JPH0314560A - Pyrrole derivative - 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 pyrrole derivative or a pharmaceutically acceptable salt thereof, which has an excellent lipid-lowering effect and is useful as a therapeutic agent for hyperlipidemia. .

[Problems to be solved by conventional technology and invention]

It has long been known that lipid metabolism abnormalities in blood lipids, such as triglycerides and cholesterol, cause an abnormal increase or imbalance in blood lipids, causing arteriosclerosis, and eventually leading to ischemic heart disease such as angina pectoris and myocardial infarction. It is thought to be a major risk factor for disease or cerebral infarction.

Conventionally, clo7igrate drugs, nicotinic acid, and its derivatives have been mainly used as drugs for hyperlipidemia, and although these drugs lower blood triglycerides, they have a weak effect on cholesterol. In recent years, probucol, which has a new structure, and cholesteramine, 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. The present invention has been completed based on the discovery that this is known.

That is, the gist of the present invention is to develop a drug that is more powerful and has fewer side effects in terms of dosage, safety, and scope of application, although drugs that lower the sterol of the following general formula (1) are already used in clinical settings. is desired. 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.
There is still no drug that satisfies these requirements.

[Means for solving problems]

As a result of extensive research to solve the above problems, the present inventors have found that a specific pyrrole derivative or its pharmaceutically acceptable salt simultaneously lowers blood triglyceride and cholesterol more strongly than conventional drugs. Excellent lipid-lowering effect H , where n is /
-/0 represents an integer. ) or a pharmaceutically acceptable salt thereof.

To explain the present invention below, the pyrrole derivative of the present invention is represented by the general formula (1).

Examples of the aromatic ring represented by Ar in the formula include benzene, naphthalene, pyridine, furan, thiophene, virol, and imidazole.

Substituents that may be substituted on this aromatic ring include a halogen atom, a hydroxyl group, a C, -C, alkoxy group, an amino group, a C, to C4 alkylthio group, a nitro group, a cyano group, a phenyl group. Substituents such as these are compounds in which the other substituent is substituted at the 7-position or S-position that are not adjacent to each other on the pyrrole ring, or 100, H is substituted at the 2-position of the pyrrole ring, and the d-position is substituted with the other substituent. Or! Compounds in which the other substituent is substituted in that position are preferred.

Specific examples of such compounds of the present invention include the following compounds.

Table l H (V) Pharmaceutically acceptable salts of the above pyrrole derivatives include:
Examples include inorganic metal salts such as sodium, potassium, calcium, and magnesium, and salts of inorganic amines.

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

Method/: (II) (IV) H (Vl) H (■) [In the above formula, R1 is A r - (CH2)rn-X
-(CH2)represents rL-1. However, A in R1
r, X, m and n are as defined above. ] That is, pyrrole-3-carboxylic acid ethyl ester (
I[) and a suitable acyl chloride (II[) in the presence of a Lewis acid such as aluminum chloride, stannic chloride or boron trifluoride diethyl ether complex are commonly used in a 7-Riedel-Crafts reaction with benzene, carbon disulfide, etc. When the reaction is carried out in a solvent within a temperature range of -/0°C to the boiling point of the solvent, 5-acylupyrrole-3-carboxylic acid ethyl ester (IV) is obtained. Next, add the ketone group,
After conversion to diteoketal (V) by a commonly used method, it can be converted to monosubstituted pyrrole-J monocarboxylic acid ethyl ester (Vl) by heating and refluxing it with excess Raney nickel in a solvent, preferably ethanol. .

If the above compound (Vl) is hydrolyzed in a conventional manner, the general formula (
The compound of the present invention represented by (2) is obtained.

The above compound (I[) can be prepared by known methods described in the literature (for example, Canadian Journal of Che
mistry, Tazamaki, 2/27,/9gO).

Method 2: (n) (■) (VIII (■) [In the above formula, R1 is Ar (CHz)m-X-(CHJ
H−+1, R2 is Ar1(CH2)m−X−
(Represents CHJH-2-. However, A in R1 and R2
r, X, m and. is already defined. ) That is, the &-7 silvirole-3-carboxylic acid ethyl ester (IV) obtained as described in the above method is treated with a suitable reducing agent, preferably sodium borohydride, in an alcoholic solvent such as methanol or ethanol. Reduction is carried out to obtain the alcohol compound (VI[D).If this compound is heated under reflux for an appropriate period of time with an excess of caustic soda or a base such as caustic potassium in an alcoholic solvent such as ethanol or ethylene glycol containing water, the carboxyl compound (VI[D) is obtained. At the same time as the acid ethyl ester is hydrolyzed, a dehydration reaction occurs to obtain the above compound (IX).This compound (IX) is dissolved in an appropriate solvent (for example, an alcohol such as ethanol, an organic acid such as acetic acid, etc.), By performing catalytic hydrogenation using palladium-black, palladium-carbon, or platinum as catalysts, the compound of the present invention represented by general formula (X) can be easily obtained.

Method 3: H α0 H ~D [In the above formula, R1 is as defined above. That is, when the above compound (1) obtained by reacting pyrrole with methyl or ethylmagnesium bromide is reacted with an appropriate acyl chloride (1) Y in an inert solvent such as diethyl ether or tetrahydrofuran, co-acyl birol is obtained. CM) is obtained. This compound CX[I
) to the normal Wolff-Ki
By carrying out the reduction, a co-substituted pyrrole in which the ketone group has been reduced can be obtained in high yield. Again in an inert solvent such as diethyl ether or tetrahydrofuran, Compound 01) is reacted with Grignard reagent and then ethyl chlorocarbonate (5) is added and the reaction is carried out at a temperature between 0'C and the boiling point of the solvent to form 3-substituted pyrrole-21. Carboxylic acid ethyl ester (6) is obtained. If this is hydrolyzed using a conventional method, the compound of the present invention represented by the general formula (9) can be obtained.

Method II: R1CH2 R'CH2 [In the above formula, R1 is as defined above. ] Namely, viro-cocarboxylic acid methyl ester (2) and a suitable acyl chloride (1)? : 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 or carbon disulfide, within a temperature range of -io°C to the boiling point of the solvent. If the reaction is carried out, daacylpyrrole-cocarboxylic acid methyl ester (M) is obtained. The keto group can then be converted to the substituted pyrrole-cocarboxylic acid methyl ester (XIX) by a suitable reduction reaction, such as diporane reduction or Raney nickel reduction of the dithioketal described in Methods. When this compound cGx:+'g is hydrolyzed in a conventional manner, the general formula (
The compound of the present invention represented by 9) is obtained.

Method! = (If) (X)G) α■) α■) [In the above formula, R is Ar-(CH2)m-X-(CH2)
Z represents a leaving group such as a halogen atom or a sulfonate group. However, Ar, X, m (f[) and the appropriate halide compound (9)) in R may be replaced with sodium hydride, metallic potassium, sodium ethoxy? When the reaction is carried out in the presence of a base such as ether, tetrahydrofuran, dimethylformamide or the like within a temperature range of -/0 DEG C. to the boiling point of the solvent, N-monosubstituted pyrrolecarboxylic acid ethyl ester 20 is obtained. If this compound (■■■) is hydrolyzed by a conventional method, the compound of the present invention represented by the general formula (XXI) can be obtained.

In addition, carboxylic acid derivative R1CO2H (Rl is Ar
1 (CH2)m-x- (CH2)n-1'
a: Represent. However, Ar, X, m and n in L and R' are already defined. ] have been described in some literature, but they can be easily synthesized, for example, according to the following general synthesis method.

EtOzC-(CH2). -2-Co,
Et hydrolysis■. . 2o1(.H!)n-2-Co2Et"" reduction (X
XV) HO-(CH2)n-I COzEt(XXVI) Mesylated MsO-(CH2)n-1-CO2Et(Ki Co., Ltd.) Coupling A r- (CH2)m=X 4(cHz)n-
1-CO2Et! Kengome (Ogi■) Ar-(CH2)m-X-(CH2)n-1-CC)2
H(XXIX) Y Nawachi, alkylene dicarboxylic acid ethyl ester■
The obtained compound (XXV) is obtained by reacting with an equivalent amount of caustic acid and only one of the esters is hydrolyzed. , hydroxyester (XXVI)'a- is obtained. This compound (XXVI) is mesylated or substituted with a leaving group such as chloro or bro7, and then treated with phenol or alcohol in a solvent such as tetrahydrone or dimethylformamide in the presence of a base such as sodium hydride or sodium ethoxide. If the reaction is carried out, a compound (surface) can be obtained in high yield. Next, if hydrolysis is carried out in a conventional manner, the general formula (1) is obtained.
This can lead to a carboxylic acid derivative represented by

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 tablets, granules, powders, capsules, etc., which contain the compound of the present invention and conventional excipients, such as glucose, lactose, corn starch, or manniol.
- Excipients such as hydroxybutylcellulose (RP)
C), a binder such as carboxymethylcellulose (CMC), a disintegrating agent such as starch or gelatin powder, a lubricant such as Merck, magnesium stearate, etc., and the like.

When administered orally, the dosage of the compounds of the present invention may be /Omg-/077 per day for a given person, more preferably /θθ
η ~ 1, which can be administered once or in 3 divided doses.

〔Example〕

Next, the present invention will be further explained in detail by showing examples. still,
Examples 1 to 12 show the synthesis of raw materials and intermediates in the process of synthesizing the compounds of the present invention, and Examples 1 to 1 show the synthesis of the compounds of the present invention.

Synthesis Example 1 Synthesis of Bimelic Acid Diethyl Ester Bimelic acid/ro. o 0 0 o. t. y mol) was dissolved in 8 tl of ethanol, thionyl chloride/'IOrd (/.93 mol) was added under water cooling, and the mixture was heated under reflux for 3 hours. After cooling the reaction solution, ethanol was distilled off under reduced pressure.
Ethyl acetate was added and the mixture was washed with saturated sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 9 g of bimelic acid diethyl ester. /21Yf, quantitatively obtained as an oil.

IR(Neat)crIL”: 2qlo, tq3
oNMR (COCI3) δ: l. x3(6H,t),
/． 311(2H,m)l,Aj(IIH,m),
x. 29(lIH,t)g. /3 (tIH, q) Synthesis Example Synthesis of Copimelic Acid Monoethyl Ester Bimelic acid diethyl ester lθ de. θ
09 (0.!; 0 mol) a-ethanol, dissolved in θO1, cooled to about -s°C, and diluted with θ7O caustic soda aqueous solution.
θθT! 1 ton was dropped. After standing for 12 hours at about 0.degree. C., ethanol was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The aqueous layer was made acidic with 4&N hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform the residue! Dissolved in O, about 5
After standing for 3 hours at C, the precipitated crystals were filtered and the F solution was distilled off under reduced pressure to obtain bimelic acid monoethyl ester rr. rsy
(yield 62%) was obtained as an oil.

I R (Neat)cWL-”: ,? uθ
0,2930,/730,/ClO NMR (CDCI 3) δ: l. 3o(sH,m)
,/． xO(<zH,m)x. 3/(lIH, m), 1
1. //C. 2H, q) Synthesis Example 3 Synthesis of 7-hydroxyhebutanoic acid ethyl ester Sodium borohydride ii, lH (o.sqs mol)
14 g of boron trifluoride diethyl ether complex was added to a suspension of 60 θd of tetrahydrone run under water cooling.
A solution of g. S r y
A solution of (θ.3/l mole) in tetrahydrofuran 200 was added dropwise and stirred for 1 hour.

Water and 113 g (θ.J//mol) of potassium carbonate were added to the reaction solution, and the aqueous layer and organic layer were separated. The aqueous layer was extracted with ethyl acetate, combined with the previous organic layer, and washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue obtained was purified by 5-muth chromatography (developed with ethyl acetate:hexane=/:S) to give 7-1. Hydroxyhebutanoic acid ethyl ester 33.
01.g (yield: 61%) was obtained as an oil.

IR (Neat) 3”: 31100, Kota!70
, 17.30NMR (CDCI 3) δ: t.
s7 (.7H, t), l. 3r(lIH,m)
t. sg(ttH,m), x. 32 (2H.t)
3.6 da(.zH,t), g. //(2H,q) Synthesis Example DA Synthesis of 7-Mesyloxyhebutanoic Acid Ethyl Ester 7-Hydroxyhebutanoic acid ethyl ester obtained in Synthesis Example 3 2! ; 11 (/1111 mmol) and triethylamine, 24 ml (//, 9 mmol) of dichloromethane JOOm! Add methanesulfonyl chloride to the solution under water cooling.
lItnt (/72 mmol) was added dropwise. The reaction solution was returned to room temperature and stirred for an hour, then washed successively with dilute hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7-mesyloxyhebutanoic acid ethyl ester 3b. 31If/(yield 100%) was obtained as an oil.

IR (Neat) a "' NMR (CDCI,) δ : 2 deda 0, / 73 θ, /. 3 jO // 70 28 2
)z. xlI(lIH,m), x. ．． yt(xH, t
)3.02(3H,s),<<,/z(2H,q)g. =6(koH,t) Synthesis example! Synthesis of 7-7enoxyhbutanoic acid 60% sodium hydride 6.3θy (ist mmol)
To a suspension of 20-dimethylformamide, phenol/3. ! ;1,11(/lIdamimol)
A solution of dimethylformamide 60 was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for lθ minutes to obtain 7-mesyloxyhebutanoic acid ethyl ester obtained in Synthesis Example D. 36. ．． 3'll
( / ! mmol) of dimethylformamide 60
One solution was added dropwise to the reaction solution under water cooling. After dropping, stir at room temperature for 3 hours, add water, extract with ethyl acetate, wash with water,
Dry over anhydrous magnesium sulfate, remove the solvent under reduced pressure,
got oil. Ethanol 3θO1I1t for this oil
Add caustic soda / /. ! ; A 7θ monoaqueous solution containing coi (λirg mmol) yal- was added, and the mixture was heated under reflux for 3 hours. After cooling, ethanol was distilled off, acidified with dilute 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 2 g of 7-phenoxyhebutanoic acid. /'A I (rate 9 g%) was obtained as an oil.

I R(Neat)3': ,? Q Oθ,
Code Sθ, /7/ONMR (CDC I.) δ
: / ,＜＜． 7 (&H, m), l. ru(<<
H. m) Co. ．． )7(2H, t), e. 0/(2H.
t) 6.9z (3H, m), 7. xt(2H, m
) Synthesis Example 6 Synthesis of r-(7-7enoxyheptanoyl)pyrrole-3-carboxylic acid ethyl ester Pyrrole-3-carboxylic acid ethyl ester t3. Synthesis example in benzene go-solution of roy (/θθ mmol)! 7-7 enoxyhbutanoic acid λ co. Add 22 g (ioo mmol) of 7-7 enoxyhepmenoyl chloride synthesized by a conventional method, and then add stannic chloride/7.3 rrt (/j
0 mm IJ mol) was added dropwise. After dropping, stir at room temperature for 2 hours, add water, extract with ethyl acetate, wash with water,
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. Purified by silica gel column chromatography (developed with ethyl acetate:hexane=/:S),
5-(7-7 enoxyheptanoyl)hyrol-3-carboxylic acid ethyl ester t! f. 3! r I (yield %) was obtained.

IR(KBr)cWL-':. y2to, tq2o,
t7θOIAA θ NMR (CDCl3δ): /. 3t,(.)H,
t), 7. B(+H,m)l,7x(<zH,m),
ko, rz(.zH,t)3. Light (2H, t), G. 30
(koH, q)6. , r7 (.7H.m), 7.2g (
3H,m) 7.3<<(/H,m) Example l Synthesis of s-(7-phenoxyheptyl)hyro-3-carboxylic acid r-(7-phenoxyhenotanoyl)hyro-3 obtained in Synthesis Example 6 -carboxylic acid ethyl ester/! ．． Oθy(
．． Sodium borohydride/. =9I1( .7 lImiIJ
After reacting at room temperature for 76 hours, ethanol was distilled off under reduced pressure, water was added and extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate to quantitatively obtain the alcohol. To this, 200 parts of diethylene glycol, 1 part of water and 0.0 parts of caustic potash are added. ieH( i
s r (IJ mol) was added and heated at /70°C for 2 hours. After cooling, water was added, 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 an oil. Ethanol 60-1 and lθ% palladium-carbon 6θOη were added to this, catalytic reduction was carried out for 2 hours, and after removing the catalyst, silica gel column chromatography (ethyl acetate:hexane=/:
3) and purified by recrystallization with hexane to yield Yuichi (7-7 enoxyheptyl)hyro-3-carvone flll3. IIgI (yield 34t%) was obtained.

m. p. : 109-///℃ IR(KBr)cnL-': JQ! θ,2
9'IO, /1.70NMR (CDCI delta: / .
．． ? 7 (t.H, m), /. &O(.2H.m)/
．． 77 (2H, m), Ko. tx(.2H.t)3.9
2(2H,t), 6.37C/H,. 5) a. 6
7 (3H, m), 7. ．． ? O(jH,m) Synthesis Example 7 Synthesis of t-(j-phenoxyglobil)hyro-3-carboxylic acid ethyl ester dithioethylene chemer 1-(,?-F) obtained in the same manner as Synthesis Example 6 /ki7
/'Robionil) Hiro-J monocarboxylic acid ethyl ester/,! Boron trifluoride diethyl ether complex 2- was added to an acetic acid lSd solution of O Ii (.!r.2 .7 mmol) and ethanedithiol 2-, and the mixture was allowed to react at room temperature for 1/2 hours, and then water was added. Extract with ethyl acetate and! After washing with % caustic soda aqueous solution and saturated saline,
It was dried with anhydrous magnesium sulfate. After removing the solvent under reduced pressure,
The residue was purified by silica gel column chromatography (developed with ethyl acetate:hexane=i:io) to obtain r-(
．． 7-phenoxyprobyl) virol-J monocarboxylic acid ethyl ester cythioethylenecheme A//. I got 901.

IR(KBr)cIrL-”: 33so, 2q/o
,/bzaONMR (CDCI g) δ: t. 33(
3H, t), Co. g6 (koH, t)3. pO(<zH
, m), <'. 06(!H, t)p, 2g(2H, t
), 6.6g (/H, m)A. A'g (.7H, m)
,? ．． ．． ．． 7/(JH,m) Synthesis Example s-(j-7enoxypropyl)hyrol-3-carboxylic acid ethyl ester Synthesis Example 7 s-(.7-phenoxypropyl)hyrol-3 -carboxylic acid ethyl ester dithioethylene ketal l. The mixture was stirred for 1 hour at room temperature in a Raney nickel solution containing 3 mmol of ethanol and Raney nickel. Using Celite, Raney nickel was filtered through F, washed thoroughly with ethanol, and the solvent was distilled off under reduced pressure.
It was purified by silica gel column chromatography (developed with ethyl acetate:hexane=1:1O) to obtain ter(3-phenoxyprobyl)hyrol-3-carboxylic acid ethyl ester/. /t# (yield g/%)'a' was obtained.

IR(KBr)c+n'': 3.yxO, .t
q. yO, /61rONMR(CDCI3)δ:
/． 33 (3H, t), 2.0? (xH, m) Yu.
gθ(2H,t), 3.9ta(,2H,t)ta. 2g
(2H.q), x. 37(lH,m)6. Ta/
(.?H,m), 7.2? (..7H,m) Example Synthesis of s-(3-phenoxyprobyl)hyrol-3-carboxylic acid s-(.7-7enoxyprobyl)hyrol-3-carboxylic acid obtained in Synthesis Example g Ethyl ester c/3. 9
(q.2t mmol) in ethanol'IOml solution! An aqueous solution containing 707η (16.7 mmol) of caustic soda/Omtf was added, and the mixture was heated under reflux for 7 hours. Ethanol was distilled off from the reaction solution, 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. This crystal was subjected to silica gel column chromatography (developed with methanol and chloroform = 1:1). ! )nH to yield j-(3-phenoxyprobyl)pyrrole-3-carboxylic acid 67θηC. bs%) I got it.

m. p. /07-/09℃ IR (KBr) cm': . 7 aso,
Jも3θ,/l,rONMR (CDCI 3)δ:u
．． /θ(2H, m),! ．． 75 (jH, t)
3. ? ? (2H, t), x. ．． 7.7 (/H.m)
x. 90 (3H, m), 7. Koji (JH, m
) Synthesis example? Synthesis of x-(7-phenoxyheptanoyl)virol Ether solution of ethylmagnesium bromide (3M
)/jffi7! Biok. 1.0 2 9 ('
Gradually add 3 mmol of I and stir for a further 30 minutes at room temperature. Synthesis example of this solution under water cooling! An ether solution of 7-phenoxyheptanoyl chloride synthesized by a conventional method was added dropwise to the obtained 7-phenoxyheptanoic acid e4lIg (20 mmol). This solution was heated under reflux for 2 hours, then added to a mixture of aqueous ammonium chloride and ice, and the aqueous layer was 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 = 1:6). enoxyhebutanoyl)pyrrole 3.6q y (yield 6
g%) was obtained.

IR(KBr)c++t': ,? Joθ, 2ta s
o, it, qs NMR (CDCI 3) δ: l. z
r(zH,m),/,7A(lIH,m)2.7g
(2H.t), 3. Dej(2H,t)x. 27(lH,
m), x. L2 (4'H, m) 7.02 (lHlm),
7. ．． 27 (2H, m)? ．． QO( /H, broa
dS) Synthesis Example IO Synthesis of s-(7-phenoxyheptyl)virol s-(7-phenoxyheptanoyl)virol obtained in Synthesis Example ta 3.6 tags (t Ja 4 mmol), /00
% hydrazine hydrate/6i (.y cot mmol) and causticide. OIi (/mmol Al) was heated in diethylene glycol 70°C at 200°C for /,j hours. The reaction solution is returned to room temperature, water is added, and extracted with ether. After washing with water, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

The resulting residue was subjected to silica gel column chromatography (
Purification with ethyl acetate:hexane=/:g) to give co(7-7enoxyhbutyl)pyrrole3. ll&
(yield g 9%) was obtained.

IR(KBr)c+n-': 3 q sθ, 29
j? ONMR (CDCI,)δ: l. +6(AH
, m), / . 63(2H,m)l. 7t (2H,
m), x. bo( .2I{ .t )3. yr(.
zi-i, m), jJ/(/H, m)6, l3(zH,
m), A. AA(/H,m)Cl(3H,m), 7,.
2, r(uH, m)7. ? θ(/H, broad S
) Synthesis Example ll r-(7-7enoxyheptyl)hyro-? - Synthesis of carboxylic acid ethyl ester x-(7-phenoxyheptyl)virol obtained in Synthesis Example A/0. 7. //y (/co./mimoles) was dissolved in 20 mm of anhydrous ether, and 6 m (/ff mmol) of an ether solution of ethylmagnesium bromide (about .?M) was added at room temperature, and the mixture was heated under reflux for 0 minutes. After returning this reaction solution to room temperature, 2.3 d (2 L) of ethyl chlorocarbonate was added.
/ mmol) was added, heated under reflux again for 30 minutes, returned to room temperature, poured into ice water containing ammonium chloride, and extracted with ethyl acetate. This extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (developed with ethyl acetate:hexane=l:/0). ;
-(7-phenoxyheptyl)virol-cocarboxylic acid ethyl ester/. Qg (yield 36%) was obtained.

IR(KBr)cm': . 33/0 ,2930
．． 1470NMR (CDCI 3) δ: /. 3
+(3H,t),/. ．． 7? (AH,m)/,A2
(koH, m), z47 (.2H, m)2. A/(2H,
t), 3. TalI (koH.t) 11.3IC . 2H
, CI), t. 9x(lH,m)A. g2(/H,
m), A. 92(.?H,m)? ．． ．． 2A'(2H, m
), g. 9k(/HbroadS)? Example 3 Synthesis of s-(7-phenoxyheptel)pyrrole-cocarboxylic acid Obtained in Synthesis Example/l! -(7-phenoxyheptyl)hyro-cocarboxylic acid ethyl ester co. o i y
(t..t i mmol) was dissolved in 30 ml of ethanol, and added with caustic soda & oomy (t 2
．． Add a water solution containing kme (h■ mol) and heat to reflux at λ. I did it for S hours. A portion of ethanol was distilled off from this reaction solution, acidified with an aqueous hydrochloric acid solution, and then extracted with ethyl acetate. This extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developed with ethyl acetate:hexane=l:3). -(kufuenoxyhefter)hiro-λ monocarboxylic acid 820? (Yield 6ta%) was obtained.

m. p, : ff lI”−4 7°CIR(KBr
) cIrL-': y3oo, 2qtio, /t
boisoo NMR (CDCI,) δ: 8+3 (xH*m), 84! (2H, m)/. 77 (2H+m), x,
6a(2H,t)3. qs(2H, t), A.
0/(/H*rrx)6. The? (3H
#rn), 197(/H,m)γ,2A(xH+r
n), f. 95 (/}{, broad S) Synthesis of p-(7-phenoxyheptanoyl)hyrol-2-carboxylic acid methyl ester Virol-co-carboxylic acid methyl ester co. ! Synthesis example in benzene/Ortdl solution of r Of (20 mmol)! 7 obtained with
-Phenoxyhebutanoic acid←. q tay (2 0
Kufuenoxyhebutanoyl chloride IJ l' synthesized by a conventional method is added from 3.0 mmol of stannic chloride under ice-cooling. ! rrttl (.70.SIJ moles) was added dropwise. After reacting at room temperature for an hour, water was added and extracted with ethyl acetate.

After washing this extract with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Noyl) hyro-cocarboxylic acid methyl ester s. tr 7 y (
Yield lIII%) was obtained.

IP. (KBr)an': 3JOO, 29gθ, lkuθ3/6 5θ NMR (CDCl,)δ:8z7(pH, m),/
．． qr(lI■4, m), 2.77(2H,t),
．． 7. ff(3}Ls), 3. q! ;( 2H
．． t), +. 9l (3H, m), q. ．． tq(.
2H, m),? ．． ．． 2q ( lH, m), K. T months (
l}{,rn), q. ro(/H, broad S
) Example ←-(7-phinoxyheptanoyl) obtained in Example 2 Synthesis of synthesis of di-(7-7enoxyhephthyl)hyrol-cocarboxylic acid
Viro-cocarboxylic acid methyl ester 2.1! ;
? f (L? 2 mmol) toethanedithiol 2
．． 20ml of acetic acid. Boron trifluoride-diether ether complex co. After adding powdered powder and leaving it overnight at room temperature, water was added and extracted with ethyl acetate, washed with caseinida aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=
/:4') to produce Ku(kufuenoxyhebutanoyl)pyrrole-2-carboxylic acid methyl ester dithioethylene ketal. s. 7y (yield/00
%) was obtained. Dissolve this in 1 liter of ethanol and 30 rttl of Raney nickel! was added and stirred vigorously at room temperature overnight.

After passing through Raney nickel using Celite, the residue was thoroughly washed with ethanol, and the solvent was distilled off under reduced pressure.

The obtained crude crystals of xi-(7-phenoxyhebutyl)virol-co-carboxylic acid methyl ester were dissolved in ethanol i.
0 0 ml, add caustic soda tooη (20
Add 2 orrtl of an aqueous solution of
I did it for an hour. A portion of ethanol was distilled off from this reaction solution, acidified with an 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 crude crystals were recrystallized from ethyl acetate θat to obtain pure tx. 'i-(7-phenoxyhebutel)virol-121carboxylic acid/. 6.7y (62% yield) was obtained.

m. p, : / II A ~ / II g. 30G
IR(KBr)c1rL': . 7 <t oθ,
2930, / Otsu90NMR (CDCI, +UMEo-d
e) δ: /. ya(AH,m)/. ．． t. 2(
2H+ m), 872 (2Hpm) Yu. +O(.zH
,t),3. g9(2H, t)b. bs( 2
H, m), g. ．． ry(3H, m)7.27(xH,
m), h. 6θ(tH.broadS)? Example! 't-(s-p-chlorophenoxypentyl)pyrrole-3-carboxylic acid in synthetic oil toX sodium hydride! 20119(/.7
mmol) was added to a mixture of 72 ml of dimethylformamide and 3 at of dimethyl sulfoxide, and further added virol-3-carboxylic acid ethyl ester/. ! θF ( /
0. g mmol) and stirred at room temperature until foaming stops. To this reaction solution, 3.602 (/3 mol) of 5-(p-chlorophenoxy)pentyl bromide was added, and the mixture was stirred at room temperature overnight, then an aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. This extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate:hexane=/:/
(expanded with ;l) and purified by i − (s − p
-chlorophenoxypentyl)hyrol-3-carboxylic acid ethyl ester x. So y (yield 69X) was obtained. To this was added ethanol ti-oWtl, 20 ml of water and caustic potash/. 2 j-r (.zx.3 mlJ mole)
was added and heated under reflux for g hours. Ethanol was distilled off from this reaction solution, acidified with an aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Wash with crystalline hexane obtained by distilling off the solvent under reduced pressure L, /-
(jp-chlorophenoxypentyl)pyrrolecarboxylic acid At (yield: 7%) was obtained.

m, p, : / 3! r ~/3 A. ! ;'
C■R(KBr)cIrL': 2qho,iAss
NMR (CDCI,)δ:8lIg(2H #
rn), t. r2(aHT rn)3.9l(
lIH. m), x, x/(.zH.m)A. gl(2H
, d), 7.23 (2H.d)? ．． JA (/H, m) Examples 6 to 27 The compounds shown in Table 2 below were synthesized according to the methods described in the examples above.

Triglyceride (TO) in Table 1 was measured using the enzymatic method using Neuclintech TO, a neutral fat measurement kit manufactured by Diatron, and cholesterol (Chol) was measured using Determiner, a cholesterol quantification kit manufactured by Kyowa Medex. TC! The amount was measured by an enzymatic method using r.

The results are T compared to the control group that does not receive the test compound.
It was determined by the rate of decrease (X) in the amount of O and the amount of Chol. The results are shown in Table 3 below.

Test Example The hypolipidemic effect of the compound of the present invention was measured by the following method.

Weight itto~l! 0? The Wista male rat s~
Group of 6 animals, 0. The test compound suspended in S% carboxymethylcellulose (CMC) solution was added to 309 (or /0η)/K2 for 7 days, g days (or 3
Administered daily.

Blood was collected 3 hours after the final administration of the test compound, and the serum table 3 It is useful.

Claims (1)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
(I) (In the formula, Ar represents an aromatic ring which may be unsubstituted or may have a substituent, X represents an oxygen atom, a sulfur atom or a methylene group, m represents an integer from 0 to 5, and n is 1
Represents an integer between ~10. ) or a pharmaceutically acceptable salt thereof.