JPH03190857A - Hyperlipidemia therapeutic agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a therapeutic agent for hyperlipidemia containing a pyrrolecarboxylic acid derivative or a pharmaceutically acceptable salt thereof having an excellent hypolipidemic effect.

[Problems to be solved by the prior art and the invention] It has been known that abnormal lipid metabolism of blood lipids, such as triglycerides and cholesterol, causes an abnormal increase or imbalance of blood lipids, leading to arteriosclerosis. It is thought to be a major risk factor for causing ischemic heart disease such as angina pectoris and myocardial infarction, or cerebral infarction.

Conventionally, clofibrate drugs, nicotinic acid, and its derivatives have been mainly used as drugs for hyperlipidemia, and although these drugs lower blood l-liglyceride, they have a weak effect on cholesterol. In recent years, probucol, which has a new structure, and cholestyramine, which is an anion exchange resin, have come to be used as drugs for lowering blood cholesterol, but these are not effective against triglycerides.

Abnormal increases in blood triglycerides and cholesterol alone are a major cause of arteriosclerosis, especially atherosclerosis, but when both lipids increase simultaneously, the risk of developing the disease increases significantly. It is known.

As mentioned above, drugs that lower blood L-liglyceride and cholesterol are already in use in clinical settings, but it is desired to develop drugs that are more powerful and have fewer side effects in terms of dosage, safety, and scope of application. ing. In particular, the development of drugs that strongly lower blood triglycerides and cholesterol at the same time is attracting 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 not fully satisfied. There are no drugs that can cause this.

[Means for solving problems]

As a result of extensive research to solve the above problems, the present inventors have discovered that a specific pyrrole carboxylic acid derivative or its pharmaceutically acceptable salt has a stronger ability to simultaneously reduce blood triglycerides and cholesterol than conventional drugs. The present invention has been completed based on the discovery that it has an excellent lipid-lowering effect that lowers the lipid level.That is, the gist of the present invention is as follows: ~25 alkyl or alkenyl groups, R2 is a hydrogen atom, a phenyl group, or has 1 to 10 carbon atoms which may have a substituent
represents an alkyl group, R3 is a hydrogen atom, and has 5 to 2 carbon atoms.
Represents 5 alkyl or alkenyl groups. ) A therapeutic agent for hyperlipidemia containing a pyrrole carboxylic acid derivative or a pharmaceutically acceptable salt thereof.

To explain the present invention below, the pyrrole carboxylic acid derivative of the present invention is represented by the general formula (I).

In the formula, the alkyl group represented by R1 and R3 is
Examples include linear, branched or cyclic alkyl groups having 5 to 25 carbon atoms, preferably alkyl groups having 10 to 16 carbon atoms. Further, examples of the alkenyl group include an alkenyl group having 5 to 25 carbon atoms and preferably an alkenyl group having 10 to 16 carbon atoms and having one or more vinyl groups in the molecule.

In the formula, the alkyl group represented by R2 has 1 carbon number.
-10 alkyl groups, especially alkyl groups having 1 to 4 carbon atoms. Examples of substituents that may be substituted on such alkyl groups include halogen atoms, hydroxyl groups,
Amino group, carbamoyl group, alkylamino group having 1 to 5 carbon atoms, dialkylamino group having 2 to 6 carbon atoms, alkylcarbonylamino group having 1 to 5 carbon atoms, 1 to 5 carbon atoms
Examples include 5 alkylthio groups, mercapto groups, argylcarbonyloxy groups having 1 to 5 carbon atoms, and aminocarbonyloxy groups.

In the present invention, compounds in which the substituents R1 and -CO2R2 are substituted at positions that are not adjacent to each other on the pyrrole ring are preferred from the viewpoint of activity. Specifically, compounds in which the 3-position of the pyrrole ring is substituted with -C○2R2 (in which case, R2 is more preferably a hydrogen atom) and the 5-position is substituted with R1, or the 2-position of the pyrrole ring. -CO□R2 (at that time,
More preferably, R2 is a hydrogen atom. ) is substituted, and a compound in which R1 is substituted at the 4th or 5th position is preferred.

Furthermore, compounds in which any one of R', R2, or R3 is a hydrogen atom are preferred.

Specific examples of such compounds of the present invention include the compounds listed in Table 1 below.

3 14 16 Pharmaceutically acceptable salts of the pyrrole carboxylic acid derivatives include, for example, salts of inorganic metals such as sodium, potassium, calcium, and magnesium, ammonium salts, triethylammonium salts, cyclohexylammonium salts, lysine salts, etc. Examples include organic amine salts.

In addition, when R2 in general formula (1) contains an amino group, inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, or organic acid salts such as maleic acid, succinic acid, citric acid, etc. can be mentioned.

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

Method 1 gX (IV) 1 H (V) (Vl) (■) [In the formula, R4 represents an alkyl group or alkenyl group having 4 to 24 carbon atoms, and X represents a halogen atom] That is, pyrrole and methyl or When the above compound (n) obtained by reacting ethylmagnesium halide is reacted with a suitable acyl chloride (I[I) in an inert solvent such as diethyl ether or tetrahydrofuran, 2-acylpyrrole (IV) is obtained. This compound (IV) was treated with ordinary Wolff-Kishner (Wolf f-Kishner).
r) By carrying out the reduction, 2-alkylpyrrole (V) in which the ketone group has been reduced can be obtained in high yield. When the Grignard reagent is reacted with the above compound (V) again in an inert solvent such as diethyl ether or tetrahydrofuran, ethyl chlorocarbonate (Vl) is added and the reaction is carried out at a temperature between 0°C and the boiling point of the solvent to form 5-alkylpyrrole-2. -Carboxylic acid ethyl ester (■) is obtained. Further, by hydrolysis in a conventional manner, the compound of the present invention represented by the above general formula (■) can be obtained.

Method 2 (IX) 0 [In the formula, 4 (X) (XI) (Xn) ++ (XIII) represents an alkyl group having 4 to 24 carbon atoms. ] Sunawachi, virol-3-carboxylic acid ethyl ester (
IX) and a suitable acyl chloride (I[) in the presence of a Lewis acid such as aluminum chloride, stannic chloride or boron trifluoride diethyl ether combresox, which is commonly used in a free delta-lat reaction with benzene, carbon disulfide, etc. When the reaction is carried out in a solvent within a temperature range of -10°C to the boiling point of the solvent, 5-acyl-pyrrole-3-carboxylic acid ethyl ester (X) is obtained. The ketone group is then converted to the dithioketal (XI) by a commonly used method, followed by heating to reflux with excess Raney nickel in a solvent, preferably ethanol, to 5-alkylpyrrole-3-carboxylic acid ethyl ester ( XII). Further, if this compound (XI[) is hydrolyzed in a conventional manner, the compound of the present invention represented by the above general formula (XIII) can be obtained.

The above compound (IX) can be prepared by known methods described in the literature (for example, Canadian, Journal of
Chemistry, Vol. 58, p. 2527, 2, 1980).

Method 3 (IX) ■ (X) (XIV) (XV) [In the formula, R4 represents an alkyl group or alkenyl group having 4 to 24 carbon atoms, and R5 represents an alkyl group or alkenyl group having 3 to 23 carbon atoms. represents. ] That is, 5-acylpyrrole-3-carboxylic acid ethyl ester (X) obtained as described in Method 2 above is mixed with a suitable reducing agent, preferably sodium borohydride, in an alcoholic solvent such as methanol or ethanol. to reduce the alcohol (X
IV). If this alcohol (XI'/) is heated and refluxed for an appropriate time with an excess of a base such as caustic soda or caustic potash in an alcoholic solvent such as ethanol or ethylene glycol containing water, 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).

3 4 Method 4 (XV) I can do that.

Method 5 RCOCH2C■2CO□CzH5 (X■) Protection protection (Xm In formula C, R5 represents an alkyl group having 3 to 23 carbon atoms.

] That is, the compound (XV) having an alkenyl group having a double bond conjugated with the virol ring obtained in the above method 3 is mixed with palladium in an appropriate solvent (for example, an alcohol such as ethanol, an organic acid such as acetic acid, etc.). -By carrying out catalytic hydrogenation using black, palladium, carbon, platinum, etc. as a catalyst, the compound of the present invention represented by the general formula (X (X) 5 6 (XXI) (XXII) [In the formula, R represents an alkyl group or an alkenyl group having 5 to 25 carbon atoms. ] That is, after protecting the ketone group of the γ-ketoester (X■) with an ethylene kecool group according to a conventional method, the obtained compound (X■) was heated with hydrogen in an inert solvent such as ethyl formate and ether or tetrahydrofuran. The above compound (XIX) is obtained by carrying out so-called Claisen condensation in the presence of a base such as sodium chloride or sodium ethoxide.
shall be.

Next, after deprotecting the ethylene kecoeur group, ammonia or ammonium acetate is reacted with the obtained compound (XX) in an alcoholic solvent to form a pyrrole ring, resulting in the formation of 5-alkylpyrrole-3-carboxylic acid ethyl ester ( XXI) is obtained. Further, by hydrolysis in a conventional manner, the compound of the present invention represented by the above general formula (XXI[) can be obtained. The starting material γ-ketoester (X■) can be prepared by known methods described in literature (for example, Chemical
al Abstract, Volume 81, 63104e;
Ion (Madrid), Volume 34, No. 397, 5
57, 1974).

Method 6 (XXIII) (III) 7 8 (XXIV) ■ (XXν) ■ (XXm [In the formula, R4 represents an alkyl group or alkenyl group having 4 to 24 carbon atoms.] That is, pyrrole-2-carboxylic acid Methyl ester (
XXm) and a suitable acyl chloride (III) in the presence of a Lewis acid such as aluminum chloride, stannic chloride, or boron trifluoride diethyl ether complex in a solvent such as benzene, carbon disulfide, or methylene chloride at -1
4-acylpyrrole-2-carboxylic acid methyl ester (XXrV) can be obtained by carrying out the free-solat fluorine reaction within the temperature range of 0°C to the boiling point of the solvent. The keto group is then converted to 4-alkylpyrrole-2-carboxylic acid methyl ester (X
V).

Further, by hydrolyzing the above compound (X

Method 7 9 0 H (XXIX) (XXX) [In the formula, R5 represents an alkyl group or an alkenyl group having 3 to 23 carbon atoms. ] 4-formylpyrrole-2 represented by the above formula (XX■)
-Carboxylic acid methyl ester (Bulletin d
e la 5ociete chemistry
de France, 283 pages (1972)
] and dodecyltriphenylphosphonium bromide (Chemistry and
Industry (L.

1086 (1958)) is subjected to the Wittig reaction, cis and/or trans 4-alkenylpyrrole-2-carboxylic acid methyl ester represented by the above formula (X X IX) is obtained.

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

Method 8 (Synthesis of pyrrole carboxylic acid ester) Pyrrole carboxylic acid is esterified by one of the following methods.

(XXXI) (×XXIII) 1 2 [In the formula, R1 and R2 are as defined above (except when R2 is a phenyl group<), and X represents a halogen atom. ] Pyrrolecarboxylic acid represented by the above formula (XXXI) is combined with a halide compound represented by the above formula (XXXII) in an inert solvent such as tetrahydrofuran or dimethylformamide in the presence of a base such as sodium hydride or triethylamine. When the reaction is carried out at 0° C. to the boiling point of the solvent, an ester of pyrrolecarboxylic acid represented by the above formula (X X X III) is obtained.

■ The above formula (XXXII
An ester of pyrrolecarboxylic acid represented by [) is obtained.

■ (XXXI) (XXXIV) HH (XXXI) (χχXIII)
[R1 and R2 in the formula are as defined above. ] Pyrrolecarboxylic acid (XXXI) is prepared by a method commonly used in the dehydration condensation reaction, for example, chlorocarbon (XXXV) 3 4 [wherein R1 and R2 are as defined above]. ] When pyrrolecarboxylic acid (XXXr) is heated in a high boiling point solvent such as ethylene glycol, diethylene glycol, xylene, dimethylformamide, etc., a decarboxylation reaction occurs and compound (XXXIV) is obtained. When this obtained compound (XXXI'V) is reacted with trichloroacetyl chloride in an inert solvent such as diethyl ether or tetrahydrofuran within a temperature range from water cooling to the boiling point of the solvent, 1-chloroacetyl chloride is added to the 2-position of the pyrrole ring. An acetyl group is introduced to obtain a compound represented by (XXXV).

Furthermore, by reacting the compound of formula (X is obtained.

Method 9 4 (XXXI) (XXXVII) 3 (XXXVIII) [wherein R1 and R3 are as defined above,
represents a halogen atom. ] Pyrrolecarboxylic acid (XXXI) and a suitable halide compound (XXXVI) are combined with sodium hydride, metallic potassium,
In the presence of a base such as sodium ethoxide, ether,
In an inert solvent such as tetrahydrofuran or dimethylformamide, the above chemical formula 5 6 metal material (XXX■) obtained by reaction at a temperature range from -io'c to the boiling point of the solvent is added to an alkaline aqueous solution containing an alcoholic solvent such as ethanol. By heating under reflux and hydrolyzing, pyrrolecarboxylic acid represented by the above formula (XXX■) is obtained. In addition, the above compound (
XXXI) An ester of pyrrole carboxylic acid can also be used.

7 38 That is, 4-formylpyrrole-2-carboxylic acid methyl ester (Bull
etin de la 5ociete Ch
France.

283 (1972)) and methoxymethyltriphenylphosphonium chloride in the presence of a base to give the compound (XXXIX).

Next, if this compound (XXXIX) is hydrolyzed in an alcoholic solvent containing water with an acid catalyst such as sulfuric acid or para-toluenesulfonic acid, it can be led to (2-methoxycarbonylpyrrole)-4-acetaldehyde (XL). can. In the reaction route (A), the compound (X L
) is reacted with alkyl 1-liphenylphosphonium bromide under Wittig reaction conditions to form the above formula (XLI).
Cis- and/or trans-4-alkenylpyrrole-2-carboxylic acid methyl ester represented by is obtained. By hydrolyzing the obtained compound (XLI) in a conventional manner, the compound of the present invention represented by the above general formula (XLn) can be obtained. In addition, in reaction route (B),
A compound represented by the formula (XL) is (XXVII)-(
XXX r X).

(X
A compound represented by the formula L') was obtained, and the reaction route (A,
) The compound of the present invention represented by the formula (XLII') containing a double bond at any position can be obtained.

The compounds of the present invention are administered to humans as therapeutic agents for hyperlipidemia, preferably by oral administration. Dosage forms for oral administration include granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, liquids, etc. Organic or inorganic, solid or liquid carriers or diluents can be used in the preparation. For example, excipients used in producing solid preparations include lactose, mannitol, corn starch, potato starch, calcium hydrogen phosphate, microcrystalline cellulose, white sugar, aluminum silicate, magnesium silicate, etc. 90 As disintegrants, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, etc. are used, and as binders, polyvinylpyrrolidone,
Polyvinyl alcohol, hydroxypropyl cellulose, etc. are used, and as the lubricant, talc, stearic acid, magnesium stearate, calcium stearate, etc. are used. Liquid preparations, i.e. emulsions, syrups, suspensions, solutions, etc., may include - inert diluents used in boat fishing;
For example, water or vegetable oil may be used. In the case of liquid preparations, auxiliary agents such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents or preservatives may be included in addition to inert diluents. In addition, the preparation method can be carried out according to a conventional method.

The dosage of the compounds of the invention, when administered orally, is 1 Omg to Log, preferably 10 Qm per day for adults.
g to 5 g, but it is more preferable to increase or decrease the amount as appropriate depending on age, medical condition, symptoms, and presence or absence of simultaneous administration.

The above daily dose of the compound of the present invention may be administered once a day, divided into two or three times a day at appropriate intervals, or may be administered intermittently.

Hereinafter, the present invention will be explained in more detail based on synthesis examples and examples, but these are not intended to limit the scope of the present invention in any way.

Synthesis Example 1 Synthesis of 2-tetradecanoylvirol 3M methylmagnesium bromide dissolved in ether fi30
mβ (90 mmol) with virol 6.0 under stirring at room temperature
After adding 4 g (90 mmol), the mixture was heated under reflux for 30 minutes. The reaction solution was cooled on ice, and 9.14 g of myristic acid (4,0
Myristoyl chloride obtained according to a conventional method from 1 mmol) 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, extracted with ethyl acetate, washed with water and dried over acid anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developed with ethyl acetate:hexane-1:5) to obtain 7.31 g (yield: 66%) of 2-tetradeca-12noylvirol.

IR(KBr)am-':3310,2940°16.
45 NMR (CDCj, +) δ: 0.88 (3H, t)
.

1.25 (20H, m), 1.71 (2H, m)
2.75 (2H, t), 6.28 (IH, m).

6.90 (L H, m), 7.01 (I H
, m) Synthesis Example 2 Synthesis of 2-tetradecylvirol 2-tetradecanoylvirol obtained in Synthesis Example 1 7.31
g (26 mmol), 100% hydrazine hydrate 30 m
! (610 mmol) and 20 g (350 mmol) of caustic
2 mmol) in 200 mff of diethylene glycol
After heating at 00°C for 3 hours, the mixture was returned to room temperature, water was added, and ether extraction was performed. After washing this extract with water and drying it over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (developed with ethyl acetate:hexane-1:10) to obtain 2-tetradecylpyrrole 6. .1
4 g (yield 88%) was obtained.

fR(KBr)cm': 3380. 294O
NMR (CDC7!,) δ: 0.89 (3H,t
) 1.27 (22H, m), 1.63
(2H, m)2.61 (2H,t), 5.
92 (1-H, m).

6.14 (LH, m), 6.68 (L
H, m>7.90 (LH, broad S) Synthesis Example 3 Synthesis of 5-tetradecylpyrrole-2-carboxylic acid ethyl ester 2-tetradecylpyrrole 4 obtained in Synthesis Example 2, OOg(
15 mmol) was dissolved in 20 ml of anhydrous ether, 7 mβ (21 mmol) of an ether solution of methylmagnesium bromide (approximately 3 M) was added at room temperature, and the mixture was heated under reflux for 30 minutes. Ethyl chlorocarbonate 2 was added while cooling the reaction solution with ice water.
After adding mβ (21 mmol) and heating under reflux for 10 hours, the mixture was returned to room temperature, poured into ice water containing ammonium chloride, extracted with ethyl acetate, washed with water, dried over acid anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developed with 1:10 ethyl acetate:hexane) to obtain 1.89 g of 5-tetradecylpyrrole-2-carboxylic acid ethyl ester.
(yield 37%).

Melting point (m, I); 60-63°C IR(KBr)cm-':3310,2930675 NMR (CDCβ3) 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 (L H,
m) 6.83 (I H, m>.

8.75 (IH, broad S) Synthesis Example 4 Synthesis of 5-tetradecylpyrrole-2-carboxylic acid 0.50 g (1.5 mmol) of 5-tetradecylpyrrole-2-carboxylic acid ethyl ester obtained in Synthesis Example 3 ) was dissolved in 20 ml of ethanol, and 3 mj2 (3 mmol) of an aqueous solution of N caustic soda was added thereto and heated under reflux for 6 hours. After cooling, the precipitate is filtered, thoroughly washed with ether, suspended in an aqueous hydrochloric acid solution, and extracted with ether. After further washing with saturated brine, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.34 g (yield: 74%) of 5-tetradecylpyrrole-2-carboxylic acid.

m, p, 68-69℃ IR (KBr) cm-': 334.0, 3255゜2
930.1660.150O NMR (CDCI!, 3) δ: o, as (3H, t
) 1.26 (22H, m), 1.64 (2
H, m).

2.62 (2H, t), 6.02 (IH, m
)6.97 (LH, m).

8.90 (LH, broad S) Synthesis Example 5 Synthesis of γ-ketooctadecanoic acid ethyl ester ethylene ketal γ-ketooctadecanoic acid ethyl ester 9.25 g (2
8 mmol) and ethylene glycol 9.00 g (145
mmol) was refluxed for 5 hours in the presence of a small amount of para-toluenesulfonic acid catalyst in 300 m4 of toluene with dehydration using a Dea5 6 n-3 tark apparatus. After sequentially washing with saturated aqueous sodium bicarbonate and saturated brine, the solvent was distilled off under reduced pressure, and the resulting oil was purified by silica gel column chromatography (developed with ethyl acetate:hexane-1:10) to obtain ethyl γ-ketooctadecanoate. 7.42 g (yield 71%) of ester ethylene ketol was obtained.

IR(Neat)cm-':2920,174ONMR
(CD(1,)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 (4H
,s).

4.10 (2H,q) Synthesis Example 6 Synthesis of 5-tetradecylpyrrole-3-carboxylic acid ethyl ester 7.42 g (20 mmol) of γ-ketooctadecanoic acid ethyl ester ethylene kecool obtained in Synthesis Example 5 and formic acid Ethyl ester 1.93 g (26 mmol) ether 2
1.20 g of 1 Lium (30
mmol) in 20 ml of ether under stirring at room temperature, and then allowed to react at room temperature for 18 hours. Additionally, 0.70 g (17 mmol) of 60% sodium hydride and 1. OOg (13 mmol) was added to the reaction solution and stirred at room temperature for 50 hours. The reaction was terminated by adding diluted hydrochloric acid, and the ether extract was distilled off under reduced pressure.
mn was added and stirred vigorously for 1.5 hours.

After extraction with ether and washing with saturated brine, drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure and purifying with silica gel column chromatography (developed with ethyl acetate:hexane-1=10) to obtain γ-keto α-formyl. 3.63 g (yield 51%) of octadecanoic acid ethyl ester was obtained.

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

m, p,: 59-62°C IR (KBr) cm-': 3320.294068O NMR (CDC/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 (IH, m>7.
29 (I H, m).

8.20 (LH, broad s) Synthesis Example 7 Synthesis of 5-tetradecylvirol-3-carboxylic acid 3.53 g (11 mmol) of 5-tetradecylvirol-3-carboxylic acid ethyl ester obtained in Synthesis Example 6 To 120 mJ of ethanol solution, add 25% of N-caustic soda aqueous solution.
After adding mIt and heating under reflux for 16 hours, ethanol was distilled off, the mixture was acidified with an aqueous hydrochloric acid solution, and extracted with ethyl acetate. After washing with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate:hexane-1=4) to obtain 5-tetradecylpyrrole-3-carvone. acid 2.19
g (yield: 68%).

m, p,: 83-85°C IR (KBr) cm-': 3470,295067O NMR (CD(13)δ: 0.88 (3H, m>
.

1.25 (22H, m>, 1.61 (2
H, m).

2.57 (2H,t), 6.36 (IH
, m).

7.38 (LH, m).

8.20 (IH, broad s) Synthesis Example 8 Synthesis of 5-tridecanoylpyrrole-3-carboxylic acid ethyl ester Pyrrole-3-carboxylic acid ethyl ester 2.78 g (
Tridecanoyl chloride, which was synthesized by a conventional method from 4.28 g (20 mmol) of tridecanoic acid, was added to a solution of 20 mj2 of benzene (20 mmol) under water cooling, and then 3°5 mj2 (30 mmol) of stannic chloride was added. dripped. After completion of the dropwise addition, the mixture was stirred at room temperature for 15 hours, diluted hydrochloric acid was added, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (ethyl acetate:hexane-
5-tridecanoyl-3
-carboxylic acid ethyl ester 4.85 g (yield 72
%) was obtained.

IR (KBr) cm-': 3290.2920°1
700.166O NMR (CDCβ3) δ: o, sa (3H, t>1
．． 25 (18H, m), 1.25 (3H, t)
.

1.71 (2H, m), 2.78 (2H
,t).

4.25 (2H,q), 7.31 (IH
, m).

7.59 (LH, m).

9.60 (IH, broad s) Synthesis Example 9 Synthesis of 5-tridecanoylpyrrole-3-carboxylic acid ethyl ester dithioethylene ketal 5 obtained in Synthesis Example 8
-To a solution of 4.85 g (1.45 mmol) of tridecanoylpyrrole 3-carboxylic acid ethyl ester and 5 mj2 of ethanedithiol in 40 ml of acetic acid, 5 ml of boron trifluoride/diethyl ether complex was added and reacted at room temperature for 2.5 hours. After that, water was added and extracted with ethyl acetate, washed with an aqueous sodium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent 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 3.14 gC yield 63 %) was obtained.

IR (KBr) cm-': 3350, 2910°68O NMR (CD(123)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 (LH,m
)1 2 7.39 (I H, m) 8.28 (LH, broad s) Synthesis Example 10 5-1- 'J Synthesis of decylvirol-3-carboxylic acid ethyl ester 5-Tridecano obtained in Synthesis Example 9 Ilvirol 3-carboxylic acid ethyl ester dithioethylene ketal 3.74.
g (9.1 mmol) and 30 mj of Raney nickel! The mixture was heated under reflux in 200 mc of ethanol for 2 hours. Using Celite, thoroughly wash Raney nickel with filtered acid ethanol,
After distilling off the solvent under reduced pressure, it was purified by silica gel column chromatography (developed with ethyl acetate:hexane-1=7).
-Tridecylpyrrole-3-carboxylic acid ethyl ester 2.60 g (yield 89%) was obtained.

m, p, 59.5-60.5°C IR (KBr) ts-': 3320.2930°68
O N)t4R(CDC7!3)δ: 0.88 (3H
,t).

1.25 (20I(, m), 1.60 (2H, m
).

2.56 (2H, t), 4.28 (2H, q)
6.31 (I H, m), 7.30 (
LH,m)8.30 (LH,broad,
m) Synthesis Example 11 Synthesis of 5-tridecylpyrrole-3-carboxylic acid 2.60 g (8.1 mmol) of 5-tridecylpyrrole-3-carboxylic acid ethyl ester obtained in Example 1'1J10
1.40 g of caustic soda in 40 ml of ethanol solution (
10 mβ of an aqueous solution containing 33 mmol) was added and heated under reflux for 36 hours. Ethanol was distilled off and the residue was 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. Silica gel column chromatography (ethyl acetate:hexane=1
: 2) to obtain 2.04 g (yield: 86%) of pure 5-tridecylpyrrole-3-carboxylic acid. m, p,: 82-84°C IR (KBr) cm-': 3450, 2920°66
5 3 4 NMR (CD (1,) δ: 0.88 (3H, t).

1.26 (20I(,m,), 1.61 (2H
, m).

2.57 (2H, t), 6.36 (IH, m)
.

7.39 (LH, m) 8.24 (LH, broad, m) Synthesis example 1
2 Synthesis of 5-(1-pentadecenyl)virol-3-carboxylic acid 4.59 g (13
Add 500 mg (13 mmol) of sodium borohydride to 100 ml of ethanol solution of
After reacting for 6 hours, ethanol was distilled off under reduced pressure, water was added and extracted with ether, washed with water and dried over anhydrous magnesium sulfate. Add 35% ethanol to the product obtained by distilling off the solvent under reduced pressure.
ml! , 12 mβ of water and 3.53 g of caustic potash (63
mmol) was added and heated under reflux for 5 days.

Acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, distilled off the solvent under reduced pressure, and purified the raw acid using silica gel column chromatography (developed with ethyl acetate:hexane-1:2). -(1-pentadecenyl)virol-3 carboxylic acid 2.33 g (yield 60
%) was obtained.

m, p, 9Q ~ 96℃ IR (KBr) cm-': 3450, 2940゜67O NMR (CDCβ3) δ: 0.88 (3H, t)
.

1.28 (22H, m), 2.17 (2
H, m).

5.88 (IH, m), 6.20 (IH, m)
.

6.53 (L H, m), 7.4.2 (I
H, m) 8.4.9 (IH, broad s)
Synthesis Example 13 Synthesis of 5-te1-radecylpyrrole-3-carboxylic acid 3.05 g (10 mmol) of 5-(1-tetradecenyl)virol-3-carboxylic acid obtained in the same manner as Synthesis Example 12 in ethanol 309 mg of 10% palladium black was added to the 20rrz2 solution, and catalytic reduction was performed for 2 hours. After removing the catalyst, the product was crystallized from 5 G of heptane to obtain the same product as in Synthesis Example 7. 2
．． 50g (yield 82%) Melting point, TR, and NMR agree with the compound of Synthesis Example 7.

Synthesis Example 14 Synthesis of 4-tetradecanoylpyrrole-2-carboxylic acid methyl ester 1.25 g of pyrrole-2-carboxylic acid methyl ester (
Add 2.71 g (11 mmol) of tetradecanoyl chloride to a 5mβ solution of benzene (10 mmol) under water cooling,
Then, 1.73 mβ (15 mmol) of stannic chloride was added dropwise. After reacting at room temperature for 2 hours, dilute hydrochloric acid was added and extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 1.80 g (yield: 54%) of 4-tetradecanoylpyrrole-2carboxylic acid methyl ester was obtained.

IR(KBr) cm-': 3290.2920170
5 1665 NMR (CDCAs) δ: 0.8B (3H, t)
1.30 (20H, m), 1.70 (2H, m).

2.75 (2H,t), 3.88 (3
H,s).

7.29 (L H, m), 7.53 (
IH, m) 9.30 (IH, broad s
) Synthesis Example 15 Synthesis of 4-tetradecylpyrrole-2-carboxylic acid methyl ester 4-tetradecanoylpyrrole-2- obtained in Synthesis Example 14
A solution of diborane (approximately 3M) in tetrahydrofuran 1.80g (5°4 mmol) of carboxylic acid methyl ester 30
Add mff (90 mmol) and further add boron trifluoride.
Diethyl ether combresox 1m7! was added and left overnight at room temperature. Methanol was added, water was further added, and the mixture was extracted with ethyl acetate. After washing with water and 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 obtain 0.22 g (yield: 13%) of 4-tetradecylvirol-278 carboxylic acid methyl ester. m, p,: 80-82°C IR (KBr) cm-': 3360, 2950°16
95 NMR (CDCj!3) δ:o, a8 (3H,t)1
．． 25 (22H, m), 1.56 (2H, m)2.
45 (2H, t), 3.83 (3H, s).

6, 74. (2H, m) 8.85 (IH, broad s) Synthesis Example 16 Synthesis of 4-tetradecylpyrrole-2-carboxylic acid 4-tetradecylpyrrole 2-carboxylic acid methyl ester obtained in Synthesis Example 15 0.22 g (0,69 mmol) of ethanol 5 ml! A warm 2N caustic soda solution (1 mβ) was added and heated under reflux for 13 hours. After adding water and washing with ether, the aqueous layer was acidified with hydrochloric acid, extracted with ether, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
9 g (yield 95%) was obtained. m, p, :14s~150
°CIR (KBr) cm-': 3400. 293
0゜169 O NMR (CDCβ3)δ: 0.88 (3H,t
).

1.25 (22H, m), 1.53 (2H
,t).

6.94 (IH, m), 6.97 (IH,
m).

9.10 (IH, broad s) Synthesis Example 17 Synthesis of 5-tridecylpyrrole-3-carboxylic acid propyl ester 1.50 g of 5-tridecylpyrrole-3-carboxylic acid (
5.11 mmol) and 1.27 g (6.15 mmol) of dicyclohexylcarbodiimide were added to 25 mA of tetrahydrofuran, followed by 3.5 g (6.15 mmol) of n-propyl alcohol.
After adding 3 m j2 and 62 mg of dimethylaminopyridine, the mixture is heated under stirring at 60° C. for 10 hours. After cooling, the precipitate was filtered off, washed with ether, and the filtrate and washings were 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.

m, p, 51-52℃ IR (KBr) cm-': 3280, 2930゜6
75 NMR (CDCβ3) δ: o, as (3H,L>0
．． 97 (3H, t), 1.25 (20H, m) 1
．． 65 (4H, m), 2.54 (2H, t
)4.17 (2H,t), 6.31 (LH
, m).

7.28 (L H,m,) 9.04 (LH, broad s) Synthesis Example 18 5-A-') Synthesis of decylpyrrole-3-carboxylic acid-2bromoethyl ester 5-tridecylpyrrole-3-carvone Acid 1.47g (
5.0 mmol) in tetrahydrofuran solution 20 m/!
0.60 g (5.53 mmol) of ethyl chlorocarbonate and 0.60 g (5.94 mmol) of triethylamine were added to the mixture, stirred at room temperature for 10 minutes, and then 1.88 g (15 mmol) of 2-bromoethanol was added. Heat to reflux for .5 hours. Furthermore, 0.94 g of 2-bromoethanol (7
, 5 mmol) and heated under reflux for 9 hours, cooled, acidified with aqueous hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography (
1.05 g (yield: 53%) of 5-tridecylpyrrole-3-carboxylic acid 2-bromoethyl ester was obtained.

m, p, 67-69.5'c IR (KBr) cm-': 3340, 2930°16
9 O NMR (CDC/!,) δ: 0.88 (3H,t)
.

1.33 (20H, m), 1.60 (2H,
m).

2.56 (2H, t), 3.59 (LH, t).

3.76 (IH, t), 4.49 (2H, m).

6.34 (I H, m), 7.34 (L H,
m) 8.20 (IH, broad s) Synthesis example 19
~38 Synthesis of 4-tridecanoylvirol-2-carboxylic acid methyl ester according to the method described in the synthesis section below in Table 2. 102.9 g (0.48 mol) of tridecanoic acid ) was dissolved in methylene chloride 48 Qm6, and thionyl chloride 5
2.6 mA (0.72 mol) and 0.2 ml of N,N-dimethylformamide! was added and the apparatus was heated overnight. Concentrate this under reduced pressure, and remove the remaining oil from anhydrous aluminum chloride.
400 ml of methylene chloride containing 6.6 g (0.8 mol)
added to. A solution of virol-2-carboxylic acid methyl ester and 50.05 g (0.4 mol) in 200 ml of methylene chloride was added dropwise to the mixture at 3 to 9 DEG C. over a period of about 40 minutes. After the dropwise addition was completed, the temperature was gradually raised to room temperature, stirred for 2 hours, and mixed with 800 ml of ice-water! , added to. Add to this 100,100O of methylene chloride! was added to dissolve all the crystals, the layers were separated, and the organic layer was washed with water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 400 m ethyl acetate.
7! and hexane 4.00 ml! 107.2 g of 4-tridecanoylvirol-2-
Carboxylic acid me56 methyl ester was obtained as almost white crystals.

Yield 83% m, p,: 92-93°C IR (KBr) cill-': 3270, 29202
855.1690, 1660.15651455.13
85,1290.1215'HNMR (CDCβ3) δ: 0.88 (3H, t, J = 6.6Hz) 1.1
5-1.38 (18H, m) 1.65-1.75
(2H, m) 2.75 (2H, t, J=7.5Hz) 3.89
(3H, S) 7.28-7.30 (I H, m) 7.517.5
5 (IH, m> 9.52 (LH, broad s) Synthesis Example 40 Synthesis of 4-tridecanoylvirol-2-carboxylic acid methyl ester dithioethylene ketal 4-Tridecanoylvirol- obtained in Synthesis Example 39 18.29 g (56.9 mmol) of 2-carboxylic acid methyl ester was dissolved in 140 ml of acetic acid, and 14.0 mj! (1 mmol) of 1,2-ethanedithiol and boron trifluoride.
Diethyl ether complex 14rnβ was added and stirred overnight under water cooling.

This was concentrated under reduced pressure, and water Loomβ was added to the residue to give 200 mI of ethyl acetate! (100mAX2). The combined extracts were washed with a 5% aqueous sodium hydroxide solution and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of acetic acid and hexane to obtain 4-tridecanoylvirol-2-carboxylic acid methyl ester dithioethylene ketal. The mother liquor was subjected to silica gel column chromatography (eluent: ethyl acetate/mugisan-1/6) to obtain the target product remaining in the recrystallization solvent. Total yield 15.44 g, yield 68%
m, p, near 7-78°C IR (KBr) cm-': 3360.2940°28
60 1705.1440,1385°1.265,1
210.1120' HN M R (CD CI!, 3) δ: 0.88
(3Ht, J=6.6Hz) 6 ma 8 1.20-1.40 (20H, m) 2.22-2.
28 (2H, m,)3.25-3.41 (4H
m) 3.84 (3H, s), 6.92 (LH,
s) 7.05-7.07 (I H, m) 9.08
(IH, broad s) Synthesis Example 41 Synthesis of 4-tridecylpyrrole-2-carboxylic acid methyl ester 4-Tridecanoylpyrrole-2 obtained in Synthesis Example 40
-carboxylic acid methyl ester dithioethylene ketal 1
5.06 g (37.9 mmol) washed with water and then ethanol, 150 ml of Raney nickel (activated type, manufactured by Aldrich), 750 m+j of ethanol!
and heated under reflux for 30 minutes. Approximately 30℃
After the mixture was cooled to 100%, Raney nickel was removed by filtration, and the filtrate was concentrated under reduced pressure. Recrystallization of the residue from ethanol yields 10.70
4-tridecylpyrrole-2-carboxylic acid methyl ester of g was obtained as white crystals. Yield 91.8%m,
p, : 80-82°C IR (KBr) cm-': 3340. 292
0°2850, 1690. 1445. 1390°1265, 1205. 1130'HNMR (CD(13) 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 = 7.6 Hz
) 3.83 (3Hs) 6.7 2-6.75 (2H, m) 8.88 (
LH, broad s) Synthesis Example 42 Synthesis of 4-tridecylpyrrole-2-carboxylic acid To 10.01 g (32.6 mmol) of 4-tridecylpyrrole 2-carboxylic acid methyl ester obtained in Synthesis Example 41 was added 200 mj2 of ethanol. , water 80mA and 95%
Add 5.5 g (131 mmol) of sodium hydroxide,
The mixture was heated under reflux for 1 hour. Cool 90 Add 100 mA of pumped water, acidify with hydrochloric acid, and 400 mI of ethyl ether! , 100 mj of ethyl acetate! and tetrahydrofuran at 300 mA. The aqueous layer was extracted again with 100 rrl of ethyl acetate, and the extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentrating this under reduced pressure, it was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain 7.55 g of 4-tridecylpyrrole-2carboxylic acid as white crystals.

m, p,: 150-151°C TR (KBr) cm-': 3390, 2960°29
25.2860.1685,1495144.0,12
80,1130.1120'HNMR (DMSO-d6
) 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 (IH,s), 6.71 (IH,s
) Synthesis Example 43 Synthesis of 4-dodecanoylvirol-2-carboxylic acid methyl ester 213 g of lauric acid (1,
06 mol) as a raw material, 4-dodecanoylvirol-2
245.5 g of -carboxylic acid methyl ester was obtained. Yield 90% m, T): 102-103°C IR (KBr) cm-': 3270,2920285
0.1690.166O N M R (CD C(13)δ+0.88 (3H,
t) 1.25 (16H, m), 1.70 (2
H, m).

2.75 (2H, t), 3.88 (3H, s).

7.30 (LH, m), 7.53 (LH, m)9.
50 (IH, broad s) Synthesis Example 44 Synthesis of 4-(1-hydroxydodecyl)virol-2-carboxylic acid methyl ester 245.5 g of 4-dodecanoylvirol-2-carboxylic acid methyl ester obtained in Synthesis Example 43 ( 0,801 mol), 1.51 mol of tetrahydrofuran and 0.8 mol of methanol.
154 and 15.1 g (0.40 mol) of sodium borohydride are added in portions while stirring at a temperature of 10-21°C. Stir at 20°C, add 7.5g (0.20 mol) of sodium borohydride after 1Vj, and stir at 20°C.
After stirring for 1 hour, the solvent was distilled off under reduced pressure and 700% of water
mβ and 2.4β of ethyl acetate were added. The organic layer was separated, washed sequentially with 700 ml of water and then with 700 ml of saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
247.0 g of light brown crystals were obtained. Yield 99%IR
(KBr)am-': 3450, 3240°2930
．． 168O NMR (CDCj23) δ: 0.88 (3H, t)
1.25 (18H, m), 1.73 (2H,
m).

3.85 (3H, s), 4.63 (LH, m)6.
88 (IH, m), 6.92 (IH, m).

9.05 (LH, broad s) Synthesis Example 45 Synthesis of 4-(1-acetoxydodecyl)virol-2-carboxylic acid methyl ester Methyl 4-(1-hydroxydodecyl)virol-2-carboxylate obtained in Synthesis Example 44 Ester 247.0g (0
, 80 mol) of toluene 1,6I! 1 part acetic anhydride in a solution of
80m! (1,91 mol) and pyridine 180 m# (2,
23 mol) was added and heated at 105°C for 2.5 hours.

After cooling to room temperature, wash twice with 700 ml of 2N hydrochloric acid solution,
After adding 1.2 A of saturated aqueous sodium hydrogen carbonate solution and stirring at room temperature for 30 minutes, the organic layer is extracted. The extracted organic layer is washed successively with a saturated aqueous sodium bicarbonate solution and a 700 ml volume of saturated saline, and then dried over anhydrous magnesium sulfate. The crystals obtained by distilling off the solvent were mixed with 70% hexane.
0m7! 258.0g of very light brown crystals recrystallized from
I got it. Yield 92% m, p,: 69-70°C IR (KBr) cm-'73300.2920705 NMR (CD CI! z) δ: o, ss (
3H, t) 1.25 (18H, m), 1.86 (2
H, m) 3 4 2.03 (3H, s), 3.85 (3H, s)
.

5.73 (IH, t), 6.89 (IH, m)
.

6.95 (LH, m) 9.08 (IH, broad s) Synthesis Example 46 Synthesis of 4-dodecylpyrrole-2-carboxylic acid methyl ester 4-(1-acetoxydodecyl)virol-2 obtained in Synthesis Example 45 -Carboxylic acid methyl ester 258.0g (0
, 73 mol) of ethanol2. 16 g of 10% palladium-carbon was added to the Ol solution, and catalytic hydrogen reduction was performed at 50° C. in a hydrogen atmosphere. The reaction took 5.5 hours to complete, 1.51 chloroform was added, the catalyst was filtered off, and the solvent was distilled off under reduced pressure to obtain crystals. Recrystallization was performed from 950 mjf of ethanol to obtain 179.6 g of 4-dodecylpyrrole-2-carboxylic acid methyl ester as white crystals.

Yield 83% m, p,: 68-69°C IR (KBr) cm-': 3340,292069O NMR (CD CA! 3) δ: o, ss (
3H, t) 1.25 (18H, m), 1.
54 (2H, m).

2.44 (2H, t), 3.83 (3H,
s) 6,74 (2H,m) 8.88 (IHbroad s) Synthesis Example 47 Synthesis of 4-dodecylpyrrole-2-carboxylic acid Synthesis Example 4
To 112.0 g (0.38 mol) of 4-dodecylpyrrole-2-carboxylic acid methyl ester obtained in step 6 were added 1.45 β of ethanol, 1.451 g of water, and 31.0 g (0.74 mol) of 95% sodium hydroxide. ) and heated under reflux for 2 hours. At 80°C, add 1.45ml of hot water, and at the same temperature, add 6N sulfuric acid little by little to adjust the pH of the reaction solution to 2. After cooling to 45°C, the precipitated crystals are filtered and washed with water. The crystals are dissolved in 4p of tetrahydrofuran, washed twice with saturated brine 1e, and then 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 92.6 g of 4-dodecylpyrrole-2-carboxylic acid as white crystals. Yield 87%m,
p,: 152 153°C TR (KBr) cm-': 3380,2920685 NMR (DMSO-d6) δ: o, as (3H, t)
1.22 (18H, m), 1.44 (2H
, m).

2.34 (2H, t), 6.52 (IH, m
).

6.71 (IH, m).

Synthesis Examples 48 to 57 The compounds shown in Table 3 below were synthesized according to the methods described in Synthesis Examples 46 and 47 above.

Table 7 78' Synthesis Example 58 Synthesis literature of 4-(1-cis-)lysocenyl)virol 2-carboxylic acid methyl ester (Chemistry and Industry)
Dodecyltriphenylphosphonium bromide 1 as described in RY (London), p. 1086 (1958))
6.0 g (31.4 mmol) of tetrahydrofuran 9
1.8.5 ml of a hexane solution of n-butyllithium (approximately 15% concentration) was added dropwise to the 5 mA suspension at -50 °C.
After raising the temperature to room temperature and stirring for 30 minutes, the temperature was returned to -50°C.
4-formylvirol-2- described in Chimique de France, page 283 (1972))
A solution of 2.4 g (15.7 mmol) of carboxylic acid methyl ester in 50 mA of TeI-rahydrofuran was added dropwise. 1
After stirring for an hour, water was added, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:hexane).
4-(1,-Ctst-'Jdecenyl)virol-2-carboxylic acid methyl ester 3. ],
1 g (65% yield) was obtained.

m, p,: 51-52°C TR (KBr) cm-': 3300, 29301685 NMR (CD (, j23) δ: 0.88 (3H,
t) 1.29 (18H, m), 2.29 (2H
, m) 3.86 (3H, s), 5.50 (I
H, m) 6.17 (LH, m), 6.93
(2H, m) Synthesis Example 59 Synthesis of 4-(1-cis-tridecenyl)virol-2-carboxylic acid Methyl 4-(1-cis-)lysocenyl)virol-2-carboxylate obtained in Synthesis Example 58 Esther 3.
10 g (1,0,2 mmol) of ethanol 50 m
Add 860 rng (2
0.4 mmol) in an aqueous solution containing 25 m! Add
The mixture was heated under reflux for 1 hour. The reaction solution was made acidic by adding 6N sulfuric acid, extracted with ethyl acetate, washed with 90 saturated brine, dried over anhydrous magnesium sulfate,
Activated carbon treatment was performed, and the solvent was distilled off under reduced pressure.

The obtained residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain 1.33 g of 4-(1-cis-1-lysocenyl)pyrrole-2-carboxylic acid (yield: 45%).
) was obtained.

m, T): 157-158℃ IR (KBr)cm-': 3390.2940゜68
O NMR (DMSO-d6) δ: 0.86 (3H, t
) 1.22 (18H, m), 2.21. (
2H, m).

5.33 (IH, m), 6.18 (IH, d
)6.72 (L H,m), 6.94 (L
H, m) Synthesis Example 60 4-(1-trans-)lysocenyl)pyrrole-2-
Synthesis of carboxylic acid methyl ester To a suspension of 32 g (62.7 mmol) of dodecyltriphenylphosphonium bromide in 200 mA of tetrahydrofuran, 40 ml of a hexane solution (approximately 15% concentration) of n-butyllithium was added dropwise on ice-cooling. .

After stirring the reaction solution for 30 minutes, the temperature was lowered to -78°C and 4.8 g of 4-pormylpyrrole-2-carboxylic acid methyl ester (
A solution of 31.4 mmol) in 100 ml of tetrahydrofuran was added dropwise, and after stirring for 1 hour, 190 ml of ethanol was added dropwise.
# was dropped. The reaction solution was stirred at 78° C. for 1.5 hours, and then gradually warmed to room temperature while stirring was continued for an additional 12 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography using a developing solvent; I! 4-(l-trans-1-lysocenyl) by recrystallizing twice with hexane (1:10) and hexane
1.30 g of pyrrole-2-carboxylic acid methyl ester (
A yield of 14%) was obtained.

m, p,: 65-67°C TR (KBr) cm-': 3350.294069O NMR (CDCβ3) δ: 0.88 (3H, t)1
．． 32 (18H, m), 2.12 (2H, m
, )1 2 3.85 (3H,t), 5.95 (IH,
s).

6.18 (LH, d), 6.83 (L
H,m) 6.95 (L H,m) Synthesis Example 61 4-(1-trans-tridecenyl)pyrrole-2
- Synthesis of carboxylic acid 4 (1 trans tridecenyl)pyrrole-2-carboxylic acid methyl ester obtained in Synthesis Example 60 1.30
g < 4.3 mmol) of ethanol 20 m7! 9 in solution
8 mj2 of an aqueous solution containing 340 mg (8.0 mmol) of 5% sodium hydroxide was added, and the mixture was heated under reflux for 1 hour. The reaction solution was made acidic 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 distilled off under reduced pressure. The obtained residue was recrystallized with a mixed solvent of hexane and tetrahydrofuran to obtain 94 Qmg of 4-(]-tran s-)lysocenyl)pyrrole-2-carboxylic acid (yield 7).
2%).

m, p,: 161-163°C IR (KBr) cm-': 3400. 2920°169 O NMR (DMSO-a6) δ: 0.84 (3H,
t) 1.22 (18H, m), 2.07
(2H, m) 5.89 (IH, m), 6.1
3 (LH, d) 6.8 1 (L H, m)
, 6.84 (I H, m) Synthesis Example 62 Synthesis of 4-1-lysosylpyrrole-2-carboxylic acid ethyl ester After washing 140 mg (3.50 mmol) of 60% sodium hydride with hexane, 20 mρ of dimethylformamide
In addition, 990 mg (3.38 mmol) of 4-tridecylpyrrole-2-carboxylic acid obtained in Synthesis Example 42 was added little by little at room temperature while stirring.

After stirring the reaction solution for 10 minutes, add 5.0 g of ethyl iodide (31°8
mmol) and heated at 55°C for 22 hours.

After cooling, the mixture was acidified with aqueous hydrochloric acid, 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 obtain 4-tridecylpyrrole-2-carboxylic acid ethyl ester (600 m
g was obtained as white crystals. Yield 55% m, p,: 59-60°C IR (KBr) cm-': 3340.292069O NMR (CDC13) δ: 0.88 (3H, t
) 1.26 (20H, m), 1.34 (3H, t)
1.55 (2H, m), 2.45 (2H, r
n) 4.29 (2H,q> , 6.72 (I
H, m) 6.75 (L H, m> 8.85 (], H, broad s) Synthesis Example 63 Synthesis of 4-tridecylpyrrole-2-carboxylic acid dimethylamine ethyl ester hydrochloride Same as Synthesis Example 62 4-Tridecyl-virol-2-carboxylic acid dimethylaminoethyl ester synthesized by the method described above is dissolved in a mixed solution of ethanol and ether, ethanol containing hydrogen chloride is added, and the precipitated crystals are collected by filtration. The resulting crystals are recrystallized from a mixture of ethanol and ether to obtain the desired product.

Yield 41% m, p,: 109-111°C IR (KBr) cm=: 3200.29302600
171O NMR (CDCβ3) 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), 4.4.9 (2H, m
) 6.85 (2H, m) Synthesis Example 64 Synthesis of 4-tridecylpyrrol-2-carboxylic acid N-butylcarbamoylmethyl ester The above target product was synthesized in the same manner as in Synthesis Example 62. Yield 36% m, p,: 101 102°C rR(KBr) cm-': 3350,2920167
0 165O NMR (CD CE 3) δ: 0.90 (6
H, m) 5 6 1.26 (22Hm), 1.55 (4H,
m) 2.45 (2H,t), 3.33 (2
H, t) 4.73 (2H, s), 6.82
(2H,m) Synthesis Example 65 Synthesis of 4-tridecylpyrrole-2-carboxylic acid NN-diethylcarbamoylmethyl ester The above target product was synthesized in the same manner as in Synthesis Example 62. Yield 46% m, p,: 107-108°C IR (KBr) cm-': 3310, 2950°171
．． 0.164O NMR (CDCE:I) δ:0.8
5 (3H, t) 1.12 (3H, t), 1.18
(23H,m)1.69 (2T-(,m),
2.42 (2H, t).

3.26 (2H,q), 3.40 (2H,q)4.
84 (2H, s), 6.84 (IH, m) 7.24
(I H, rn) Synthesis Example 6G 4-t'J 7'silpyrrole-2-carboxylic acid N.

Synthesis of N-bis(2-hydroxyethyl)carba'moylmethyl ester The above target product was synthesized in the same manner as in Synthesis Example 62.

Yield 14% m, p,: 99.5-101°C IR (KBr) cm-': 3330, 29401710
．． 164O NMR (CD C7!3) δ: 0.88
(3H, m) 1.25 (20H, m), 1.69 (
2H, m) 2.4.3 (2H, t), 3.47
(2H, t) 3.56 (2H, t), 3.84 (
4H, m) 6.71 (LH, m), 6.85
(LH, m).

Synthesis Example 67 Synthesis of 3-tridecylvirol 4-l-'J Decylvirol-2-carboxylic acid 118
g (0.40 mol) to ethylene glycol 1.711!
Add potassium hydroxide to 100 ml of water and react at 190°C for 5 hours, then add water and extract with ethyl acetate. After washing the organic layer with water, dry over anhydrous magnesium sulfate and reduce pressure. Concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane-115) to obtain 96.0 g of 3-tridecylvirol.

Yield 96% m, T): 32.5-33.5°CIR(K
Br) cm'': 3420.29502860.7
65 NMR (CDCβ3)δ: 0.88 (3H,t)1
．． 25 (20H, m), 1.57 (2H, m
) 2.48 (2H, t), 6.09 (LH, m)
6.57 (I H, m), 6.72 (I
H, m) 7.97 (LH, broad s) Synthesis Example 68 = Synthesis of ll-lysosil-2-trichloroacetylpyrrole In a solution of 80.7 g (0.44 mol) of trichloroacetyl chloride in 200 mn of TeI-lahydrofuran, synthesize 96.0 g of 3-tridecylvirol obtained in Example 67 (0,3
8 mol) of tetrahydrofuran in 400ml/29
It was added dropwise at a temperature of -34°C, and then reacted for 30 minutes at room temperature. Under water cooling, 34 g of potassium carbonate (0,2
After adding 200 mβ of an aqueous solution of 5 mol) and stirring for 10 minutes, the mixture was separated and extracted with ethyl acetate. The separated organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and treated with activated carbon at the same time. The filtrate filtered through Cellai I was concentrated under reduced pressure, and the residue was recrystallized from 700 ml of hexanoyl to give 4-1.υdecylpyrrole-2-trichloroacetylpyrrole (103.4 gH8).

Yield 68% m, p,: 80.5-81.5°C IR (KBr) cm-': 3340.29202850
．． 1635,84α 75O NMR (CDCβ3) δ: 0.88 (3H, t)1.
26 (20H, m), 1.55 (2H, m)
2.4.8 (2H, t), 6.96 (1, H, m)7.
18 (IH, m) 9.24 (IH, broads) 9 0 Synthesis Example 69 Synthesis of 4-tridecylpyrrole-2-carboxylic acid 2°3 dihydroxy-propyl ester 4-obtained in Synthesis Example 68
Tridecyl-2-trichloroacetylvirol 70.0
g (0.18 mol) in 700 ml of tetrahydrofuran
70.0 g (0.53 mol) of 1,2-isopropylidene glycerol and 3.5 g of sodium hydride (60% oil dispersion) were added thereto, and the mixture was stirred at room temperature for 1 hour. An aqueous potassium carbonate solution was added to separate the layers, and the mixture was extracted with ethyl acetate. The organic layers obtained were combined, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate/hexane-115) to obtain 68.5 g of an ester. The crystals were mixed with 1.0β of tetrahydrofuran and 1.0% of water. Dissolved in Oj2, concentrated hydrochloric acid 0
．． After adding 3β and reacting at room temperature for 15 hours, under water cooling,
The mixture was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting crystals were recrystallized from a mixed solvent of ethyl acetate (200 mA) and hexano (50 mff) to obtain 4-tridecyl. Pyrrole-2-carboxylic acid 2,3-dihydroxypropyl ester 54.4 g
was obtained as white crystals.

Yield 84% m, p,: 80-82°C TR (KBr) cm-': 3400,3350295
0.2870.1695 N M R (CD C (13) δ: 0.88 (
3H, t) 1.26 (20H, m), 1.55
(2H, m)2.44 (2H,t), 2.52 (
IH,t).

3.02 (], H, d), 3.76 (2H, m
).

4.00 (I H, m), 4. ．． 35 (2
H, m) 6.76 (LH, m), 6.80 (LH
, m).

9.16 (IH, broad s) Synthesis Example 70 Synthesis of 1-tetradecylpyrrole-3-carboxylic acid ethyl ester Dry 0.84 g (21 mmol) of thorium hydride (60% oil disversion 12 version) Dimethylformamide (DMF) 15 mjl! In addition to this, 2.78% of pyrrole-3-carboxylic acid ethyl ester was added under water cooling.
g (20 mmol) in small portions.

After stirring for 10 minutes at room temperature, bromotetradecane 6665
g (24 mmol) was added dropwise over water cooling. After stirring at room temperature for 3.5 hours, 30 mβ of water was added and extracted with 70 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine 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 (1720 to 1/10),
6.33 g of 1-tetradecylpyrrole-3-carboxylic acid ethyl ester was obtained as white crystals.

Yield 89.0% m, p,: 32-33°C IR (KBr) cm-': 2940, 2860°17
00.154O NMR (CD C12s) δ: o, ss (3H,
t) 1.25 (22H, m), 1.35 (3H,
t).

1.77 (2H, m), 3.85 (2Ht
)4.26 (2H,q), 6.55 (2H
, m) 7.2 7 (I Hm) Synthesis Example 71 ■-Synthesis of Tetradecylpyrrole-3-carboxylic acid 5.43 g (15,3 2.58 g (61.3 mmol) of 95% I.lium hydroxide in 100 mβ of ethanol and 4.5 mmol of water. Om
Add to the mixed solution of R and heat under reflux for 5 hours. Ethanol was distilled off under reduced pressure, leaving 100m7 of water! was added, acidified with concentrated hydrochloric acid, and the precipitated crystals were dissolved in 70 mI ethyl acetate.
! and 5 Q m j2.

This extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from hexane to yield 3.76 g of 1-tetradecylpyrrole-3-carboxylic acid as white crystals. Obtained. Yield 79.
9% m, p,: 66-67°C 3 4 TR (KBr) cm-': 2930, 2860°1
650, 1545 NMR (CDCj23) δ: 0.88 (3
H, t) 1.25 (22H, m>, 1.7
4- (2H, m).

3.86 (2H,t), 6.60 (2H
,,m).

7.36 (IH, m) Synthesis Examples 72 to 95 According to Synthesis Example 70 or 71 above, the compounds shown in Table 4 below were synthesized.

Table 5 6 Synthesis Example 96 Synthesis of 1-hexyl-5-tridecylpyrrole-3 carboxylic acid 60% hydrogenated I.lium in oil 360 mg (9,
After washing with hexane, 0 mmol) was added to a mixture of 8 mρ of dimethylformamide and 2 mβ of dimethylformamide, and 1.0 mmol of 5-tridecylpyrrole-3-carboxylic acid was added.
Add 20 g (4.1 mmol) and stir at room temperature for 1 hour. To this reaction solution was added 1.50 g of hexyl bromide (9,1
mmol) and stirred at room temperature for 48 hours, acidified with aqueous hydrochloric acid, extracted with ethyl acetate, washed with water,
Ethanol 20'mβ was added to the residue obtained by distilling off the solvent under reduced pressure.
Add 10 mA of water and 1.0 g of caustic potash. The mixture was heated under reflux for 24 hours, cooled, acidified with an aqueous hydrochloric acid solution, and extracted with ethyl acetate.

An 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 obtain 1.20 g of the pure target product (yield 78%).
) was obtained.

m, p,: 44-46℃ IR (KBr) cm': 2940, 1660゜N M
R(CD C123)δ: 0.88 (6H, m)
1.29 (26H, m), 1.66 (4
, H, m).

2.47 (2H, t), 3.78 (2H,
t) 6.34 (LH, d), 7.29 (LH, d
) Synthesis Examples 97 to 100 According to the method of Synthesis Example 96, the compounds shown in Table 5 below were synthesized.

9 00 Synthesis Example 101 Synthesis of 4-methoxyvinylpyrrole-2-carboxylic acid methyl ester Methoxymethyl I.Riphenylphosphonium chloride 2
00 g (0.58 mol) in tetrahydrofuran solution 1.
5j! Then, under water cooling and stirring, a solution of lithium diisopropylamide in tetrahydrofuran (2.01 molar concentration) 220
mIl (0.44 mol) was added dropwise, and after stirring at room temperature for 1 hour, 400 ml of a solution of 57.6 g (0.38 mol) of 4-formylvirol-2-carboxylic acid methyl ester in tetrahydrofuran was added 5 ml under water cooling again. It was added dropwise at a temperature of ~8°C. After reacting at room temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure was subjected to silica gel column chromatography (eluent: ethyl acetate/
Hexane-1/4) was used to obtain 4-methoxyvinylpyrrole-2-carboxylic acid methyl ester 34.4.8 as a mixture of E-form and 7-form.

Yield 50% NMR (CDCβ3) δ: 3.63 (s, E form) 3.7
6 (s, 7 bodies), 3.85 (3H, s).

5.20 (d, 7 bodies, J=6.5Hz) 5.68 (d,
E body, J””13Hz) 6.01 (d, 7 bodies).

6.82 (2H, m), 7.00 (I
H, m).

7.17 (IH, m') 9.10 (LH, broad s) Synthesis example 10
2 Synthesis of (2-methoxycarbonylpyrrole)-4-acetaldehyde 4-methoxyvinylpyrrole-2- obtained in Synthesis Example 101
Carboxylic acid methyl ester 13.0g (72 mmol)
280mβ of isopropyl alcohol solution and 280j of water
! 1.13 g of para-toluenesulfonic acid was added to the mixed solution, and the mixture was heated under reflux for 3.5 hours. After cooling, saturated brine was added and extracted with ethyl acetate. The organic layer was washed with brine containing a small amount of sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column 01-020 chromatography (eluent: ethyl acetate/hexane-2).
15) to obtain 7.50 g of (2-methoxycarbonylpyrrole)-4-acetaldehyde as an oily substance. Yield 62% JR (KBr) cm-': 33
40,1720°1695.1220.77O NMR (CDCβ3) δ: 3.57 (2H, t)3.
85 (3H, s), 6.81 (IH, m
).

6.88 (IH, m).

9.26 (LH, broad, s).

9.72 (IH, d) Synthesis Example 103 Synthesis of 4-(2-tridecenyl)virol-2-carboxylic acid methyl ester 14.1 g (60 mmol) of undecyl bromide and 15.7 g (60 mmol) of triphenylphosphine After heating under reflux in xylene for 15 hours, the 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 undecyltriphenylbosbonium bromide. This bromide compound was dissolved in 200 m# of tetrahydrofuran, and 20 mj2 (32 mmol) of a 15% n-butyllithium hexane solution (1.6 molar concentration) was added dropwise while stirring while cooling with water. After 10 minutes of stirring, the product obtained in Synthesis Example 102 was cooled with water (
A tetrahydrofuran solution (6j!) containing 2.17 g (13 mmol) of 4-acetaldehyde (2-methoxycarbonylpyrrole) was added dropwise, and the reaction was continued for an additional 30 minutes. Water was added and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate/hexane-1/10) to obtain 4(2-
3.41 g of (tridecenyl)virol-2-carboxylic acid methyl ester were obtained as an oily substance. Yield 86% IR (Neat) cm-': 334.0.2940
2860.1690.77O NMR<CDCl13) δ:0.88 (3H,t
) 1.26 (16H, m), 2.00 2.2
003 04 (2H, m), 3.17. 3.22 (2Hd)
, 3.83 (3H,s) , 5.50
(2Hm), 6.74 (2H,m).

8.95 (LH, broad s) Synthesis Example 10
4 Synthesis of 1(1-1-lysocenyl)pyrrole-2-carboxylic acid Ethanol solution of 3.41 g (11 mmol) of 4-(2-1-lysocenyl)pyrrole-2-carboxylic acid methyl ester obtained in Synthesis Example 103 3 Add 1.00 g (24%) of sodium hydroxide (95%) to a mixed solution of Qm6 and 20 mβ of water.
mmol) and heated under reflux for 1 hour. After cooling, it is made acidic by adding an aqueous hydrochloric acid solution, and the precipitated crystals are filtered, thoroughly washed with water, and then recrystallized from a mixed solvent of methanol and water to obtain 4-(2-tridecenyl)pyrrole-2-carboxylic acid 2. 80 g was obtained as white crystals. Yield 86% m, p,
:126-129℃ IR(KBr)am-': 3400, 2940℃28
70.1695 NMR (CDCβ3) δ: 0.88 (3H,t)1
．． 26 (16H, m), 2.00. 2.
09(24(,m), 3.20. 3.24
(2H, m).

5.50 (2H, m), 6.80 (LH, m)
6.88 (LH, m) 9.05 (IH', broads) Example (1) Lipid-lowering effect in normal-fed rats The lipid-lowering effect of the compound of the present invention on rats was measured by the following method.

5-6 Wistar male rats weighing 140-150g
One group of animals was given 10 mg, 3 Q mg or 4 Q mg of the test compound suspended in 0.5% carboxymethyl cellulose (CMC) or 0.05% Tween 80 solution.
It was orally administered at 0 mg/kg body weight once a day for 5 or 8 days. Blood was collected 3 hours after the final administration of the test compound, and triglyceride (TG) in the serum was measured by an enzymatic method using Neuclinch TG, a kit for measuring neutral fats manufactured by Diatron.
Chop) 05 06 is a cholesterol quantification kit manufactured by Kyowa Medesox Co., Ltd.
The amount was measured by an enzymatic method using Determiner TC5.

The results were determined as the percentage decrease in TG and Chop levels relative to the Control I/Role group that was not given the test compound. The results are shown in Table 6 below (the compound results correspond to Table 1).

Table 07 08 (2) Lipid-lowering effect in hamsters fed a high-cholesterol diet A diet containing 1% cholesterol and 0.5% sodium cholate (high-cholesterol diet) was fed to 6-week-old golden male hamsters (6 animals per group) for 5 days. Donate, 0.05
0.1,0% test compound suspended in pween 80
．． 3.1.3. Alternatively, it was orally administered at a dose of 10 mg/kg body weight once a day for 5 days at the same time as the high-cholesterol diet.

Blood was collected 2.5 hours after the final administration of the test compound, and serum triglyceride levels (TG) and cholesterol levels (C
hol) was measured in the same manner as in (1) above. The average serum lipid value (A) of the test compound non-administration group and the average serum lipid value (B) of the test compound administration group were calculated, and the following formula (a) was calculated.
The respective reduction rates of TG and Chol were determined. The results are shown in Table 7 below (the shaded compounds correspond to Table 1).

Table (3) Cholesterol lowering effect in rabbits on high cholesterol diet New Sealant White Rabbit (SPF) 0.5
The mice were raised for 14 days while being fed % cholesterol-containing feed at a rate of 100 g per day to create a high cholesterol state, and then divided into a control group and a test compound administration group. Control group (
8 birds) were fed the same diet for an additional 7 days. The test compound administration group received 0.1, 0.3 or 1 mg/kg of the test compound suspended in 0.005% Tween 80 at the same time as the same feed.
g body weight, once a day for 7 days (8 birds in each group)
. Blood was collected 6 hours after the final administration of the test compound, and serum C.
The hol value was measured in the same manner as in (1) or (2) above. Average serum Chol value of test compound-free group (A
') and the mean serum Chal value of the test compound administration group (B'
) was calculated, and the rate of decrease was determined using the following formula (b). The results are shown in Table 8 below (compound levels correspond to Table 1).

Table (CM'C) 5-week-old SD suspended in sodium aqueous solution
The test substance was orally administered to 5 male and 5 female rats of strain 1. After that, they were kept normally and observed for one week for general symptoms, changes in body weight, and the presence or absence of death. As a result of the above acute toxicity test using compound level 14 in Table 1, no deaths were observed even at a dose of 2 g/kg body weight.

〔Effect of the invention〕

The therapeutic agent for hyperlipidemia of the present invention exhibits an effective lowering effect on triglyceride and cholesterol in serum, and has excellent lowering effect even in small amounts, especially when triglyceride and cholesterol in serum exceed normal values. It is an extremely useful drug in the pharmaceutical industry, as it exhibits excellent efficacy and is highly safe.

(4) Acute toxicity test

Claims (6)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (I) (In the formula, R^1 represents a hydrogen atom, an alkyl group or an alkenyl group having 5 to 25 carbon atoms. , R^2 is a hydrogen atom, a phenyl group, or a carbon number of 1 to 1 which may have a substituent
It represents 10 alkyl groups, and R^3 represents a hydrogen atom, an alkyl group having 5 to 25 carbon atoms, or an alkenyl group. ) A therapeutic agent for hyperlipidemia containing a pyrrole carboxylic acid derivative or a pharmaceutically acceptable salt thereof. (2) The 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,
2. The group according to claim 1, which is a carbamoyl group, an alkylcarbonylamino group having 1 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 therapeutic agent for hyperlipidemia containing a pyrrole carboxylic acid derivative or a pharmaceutically acceptable salt thereof. (3) A therapeutic agent for hyperlipidemia containing the 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) The pyrrole carboxylic acid derivative or its pharmaceutically acceptable derivative according to claim 1 or 2, wherein R^2 is a hydrogen atom, a phenyl group, or an alkyl group having 1 to 4 carbon atoms which may have a substituent. A therapeutic agent for hyperlipidemia containing salts. (5) A therapeutic agent for hyperlipidemia containing the pyrrolecarboxylic acid or a pharmaceutically acceptable salt thereof according to claim 1, wherein R^3 is a hydrogen atom. (6) A therapeutic agent for hyperlipidemia containing the pyrrole carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R^3 is an alkyl group or alkenyl group having 10 to 16 carbon atoms.