substituted alkyl group having 1 to 4 carbon atoms, or a pharmaceutically acceptable derivative thereof. Acceptable salt. 5. The pyrrolecarboxylic acid according to claim 1, wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 6. 4-Tridecylpyrrole-2-carboxylic acid.