JPH06116239A - 7-substituted-3, 5-dihydroxyhept-6-ynoic acid compounds - Google Patents

Abstract

PURPOSE:To provide the novel compound useful as a HMG-CoA reductase inhibitor, especially as therapeutic agents for hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis. CONSTITUTION:A compound of formula I [X ring is (substituted)phenyl, five to six membered heteroaryl ring; R<1>, R<2> are H, 1-8C alkyl, 3-7C cycloalkyl, 1-3C alkoxy, n-, i-, sec- or t-butoxy, CF3, OCF3, F, Cl, Br, phenyl, phenoxyl, OH, etc., or R<1> and R<2> together form CH=CH-CH=CH, when substituted at the o-positions; R<3> is H, 1-8C alkyl, 2-6C alkenyl, 3-7C cycloalkyl, group of formula II (R<7> is H, alkyl, alkoxy, phenoxy, OH, etc.), etc.; Z is group of formula III or IV (R<11> is H, 1-3C alkyl), etc.], e.g. (E)-3, 5-dihydroxy-7-[2'- cyclopropyl-4'-(4'-fluorophenyl)quinolin-3'-yl]-6-heptynoic acid.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel 7-substituted-3,5-dihydroxyhepta-6-ynoic acids having a triple bond, and a process for producing the same. The compound of the present invention is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is one of the antihyperlipidemic agents, and particularly, hypercholesterolemia, hyperlipoproteinemia and atheroma. It can be used to treat atherosclerosis.

[0002]

BACKGROUND OF THE INVENTION The natural substance mevinolin specifically inhibits HMG-CoA reductase, which plays a central role as a rate-limiting enzyme in cholesterol biosynthesis in vivo. Therefore, it is very important for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Many synthetic analogs have been synthesized based on the natural substance mevinolin, and it has been reported that they have HMG-CoA reductase inhibitory activity [Drug
sof the Future, 12,437 (1987)]. The mevalonate chain portion (3,5-dihydroxyheptanoic acid chain or 3,5-dihydroxy-6-heptenoic acid chain) is an essential partial structure for these synthetic compounds to exhibit enzyme inhibitory activity.
These compounds have a structure in which an appropriate lipophilic group is substituted at the 7-position of the mevalonic acid chain portion, and the strength of activity depends on this.

Of these, the following examples are already known, especially for mevalonic acid derivatives substituted with ortho-fused bicyclic pyridyl groups. (Quinoline ring) U.S. Pat. No. 4,761,419 (published '88 8/2),
European Published Patent No. 304063 ('89 2/22 published), European Patent No.
356788 (Published '90 3/7), U.S. Patent No. 4923681 ('90
5/8 published), West German Patent No. 3905908 ('90 9/6 published), US Patent No. 5011930 ('91 4/30 published). (Pyrazolo [3,4-b] pyridine ring) US Patent No. 4822799 ('89 4/18 published), European Published Patent No. 339358 ('89 11/2
Published), Australian Patent No. 8933335 ('89 11/2
Published), US Pat. No. 5,024,999 ('91 6/18 published). (Thieno [2,3-b] pyridine ring) US Pat. No. 5026698
('91 6/25 published), European Published Patent No. 367235 ('90 5 /
9 published). Most of these compounds are 7-substituted-3,5-dihydroxyheptanoic acid derivatives and (E) 7-substituted-3,5-
It is a dihydroxy-6-heptenoic acid derivative. On the other hand, 7
Little is known so far regarding -substituted-3,5-dihydroxy-6-heptinoic acid derivatives, and to the best of our knowledge, 7-phenyl substituted derivatives [J. Med.
Chem., 28,3,347 (1985)], 7-aryl or heteroaryl substituted derivative (triply substituted ethenyl or biphenyl, pyridyl, pyrimidyl, pyridazyl, pyrrolyl)
The example of [West German Patent No. 3832570 ('90 3/29 published)] is only known.

The present inventors have substituted the 7-position with an ortho-fused bicyclic pyridyl group such as quinolyl, pyrazolo [3,4-b] pyridyl and thieno [2,3-b] pyridyl which have not been known so far. It was found that the thus-obtained 3,5-dihydroxy-6-heptic acid derivative has a strong HMG-CoA reductase inhibitory activity, and completed the present invention. Further, compounds represented by the general formulas [I-1], [I-2], [I-3], [I-4] and [I-5] are described in European Patent No. 304063 ('89 2/22). Publication), European Patent 339358 ('89 11/2 publication) and European Patent 367235 ('90 5/9 publication) and are useful as synthetic intermediates for HMG-CoA reductase inhibitors.

The novel mevalonolactone derivative relating to the present invention is a compound represented by the following general formula [1].

[0006]

The present invention has the general formula [I]

[0007]

[Chemical 19]

[Wherein X ring is phenyl, substituted phenyl or
Represents a 5-6 membered heteroaryl, R¹And R²Each is German
Vertically hydrogen, C₁-C₈Alkyl, C₃-C₇Cycloalkyl, C₁-C
₃Alkoxy, n-butoxy, i-butoxy, sec-butoxy
Ci, tert-butoxy, R²⁰R^{twenty one}N- (R²⁰, R^{twenty one}Are independent
Hydrogen or C₁-C₃Means alkyl. ), Trifluoro
Methyl, trifluoromethoxy, difluoromethoxy,
Fluoro, chloro, bromo, phenyl, phenoxy,
Benzyloxy, hydroxy, trimethylsilyloxy,
Diphenyl-tert-butylsilyloxy, hydroxymethy
Or -O (CH ₂)_lOR^{twenty two}(R^{twenty two}Is hydrogen or C₁-C₃Means alkyl
Taste, l means 1, 2 or 3. ) Means;
R when in ortho position with each other¹And R²Together-C
H = CH-CH = CH- or means methylenedioxy; R³Is water
Elementary, C₁-C₈Alkyl, C₂-C₆Alkenyl, C₃-C₇Cycloa
Rukiru, C_Five-C₇Cycloalkenyl or

[0009]

[Chemical 20]

(R ⁷ is hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₃ alkylthio, chloro, bromo, fluoro, chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, Means trichloromethoxy, difluoromethoxy, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, or hydroxymethyl);

[0011]

[Chemical 21]

1-and C ₁ -C ₃ alkyl substituted by 0, 1 or 2 of C ₁ -C ₃ alkyl; Z
_{-Q-CH 2 -W-CH 2} -CO 2 R 12 is

[0013]

[Chemical formula 22]

(Q means -C (O)-, -C (OR ¹³ ) ₂ -or -CH (OH)-, and W is -C (O)-, -C (OR ¹³ ) ₂ -or -C (R ¹¹ ) (0H)-, R ¹¹ represents hydrogen or C ₁ -C ₃ alkyl, R ¹² represents hydrogen, and R ¹⁴ (R ¹⁴ is chemically or physiologically hydrolyzed. Alkyl of the resulting alkyl ester moiety, NHR ²³ R ²⁴ R ²⁵ (R ²³ R ²⁴ R
²⁵ means hydrogen or C ₁ -C ₄ alkyl. ), Sodium, potassium or 1/2 calcium. ), And R ¹³ independently represents primary or secondary C ₁ -C ₆ alkyl, or two R ^{13 taken} together are — (CH ₂ ) ₂ — or — (C
H ₂ ) _3- , R ¹⁵ and R ¹⁶ independently represent hydrogen or C ₁ -C ₃ alkyl, or R ¹⁵ and R ^{16 taken} together are-(CH ₂ ) ₂ -or
-(CH ₂ ) _3- means. )].

Further, these compounds are at least 1 or 2
May have at least 2 asymmetric carbon atoms, each having at least 2
There may also be 4 to 4 optical isomers. The compound represented by the general formula [I] includes all of these optical isomers and all of these mixtures.
The substituent Z of the compound represented by the general formula [I] of the present invention
Among the compounds whose carboxylic acid derivative moiety (-CO ₂ R ¹² ) of is a carboxylic acid derivative moiety other than that defined by -CO ₂ R ¹² , the carboxylic acid (-CO ₂ R ¹²
_A compound in which the ₂ R ¹² moiety is —CO ₂ H) is a compound equivalent to the compound of the present invention.

The mevalonolactone represented by the general formula [I] which is the compound of the present invention is synthesized according to the following reaction formula. In the reaction formula, R ¹ , R ² , R ³ , R ¹² and the X ring are the substituents defined in the compound represented by the above general formula [I], and R ³¹ is a C ₁ -C ₄ lower group. Alkyl, ie methyl, ethyl,
n-propyl, i-propyl, t-butyl, i-butyl, sec-butyl or n-butyl, or benzyl optionally substituted with methyl, methoxy, nitro or chloro,
Hal represents chloro, bromo and iodo. Further, THP represents a tetrahydropyranyl group and TBDMS represents a tert-butyldimethylsilyl group.

[Synthesis Method of Compound [I-4]]

[0018]

[Chemical formula 23]

The compound represented by the general formula [I-4] can be synthesized, for example, by coupling the halogen compound represented by the general formula [XIV] with the 6-heptic acid derivative [XIII].

The 6-heptic acid derivative [XIII] is a commercially available trimethylsilylacetylene (compound [XXI]).
Can be synthesized using as a starting material. That is, the compound [XX
I] according to a known method ((WV Komarov et al., J. Gen.
hem. USSR, 36 , 920 (1966)), a magnesium compound is prepared and reacted with dimethylformamide to give an aldehyde (compound [XX]). Hereinafter, according to the usual mevalonate compound synthesis method (Suzuki et al., Japanese Patent Publication No. 1-279866, G. W.
ess et al., Tetrahedron Lett., 31 , 2545, (1990)), and reacts with the dianion of ethyl acetoacetate to give a ketoester (compound [XIX]). According to a conventional method, for example, in order to selectively obtain a syn-form, a dihydroxy form (compound [XVIII]) is obtained by a low-temperature reduction method using diethylmethoxyborane and sodium borohydride. ) Is obtained. If a protecting group is introduced into the hydroxyl group (for example, in the case of acetonide, 2,2-dimethoxypropane and triethylamine in methylene chloride), the compound [XVII] can be obtained. Furthermore, the compound [XIII] can be obtained by deprotecting the trimethylsilyl group using a desilylation agent such as hydrofluoric acid or tetrabutylammonium fluoride.

The halogen compound [XIV] is obtained by hydrolyzing a carboxylic acid ester (compound [XVI]) under basic conditions, for example, potassium hydroxide or sodium hydroxide in dioxane to give a carboxylic acid derivative (compound [XV]). It is then obtained by irradiating it with light using iodosobenzene diacetate in carbon tetrachloride and iodine. Among carboxylic acid esters (compounds [XVI]) as starting materials, quinoline compounds are disclosed in EP-304063 publication, pyrazolo [3,4-b] pyridine compounds are disclosed in EP-339358 publication, and thieno [2 A synthesis method of a [3-b] pyridine compound is described in EP-367235.

The coupling reaction between the halogen compound [XIV] and the 6-heptynoic acid derivative [XIII] proceeds with a transition metal catalyst under basic conditions.

As the base, organic bases such as t-butylamine, diethylamine, triethylamine and DBU, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydrogen carbonate and sodium ethoxide are used.

As the metal catalyst, tetrakistriphenylphosphine palladium, bistriphenylphosphine dichloropalladium, palladium acetate, chloroallyl palladium dimer, tetrakistritri, in the presence of a Group II metal catalyst such as copper iodide or copper trifluoromethanesulfonate. A transition metal catalyst such as phenylphosphine nickel or tetrakistriphenylphosphine platinum is used. Preferably,
Palladium acetate, palladium chloride, and chloroallyl palladium dimer.

The reaction proceeds without solvent or, if necessary, in an organic solvent such as benzene, tetrahydrofuran, acetonitrile and dimethylformamide.

In this reaction, it is desirable to add a reaction aid if necessary. Examples of the auxiliary agent include organic bases such as t-butylamine, diethylamine, triethylamine and DBU, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydrogencarbonate and sodium ethoxide, fluoride ions, triethylphosphite and triphenylphosphine. Can be mentioned.

[Synthesis Method of Compound [I-6]]

[0028]

[Chemical formula 24]

Examples of the compound represented by the general formula [I-6] include compounds represented by the general formula [VII] from Tetrahedron L
acetyl.carboxylic acid [V] obtained according to the method described in ett. 36 , 3769 (1972).

Among the compounds represented by the general formula [VII],
The quinoline compound (compound [VIIa]) is disclosed in EP-304063, the pyrazolo [3,4-b] pyridine compound (compound [VIIb]) is disclosed in EP-339358, and thieno [2,3-
b) Pyridine compounds (compound [VIIc]) are disclosed in EP-367235, each of which discloses a synthetic method.

The dibromoolefin (compound [VI]) is obtained from the aldehyde (compound [VII]) by using Ph ₃ P and CBr ₄ in methylene chloride in the presence of zinc powder.
The dibromoolefin (compound [VI]) can be derived to the corresponding acetylenecarboxylic acid (compound [V]) using CO ₂ gas in tetrahydrofuran in the presence of a strong base such as n-butyllithium. Acetylenecarboxylic acid (compound [V]) is esterified by a method known per se. For example, the corresponding acetylene carboxylic acid ester (compound [IV]) can be synthesized using hydrochloric acid / ethanol, isobutene / dichloromethane, benzyl chloride, potassium carbonate / DMF and the like. The acetylene carboxylic acid ester (compound [IV]) is reduced by using, for example, a metal hydride such as lithium aluminum hydride, diisobutylaluminum hydride or Vitride to give hydroxymethylacetylene (compound [II]
I]). Hydroxymethylacetylene (compound [III]) is converted to acetylene aldehyde (compound [II]) by oxidation with, for example, pyridinium chlorochromate in dichloromethane. Compound [II] can be converted to compound [I-6] by a known method, for example, by condensing acetoacetic acid ester such as ethyl acetoacetate in tetrahydrofuran in the presence of a strong base such as sodium n-butyllithium hydride.

[Synthesis Method of Compound [I-7]]

[0033]

[Chemical 25]

The compound represented by the general formula [I-7] is, for example, a compound represented by the general formula [II] from Tetrahedron Le
tt. 26 , 2951 (1985), and is synthesized via the compound [VIII] obtained.

The compound [X] can be synthesized by adding sodium cyanide to a compound [II] in a mixed solvent of hydrochloric acid / acetonitrile to obtain cyanohydrin, and adding dihydropyran to this. The compound [VIII] can be obtained by condensing the compound [X] and the γ-halo-β-hydroxybutanoic acid ester [IX] in tetrahydrofuran in the presence of a strong base such as n-butyllithium. Compound [VIII] is a compound of tetrahydropyranyl group and te in a mixed solvent of acetic acid / water / tetrahydrofuran.
The compound [I-7] can be derived by hydrolyzing the rt-butyldimethylsilyl group.

Further, as the compound represented by the general formula [I-7], the compound represented by the general formula [I-1] is prepared by using activated manganese dioxide in an organic solvent such as ether, tetrahydrofuran or benzene. It can also be obtained by selectively oxidizing the hydroxyl group at the 5-position.

[Synthesis Method of Compound [I-8]]

[0038]

[Chemical formula 26]

The compound represented by the general formula [I-8] can be obtained, for example, from an acetylcarboxylic acid represented by the general formula [V] in EP
-475627 is synthesized according to the method described in the official gazette.
Acetylcarboxylic acid (compound [V]) can be prepared by a known method,
For example, SOCl ₂ / Et ₃ N / CH ₂ Cl ₂ or (COCl) ₂ -Py / CH ₂ Cl ₂ is used to synthesize acetylcarboxylic acid chloride (compound (XI
I]). Compound [XII] is HN (Me) OMe-Et ₃ N / C
It can be derivatized to methoxymethylamide (compound [XI]) by using H ₂ Cl ₂ . Compound [XI] is a known method,
For example, compound [I-8] can be derived by condensing acetoacetic acid ester such as ethyl acetoacetate in tetrahydrofuran in the presence of a strong base such as sodium n-butyllithium hydride.

[Synthesis Method of Compound [I-1]]

[0041]

[Chemical 27]

The compound represented by the compound [I-1] can be produced from the compound [I-6], [I-7] or [I-8].

(Step A) Compounds [I-6], [I-7]
Alternatively, it is a reaction of reducing [I-8] with various reducing agents. For example, sodium borohydride, sodium cyanoborohydride, zinc borohydride, disiamylborne, diborane, t-butylaminoborane, pyridine-borane complex , Dicyclohexylborane, thexylborane (thexy
lborane), 9-borabic 3.3.1 Nonane
yclo 3.3.1 nonane), diisopinocamphenylborane (d
iisopinocamphen-yl borane), lithium tri-sec-
The carbonyl group is reduced using butylborohydride or the like to give the corresponding dihydroxycarboxylic acid ester [I-
It is a reaction leading to 1]. This reaction is carried out in a solvent selected from hydrocarbons, halogenated hydrocarbons, C ₁ -C ₄ alcohols, ethers and mixed solvents thereof at −100 ° C.
It is carried out at 50 ° C., preferably −78 ° C. to 30 ° C. Furthermore, J. Am
er. Chem. Soc., 105 , 593 (1983), using trialkylboranes such as tri-n-butylborane, triethylborane and sodium borohydride at low temperature. See also Tetrahedron Letters, 28, 155 (1987).
By using an alkoxydialkylborane, such as methoxydiethylborane or ethoxydiethylborane, and sodium borohydride as described in
An erythro body having a biologically stronger activity can be preferentially obtained. This reaction uses a mixed solvent of C ₁ -C ₄ alcohols and tetrahydrofuran at −80 ° C. to −50.
C. Preferably, it can be carried out at -72 to -68.degree.

Further, the compound represented by the general formula [I-1] can be obtained by deprotecting the compound represented by the general formula [I-4] under an appropriate acidic condition. This reaction is carried out, for example, in a C ₁ -C ₄ alcohol such as methanol or ethanol, a halogenated hydrocarbon such as methylene chloride, or an ether such as tetrahydrofuran in an acid catalyst such as hydrogen chloride or trifluoroacetic acid. It can be carried out at −50 ° C. to 50 ° C., preferably −15 to 25 ° C.

[Compound [I-2], [I-3] or [I
-5] Synthesis Method]

[0046]

[Chemical 28]

(Step B) This is a step of ester hydrolysis, using equimolar amounts of a base, preferably potassium hydroxide or sodium hydroxide, in a mixed solvent of methanol or ethanol and water at 10 ° C to 25 ° C. It can be performed at ° C. The free acid obtained here can be salted with a suitable base.

(Step C) Free hydroxy acid [I-2]
Is a step of producing mevalonolactone by dehydration reaction, and can be performed by removing water produced by heating under reflux in benzene or toluene, or by further adding an appropriate dehydrating agent such as molecular sieves. Further, a lactonizing agent such as carbodiimide, preferably water-soluble carbodiimide such as N-cyclohexyl-in anhydrous methylene chloride.
N '-[2'-(methylmorpholinium) ethyl] carbodiimide p-toluenesulfonate was used at 10 ° C.
To 35 ° C, preferably 20 ° C to 25 ° C.

[Synthesis Method of Compounds [XIV], [XV] and [XVI]]

[0050]

[Chemical 29]

General formula [I-1], [I-2] or [I-
The compound represented by 5] can be converted to a compound [XIV] having a corresponding double bond by reducing the triple bond site.

As this reaction, a method using metal sodium or potassium in liquid ammonia (Birch reduction)
Alternatively, a method of performing catalytic hydrogenation in the presence of a metal catalyst such as palladium or platinum, or a method of using a metal hydrogen complex compound such as lithium aluminum hydride may be applied depending on the case. Similarly, the compound [I-4] can be derived into the compound [XV] and the compound [I-3] can be derived into the compound [XVI].

As specific examples of the compound of the present invention, the compounds listed in Tables 1 to 4 including the compounds described in Examples are one example of the compound of the present invention. In the formula, the substituent Z is shown in Table 1, and the other substituents are shown in Tables 2 to 4, respectively.

In the following notation of substituents, each symbol means the following substituents. That is, n- is normal and i-
Is iso, sec- is secondary, tert- is tertiary, c- is cyclo, Me is methyl, Et is ethyl,
Pr is propyl, Bu is butyl, Pent is pentyl, He
x means hexyl and Ph means phenyl.

[0055]

[Chemical 30]

[0056]

[Chemical 31]

Table 2

[Chemical 32]

[0058]

[Table 1]

[0059]

[Table 2]

[0060]

[Table 3] Table 2 (continued) ──────────────────────────── R ^4a R ^5a R ¹ R ² R ³ R ^6a ──────────────────────────── H H H H i-Pr H H H 4-Cl H i-Pr H H H H H c-Pr H H H 4-Cl H c-Pr H H H 4-F H c-Pr H H H 4-Me H c-Pr H H H 4-n-Pent H c-Pr H H H 4- c-Pr H c-Pr H H H 4-c-Hex H c-Pr H H H 4-MeO H c-Pr H H H 4-n-BuO H c-Pr H H H 4-NMe H c- Pr H H H 4-NHEt H c-Pr H H H 4-CF ₃ H c-Pr H H H 4-CF ₃ O H c-Pr H H H 4-Cl H c-Pr H H H 4-Br H c-Pr H H H 4-PhO H c-Pr H H H 4-PhCH ₂ O H c-Pr H H H 4-OH H c-Pr H H H 4-OCH ₂ CH ₂ OH H c-Pr H H H 3,4-CH = CH-CH = CH- H c-Pr H ─────────────────────────────

[0061]

[Table 4] Table 2 (continued) ──────────────────────────── R ^4a R ^5a R ¹ R ² R ³ R ^6a ──────────────────────────── H H 3,4-OCH ₂ O- H c-Pr H H H H H c-Pr H H H H H H H H H H H n-Pr H H H H H n-Pent H H H H H -CH = CH ₂ H H H H H -CH = CHCH ₃ H H H H H 3-c -Pentenyl H H H H H Ph H H H H H 4-Me-Ph H H H H H 4-MeO-Ph H H H H H 4-MeS-Ph H H H H H 4-Cl-Ph H H H H H 4-CF ₃ -Ph H H H H H 4-PhO-Ph H H H H H 4-OH-Ph H H H H H 4-CH ₂ OH-Ph H H H H H PhCH ₂ -H H H H H PhCH (Me) H 6-n-Pent H 4-F H c-Pr H 6-c-Pr H 4-F H c-Pr H 6-n-BuO H 4-F H c-Pr H ────────────────────────────

[0062]

[Table 5] Table 2 (continued) ──────────────────────────── R ^4a R ^5a R ¹ R ² R ³ R ^6a ──────────────────────────── 6-CF ₃ H 4-F H c-Pr H 6-F H 4-F H c -Pr H 6-Ph H 4-F H c-Pr H 6-OH H 4-F H c-Pr H 6-HOCH ₂ H 4-F H c-Pr H 6-MeOCH ₂ H 4-F H c -Pr H 6,7-OCH ₂ O- H 4-F H c-Pr H ─────────────────────────────

Table 3

[Chemical 33]

[0064]

[Table 6]

[0065]

[Table 7]

[0066]

[Table 8]

[0067]

[Table 9]

[0068]

[Table 10]

[0069]

[Table 11]

[0070]

[Table 12]

[0071]

[Table 13] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── Me 1-Et 4-FH c-Pr Me 1-i-Pr 4-FH c-Pr Me 1- (4- Cl-Ph) 4-FH c-Pr Me 1- (4-Me-Ph) 4-FH c-Pr Me 1- (4-Me0-Ph) 4-FH c-Pr Me 1- (4-F- Ph) 4-FH c-Pr Me 1-Ph 4-FH c-Pr Me 2-Ph 4-FH c-Pr Me 1-CH ₂ Ph 4-FH c-Pr Me 1- (2'-pyridyl) 4 -FH c-Pr Et 1-Me 4-FH c-Pr Et 1-Et 4-FH c-Pr Et 1-i-Pr 4-FH c-Pr Et 1-Ph 4-FH c-Pr c-Pr 1-Me 4-FH c-Pr c-Pr 1-Et 4-FH c-Pr c-Pr 1-i-Pr 4-FH c-Pr c-Pr 1-Ph 4-FH c-Pr i-Pr 1-Me 4-FH c-Pr i-Pr 2-Me 4-FH c-Pr i-Pr 1-Et 4-FH c-Pr i-Pr 1-i-Pr 4-FH c-Pr ─── ───────────────────────

[0072]

[Table 14] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── i-Pr 1-tert-Bu 4-FH c-Pr i-Pr 2-Ph 4-FH c-Pr i- Pr 1-Ph 4-FH c-Pr tert-Bu 1-Me 4-FH c-Pr tert-Bu 2-Me 4-FH c-Pr tert-Bu 1-Et 4-FH c-Pr tert-Bu 1 -i-Pr 4-FH c-Pr tert-Bu 1-tert-Bu 4-FH c-Pr tert-Bu 1-Ph 4-FH c-Pr Ph 1-Et 4-FH c-Pr Ph 1-i -Pr 4-FH c-Pr Ph 1-Ph 4-FH c-Pr 4-Cl-Ph 1-Me 4-FH c-Pr 4-Cl-Ph 1-Et 4-FH c-Pr 4-Cl- Ph 1-Ph 4-FH c-Pr 4-Me-Ph 1-Me 4-FH c-Pr 4-MeO-Ph 1-Me 4-FH c-Pr H 1-Ph 4-Cl H c-Pr H 1-Me 4-Cl H c-Pr H 1-Et 4-Cl H c-Pr H 1-i-Pr 4-Cl H c-Pr H 1-tert-Bu 4-Cl H c-Pr ─── ───────────────────────

[0073]

[Table 15] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── H 1-Ph 4-Cl H c-Pr H 1- (4-Cl-Ph) 4-Cl H c-Pr H 1- (4-Me-Ph) 4-Cl H c-Pr H 1- (4-MeO-Ph) 4-Cl H c-Pr H 1- (4-F-Ph) 4-Cl H c- Pr H 1-CH ₂ Ph 4-Cl H c-Pr Me 1-Me 4-Cl H c-Pr Me 1-Et 4-Cl H c-Pr Me 1-i-Pr 4-Cl H c-Pr Me 1- (4-Cl-Ph) 4-Cl H c-Pr Me 1- (4-Me-Ph) 4-Cl H c-Pr Me 1- (4-MeO-Ph) 4-Cl H c-Pr Me 1- (4-F-Ph) 4-Cl H c-Pr Me 1-tert-Bu 4-Cl H c-Pr Me 1-Ph 4-Cl H c-Pr Me 1-CH ₂ Ph 4-Cl H c-Pr Me 1- (2'-pyridyl) 4-Cl H c-Pr Et 1-Me 4-Cl H c-Pr Et 1-Et 4-Cl H c-Pr Et 1-i-Pr 4- Cl H c-Pr Et 1-Ph 4-Cl H c-Pr c-Pr 1-Me 4-Cl H c-Pr ────────────────────── ─────

[0074]

[Table 16] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── c-Pr 1-Et 4-Cl H c-Pr c-Pr 1-i-Pr 4-Cl H c-Pr c-Pr 1-tert-Bu 4-Cl H c-Pr i-Pr 1-Me 4-Cl H c-Pr i-Pr 1-Et 4-Cl H c-Pr i-Pr 1-i-Pr 4 -Cl H c-Pr i-Pr 1-tert-Bu 4-Cl H c-Pr i-Pr 1-Ph 4-Cl H c-Pr tert-Bu 1-Me 4-Cl H c-Pr tert-Bu 1-Et 4-Cl H c-Pr tert-Bu 1-i-Pr 4-Cl H c-Pr tert-Bu 1-tert-Bu 4-Cl H c-Pr tert-Bu 1-Ph 4-Cl H c-Pr Ph 1-Et 4-Cl H c-Pr Ph 1-i-Pr 4-Cl H c-Pr Ph 1-tert-Bu 4-Cl H c-Pr Ph 1-Ph 4-Cl H c- Pr 4-Cl-Ph 1-Me 4-Cl H c-Pr 4-Cl-Ph 1-Et 4-Cl H c-Pr 4-Cl-Ph 1-Ph 4-Cl H c-Pr 4-Me- Ph 1-Me 4-Cl H c-Pr 4-MeO-Ph 1-Me 4-Cl H c-Pr ───────────────────────── ──

[0075]

[Table 17] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── H 1-Ph HH c-Pr H 1-Me HH c-Pr H 1-Et HH c-Pr H 1-i -Pr HH c-Pr H 1-tert-Bu HH c-Pr H 1- (4-Cl-Ph) HH c-Pr H 1- (4-Me-Ph) HH c-Pr H 1- (4- MeO-Ph) HH c-Pr H 1- (4-F-Ph) HH c-Pr H 1-CH ₂ Ph HH c-Pr Me 1-Me HH c-Pr Me 1-Et HH c-Pr Me 1 -i-Pr HH c-Pr Me 1- (4-Cl-Ph) HH c-Pr Me 1- (4-Me-Ph) HH c-Pr Me 1- (4-MeO-Ph) HH c-Pr Me 1- (4-F-Ph) HH c-Pr Me 1-tert-Bu HH c-Pr Me 1-Ph HH c-Pr Me 1-CH ₂ Ph HH c-Pr Me 1- (2'-pyridyl ) HH c-Pr Et 1-Me HH c-Pr ──────────────────────────

[0076]

[Table 18] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── Et 1-Et HH c-Pr Et 1-i-Pr HH c-Pr Et 1-Ph HH c-Pr c- Pr 1-Me HH c-Pr c-Pr 1-Et HH c-Pr c-Pr 1-i-Pr HH c-Pr c-Pr 1-tert-Bu HH c-Pr i-Pr 1-Me HH c -Pr i-Pr 1-Et HH c-Pr i-Pr 1-i-Pr HH c-Pr i-Pr 1-tert-Bu HH c-Pr i-Pr 1-Ph HH c-Pr tert-Bu 1 -Me HH c-Pr tert-Bu 1-Et HH c-Pr tert-Bu 1-i-Pr HH c-Pr tert-Bu 1-tert-Bu HH c-Pr tert-Bu 1-Ph HH c-Pr Ph 1-Et HH c-Pr Ph 1-i-Pr HH c-Pr Ph 1-tert-Bu HH c-Pr Ph 1-Ph HH c-Pr 4-Cl-Ph 1-Me HH c-Pr ── ────────────────────────

[0077]

[Table 19] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── 4-Cl-Ph 1-Et HH c-Pr 4-Cl-Ph 1-Ph HH c-Pr 4-Me- Ph 1-Me HH c-Pr 4-MeO-Ph 1-Me HH c-Pr n-Oct 1-Me 4-FH c-Pr MeO 1-Me 4-FH c-Pr n-BuO 1-Me 4- FH c-Pr c-Hex 1-Me 4-FH c-Pr -CH = CH ₂ 1-Me 4-FH c-Pr -CH = CHCH ₃ 1-Me 4-FH c-Pr α-naphthyl 1-Me 4-FH c-Pr β-naphthyl 1-Me 4-FH c-Pr 3-pyridyl 1-Me 4-FH c-Pr 2-thienyl 1-Me 4-FH c-Pr 2-furyl 1-Me 4- FH c-Pr F 1-Me 4-FH c-Pr Cl 1-Me 4-FH c-Pr Br 1-Me 4-FH c-Pr 4-n-Hex-Ph 1-Me 4-FH c-Pr 4-n-BuO-Ph 1-Me 4-FH c-Pr 4-MeS-Ph 1-Me 4-FH c-Pr 4-Me ₂ N-Ph 1-Me 4-FH c-Pr ──── ──────────────────────

[0078]

[Table 20] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── 4-ClCH ₂ -Ph 1-Me 4-FH c-Pr 4-CF ₃ O-Ph 1-Me 4-FH c-Pr 4-PhO-Ph 1-Me 4-FH c-Pr 4-OH-Ph 1-Me 4-FH c-Pr 4-HOCH ₂ -Ph 1-Me 4-FH c-Pr 3,4- _{OCH 2 O-Ph 1-Me} 4-FH c-Pr 4-Ph-Ph 1-Me 4-FH c-Pr PhCH = CH- 1-Me 4-FH c-Pr PhCH 2 - 1-Me 4 -FH c-Pr 4-Me- PhCH 2 - 1-Me 4-FH c-Pr 4-Cl-PhCH 2 1-Me 4-FH c-Pr PhCH (Me) - 1-Me 4-FH c-Pr _{MeOCH 2 - 1-Me 4-} FH c-Pr MeOCH 2 CH 2 - 1-Me 4-FH c-Pr Me 1-H 4-FH c-Pr Me 1-n-Hex 4-FH c-Pr Me 1 -CF ₃ 4-FH c-Pr Me 1-c-Pr 4-FH c-Pr Me 1-c-Hex 4-FH c-Pr Me 1-α-naphthyl 4-FH c-Pr Me 1-β- naphthyl 4-FH c-Pr Me 1- (3'-pyridyl) 4-FH c-Pr ───────────────────────────

[0079]

[Table 21] Table 3 (continued) ────────────────────────── R ^4b R ^5b R ¹ R ² R ³ ──── ────────────────────── Me 1- (2'-pyridyl) 4-FH c-Pr Me 1- (2'-thienyl) 4-FH c -Pr Me 1- (2'-furyl) 4-FH c-Pr Me 1- (4-MeS-Ph) 4-FH c-Pr Me 1- (4-Me ₂ N-Ph) 4-FH c- Pr Me 1- (4-ClCH ₂ -Ph) 4-FH c-Pr Me 1- (4-CF ₃ O-Ph) 4-FH c-Pr Me 1- (4-PhO-Ph) 4-FH c -Pr Me 1- (4-OH-Ph) 4-FH c-Pr Me 1- (4-HOCH ₂ -Ph) 4-FH c-Pr Me 1- (3,4-OCH ₂ O-Ph) 4 -FH c-Pr Me 1- (4-Ph-Ph) 4-FH c-Pr Me 1- (4-Me-PHCH ₂ ) 4-FH c-Pr Me 1- (4-Cl-PhCH ₂ ) 4 -FH c-Pr Me 1-PhCH (Me) 4-FH c-Pr Me 1-MeOCH _2-4 -FH c-Pr Me 1-MeOCH ₂ CH _2-4 -FH c-Pr ────── ────────────────────

Table 4

[Chemical 34]

[0081]

[Table 22]

[0082]

[Table 23]

[0083]

[Table 24]

[0084]

[Table 25]

[0085]

[Table 26]

[0086]

[Table 27]

[0087]

[Table 28]

[0088]

[Table 29]

[0089]

[Table 30]

[0090]

[Table 31]

[0091]

[Table 32]

[0092]

[Table 33]

[0093]

[Table 34]

[0094]

[Table 35]

[0095]

[Table 36]

Further, pharmacologically possible salts of these compounds,
For example, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, barium salt, and further ester such as methyl ester, ethyl ester, n-propyl ester, i-propyl ester, c
-Propyl ester, n-butyl ester, i-butyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester, i-pentyl ester, n
-Hexyl ester, n-octyl ester, ammonium salt, tetramethylammonium salt, trimethylamine salt, diethylamine salt, piperazine salt, morpholine salt, piperidine salt, olamine salt, diolamine salt, tromethamine salt and the like can be similarly synthesized.

The compound of the present invention has a high inhibitory activity on cholesterol biosynthesis using HMG-CoA reductase as a rate-determining enzyme, as shown by the test results described later, and therefore, as a lipoprotein, it has a high inhibitory activity. The amount of medium cholesterol can be suppressed or reduced. Therefore, it is useful as a therapeutic drug for hyperlipidemia, hyperlipoproteinemia, and atherosclerosis. The active ingredient can be formulated into various types depending on its administration route.

The compounds can be administered in the free acid form, or in the form of physiologically hydrolyzable and acceptable esters or lactones, or in the form of pharmaceutically acceptable salts. . The pharmaceutical composition according to the present invention comprises the compound of the present invention itself or an appropriate pharmacologically acceptable binder (hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, CMC-Ca, etc.), excipient Mix with agents (lactose, sugar, corn starch, calcium phosphate, sorbit, glycine, microcrystalline cellulose, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.), powder, Can take the form of granules, tablets or capsules,
Oral administration is preferred.

However, of course, it is not limited to this, and there is a possibility of parenteral administration. For example, suppositories using oleaginous bases such as cocoa butter, polyethylene glycol, lanolin, and fatty acid triglycerides, or liquid paraffin, white petrolatum, higher alcohols, macrogol ointment, hydrophilic ointment, aqueous gel bases, etc. Percutaneous absorption type preparations, further injections using one or more selected from polyethylene glycol, aqueous gel base, distilled water, distilled water for injection, excipients (lactose, corn starch, etc.), and ocular mucosa There is also a possibility of administration as a mucosal absorption type preparation for nasal mucosa, oral mucosa and the like.

Furthermore, the compounds according to the invention can be combined with basic anion exchange resins in a form which binds bile acids and is not absorbed in the gastrointestinal tract. When treating an adult, the dose is 0.05 to 500 mg per day,
The dose is preferably 0.5 to 50 mg and is administered 1 to 3 times a day, but the dose may be increased or decreased depending on the age, body weight, symptoms and the like.

The compounds represented by the general formulas [II] to [XI] are novel and, for example, are important intermediates for producing the compound represented by the general formula [I]. Therefore, the present invention is not limited to compounds represented by the general formula [I]
To a compound represented by [XI] and a method for producing them.

[Examples] The pharmacological test examples, synthesis examples and formulation examples of the compounds of the present invention are described below.

The present invention is not limited to these. Pharmacological Test Example Test A: In Vitro Cholesterol Biosynthesis Inhibition Test from Acetic Acid Male Wistar rats (body weight 200 to 250 g) were subjected to bile duct cannulation, and bile was released for 24 hours or more, and then in mid-dark. It was slaughtered and the liver was extracted.

Modified Knauss et al .; Kuroda, M., et.al., Bioc
According to him.Biophys.Acts, 489, 119 (1977), a liver microsome fraction and a 40-80% saturated ammonium sulfate precipitation fraction of 105000 xg supernatant were obtained. It has been confirmed that cholesterol biosynthesis is increased several to ten times by subjecting the rat to bile duct cannulation. The cholesterol biosynthesis ability was measured according to the method of Endo; Metabolism, 16, 1757 (1979).

That is, 1 mM ATP, 6 mM Glutatione, 0.2
mM ^[2-14 C] sodium acetate (0.1 [mu] Ci), the reaction solution 200 containing microsomes 0.1 mg, the supernatant fraction 1.0mg
After reacting μl with purified water or 4 μl of the test drug dissolved in dimethylsulfoixde (DMSO) at 37 ° C. for 2 hours,
15% ethanolic potassium hydroxide (EtOH-KOH) 1 ml
Was added for 1 hour at 75 ° C., and the unsaponifiable lipid was extracted with petroleum ether, and the radioactivity was measured.

The inhibitory activity was expressed as the concentration (IC ₅₀ ) at which the radioactivity incorporated into the unsaponifiable lipid was inhibited by 50%. Test B: Cholesterol biosynthesis inhibition test by cultured cell line Human hepatoma cells (Hep G2) 37 in Dulbecco's modified Eagle (DME) medium containing 10% fetal bovine serum (FBS)
Twelve cells subcultured for more than 5 passages in the presence of 5% CO _{2 at} ℃
Lipoprotein-deficient serum prepared by ultracentrifugation after being plated on a well plate and allowed to confluent under the same conditions (about 7 days).
(LpDS) was replaced with DME medium containing 5%, and the culture was continued.

It has been confirmed that the intracellular cholesterol biosynthesis ability is increased about 1.4-fold by replacing FBS with LpDS. After culturing for 24 hours, medium was removed, DME medium (0.5 ml) containing 5% LpDS was newly added, and about 10 μl of the test dissolved in purified water or DMSO was added.
0 hours (method B-1) or 4 hours (B-
2 method) was added ^[2-14 C] sodium acetate (0.2 [mu] Ci) was continued for an additional 4 hours incubation. After the culture was completed, the medium was removed, and the cells were cooled to 4 ° C in phosphate buffered saline (P
After washing 3 times with BS), the cells were collected in a centrifuge tube with a rubber policeman.

The cell pellet obtained was added to 200 μl of 0.
After adding 5N potassium hydroxide and heating at 37 ° C. overnight to lyse the cells, a certain amount of this was saponified with a 15% potassium hydroxide ethanol solution. The resulting unsaponifiable lipid was extracted with petroleum ether and its radioactivity was measured. Further, the amount of protein was measured from a fixed amount of the rest of the cell lysate, and the specific radioactivity per mg of cellular protein was taken as the cholesterol biosynthesis ability.

The inhibitory activity was expressed as a concentration (IC ₅₀ ) at which the radioactivity incorporated into unsaponifiable lipid was inhibited by 50%. Test C: In Vivo Cholesterol Biosynthesis Inhibition Test Male Sprague-Dawley rats weighing approximately 150 g under normal commercial diet and free intake, alternating light cycle (2:00 pm)
In vivo after breeding for 7-10 days in the dark (2:00 am)
It was used for the cholesterol biosynthesis inhibition test in.

Immediately before the test 1
There were 5 animals per group. 2 from Middark (8:00 pm), which has the highest cholesterol biosynthesis capacity in rats
Approximately 3 hours before, the test compound dissolved or suspended in pure water or 0.5% methylcellulose was orally administered at a dose of 0.02 to 2 mg / kg to give 0.4 ml / 100 g body weight.

Water alone or vehicle alone was orally administered to the control group. After administration of the test compound 90 minutes ^[2-14 C] - 10 [mu] per mouse of sodium acetate (58 mCi / mmol)
Ci (0.2 ml) was intraperitoneally injected, and 2 hours after that, blood was collected under anesthesia with hexobarbital to obtain a serum sample. Lipids were extracted with 2 ml of the obtained serum according to the method of Folch et al. After saponification with ethanolic KOH, the unsaponifiable matter was extracted with petroleum ether and its radioactivity was measured.

The inhibitory activity was measured by the control group (DPM /
It was expressed as the rate of decrease in the measured value of the test group for 2 ml serum / 2 hr). With respect to the compound according to the present invention, the inhibitory activity against cholesterol biosynthesis using HMG-Co reductase as a rate-limiting enzyme was measured by the above test methods A and B.

Compounds Ia-1-1, I in Test A Method
The enzyme inhibitory activities of a-3-1 and Ia-5-1 at 100 nM were 43.8%, 46.4% and 54.6%, respectively.

[Synthesis Example] Reference Example 1 7- (2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl) -3,5-O-isopropylidene-3,5- Synthesis of ethyl dihydroxy-6-heptate (Compound Ia-4-1) 3,5-O-isopropylidene-under an argon atmosphere.
Copper iodide (8 mg), 2-cyclopropyl-4- (4'-fluorophenyl) -3-iodoquinoline (60 mg) and diethylamine (0.8 ml) were added to ethyl 3,5-dihydroxy-6-heptate (42 mg). , Bistriphenylphosphinedichloropalladium (13 mg) were added, and the mixture was stirred at room temperature for 4 hours. After adding ether, washing with water, washing with saturated brine, and drying over anhydrous sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (ether: hexane = 1: 5) to give the desired compound (35 mg, yield 46%). ) Got.

Synthesis Example 1 Ethyl 7- (2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl) -3,5-dihydroxy-6-heptate (Compound Ia-1- Synthesis of 1) 7- (2′-cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl) -3,5-O-isopropylidene-3,5-dihydroxy-6-heptinoic acid Ethyl (Compound Ia-4-1) (203 mg) was dissolved in tetrahydrofuran-water (3: 1, 10 ml), p-toluenesulfonic acid (118 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 2 days. The reaction mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, the solvent was evaporated and the residue was purified by silica gel column chromatography (ether: hexane = 2: 1).
150 mg (yield 81%) of the target compound was obtained.

IR (KBR, cm ^-1 ) 4000, 2200, 1720, 1595,
1550. ¹ H-NMR (90MHz, CDCl ₃ , δ) 1.0-1.2 (m, 4H), 1.29 (t, J =
7.3Hz, 3H), 1.6-2.0 (m, 3H), 2.42 (d, J = 5.9Hz, 2H),
2.7-3.0 (m, 2H), 3.42 (bd, J = 2.9Hz, 1H), 3.9-4.2 (m,
1H), 4.19 (q, J = 7.3Hz, 2H), 4.7-4.9 (m, 1H), 7.0-7.7
(m, 7H), 7.8-8.0 (m, 1H) .MS (m / z) 448 (M ⁺ , 100), 402 (M ⁺ -OEt, 27.8), 374 (M ⁺ -C
OOEt, 2.1).

Synthesis Example 2 7- (2'-Cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl) -3,5-dihydroxy-6-heptynoic acid lactone (Compound Ia-3- 1)
Synthesis of 7- (2′-cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl) -3,5-dihydroxy-6-heptate ethyl (Compound Ia-1-1) (1
10 mg) was dissolved in ethanol (0.2 ml), 1N aqueous sodium hydroxide solution (0.26 ml) was added, and the mixture was stirred at room temperature for 1 hr. 1
After adding N hydrochloric acid (0.26 ml) and stirring for 30 minutes, the reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The produced carboxylic acid was dissolved in methylene chloride (2 ml), trifluoroacetic acid (4 μl) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (ether: hexane =
Purification by 5: 1) yielded 72 mg of the target compound (yield 73%).

Synthesis Example 3 7- (2'-Cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl) -3,5-dihydroxy-6-heptynoic acid 1 / 2Ca salt (Compound Ia -5
Synthesis of 1) 7- (2′-cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl) -3,5-dihydroxy-6-heptate ethyl (Compound Ia-1-1) (7
Carboxylic acid was obtained from 4 mg) in the same manner as in Synthesis Example 2, 1N aqueous sodium hydroxide solution (0.17 ml) and water (1.6 ml) were added, and the mixture was stirred at room temperature for 30 minutes. Calcium chloride (21m
An aqueous solution (1.6 ml) of g) was added dropwise and the mixture was stirred overnight. The produced white crystals are filtered, washed with water, washed with acetonitrile, washed with water,
It was dried in a drier to obtain 45 mg of the target compound (yield 62%).

Formulation Example Formulation Example 1 After the above ingredients were mixed by a conventional method, 100 sugar-coated tablets each containing 10 mg of the active ingredient were produced.

Formulation Example 2 The above ingredients were mixed by a conventional method and filled into No. 4 gelatin capsules to prepare 100 capsules containing 10 mg of the active ingredient in each capsule.

Formulation Example 3 After mixing the above ingredients, No. 3 soft gelatin capsules were filled by a conventional method to prepare 100 capsules of a soft capsule containing 10 mg of the active ingredient in each capsule.

Formulation Example 4 The above ingredients were mixed by a conventional method to prepare a 1% (10%) ointment.

Formulation Example 5 1 g suppository 1 containing 10 mg of the active ingredient by melt-mixing the above ingredients in a conventional manner, pouring into a suppository container and solidifying by cooling.
00 pieces were manufactured.

Formulation Example 6 Dissolve before use.

Formulation Example 7 The above ingredients were granulated by a conventional method, and 200 mg was packaged so as to contain 10 mg of the active ingredient, and 100 pieces were packaged.

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07D 495/04 105 A 9165-4C

Claims (13)

[Claims] 1. A compound represented by the general formula [I]:[Wherein, X ring is phenyl, substituted phenyl or 5-6 membered ring
Represents heteroaryl, R¹And R²Are independently hydrogen and C₁-C₈Alkyl, C₃-C₇Shi
Croalkyl, C₁-C₃Alkoxy, n-butoxy, i-but
Xy, sec-butoxy, tert-butoxy, R²⁰R^{twenty one}N- (R²⁰,
R^{twenty one}Are each independently hydrogen or C₁-C₃Means alkyl
It ), Trifluoromethyl, trifluoromethoxy,
Difluoromethoxy, fluoro, chloro, bromo, fe
Nyl, phenoxy, benzyloxy, hydroxy, tri
Methylsilyloxy, diphenyl-tert-butylsilylo
Xy, hydroxymethyl or -O (CH ₂)_lOR^{twenty two}(R^{twenty two}Is hydrogen
Or C₁-C₃Means alkyl, l means 1, 2 or 3
To do. ) Is meant; R when in ortho position to each other
¹And R²Together with -CH = CH-CH = CH- or methylene dioxy
Means Shi; R³Is hydrogen, C₁-C₈Alkyl, C₂-C₆Archeni
Le, C₃-C₇Cycloalkyl, C_Five-C₇Cycloalkenyl or embedded image(R⁷Is hydrogen, C₁-C₈Alkyl, C₁-C₈Alkoxy, C₁-C₃A
Ruquilthio, chloro, bromo, fluoro, chloromethy
, Trichloromethyl, trifluoromethyl, triflu
Oromethoxy, trichloromethoxy, difluoromethoxy
Ci, phenoxy, benzyloxy, hydroxy, trime
Tylsilyloxy, diphenyl-tert-butylsilyloxy
It means Ci or hydroxymethyl. ) Means
Or; [Chemical 3]No. 1 and C₁-C₃Depending on the alkyl 0, 1 or 2
Replaced by C₁-C₃Means alkyl; Z is -Q-CH₂-W-CH
₂-CO₂R¹²,(Q is -C (O)-, -C (OR¹³)₂-Or-CH (OH)-means W is -C (O)-, -C (OR¹³)₂-Or-C (R¹¹) (0H) -means R¹¹Is hydrogen or C₁-C₃Means alkyl, R¹²Is hydrogen, R¹⁴(R¹⁴Is hydrolyzed chemically or physiologically
The alkyl of the obtained alkyl ester moiety, NHR^{twenty three}R^{twenty four}R^{twenty five}(R
^{twenty three}R^{twenty four}R^{twenty five}Is hydrogen or C₁-C_FourMeans alkyl. ), Nato
Means strontium, potassium or 1/2 calcium. )
Means R¹³Is a first- or second-grade C independently₁-C₆Means alkyl
Ruka 2 R¹³Together- (CH₂)₂-Or- (CH₂)₃-
Means R¹⁵, R¹⁶Independently hydrogen or C₁-C₃Means alkyl
Or R¹⁵, R¹⁶Together- (CH₂)₂-Or- (CH₂)₃-I mean
To taste. )]. 2. A compound represented by the formula [Ia]: [In the formula, R ^4a , R ^5a and R ^6a are each independently hydrogen, C ₁ -C ₆
Alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₃ alkoxy, n-
Butoxy, i- butoxy, sec- ^{butoxy, R 26 R 2 7 N- (} R 26,
R ^27's each independently represent hydrogen or C ₁ -C ₃ alkyl. ), Trifluoromethyl, trifluoromethoxy,
Difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -O (CH ₂ ) mOR ²⁸ (R ²⁸ is hydrogen or C ₁ -C ₃ alkyl and m means 1, 2 or 3); or R ^4a and R ^5a together are —CH═C.
Do you mean H-CH = CH-; R when in ortho position to each other
^4a and R ^{5a taken} together represent -OC (R ²⁹ ) (R ³⁰ ) O- (R ²⁹ , R ³⁰ independently represent hydrogen or C ₁ -C ₃ alkyl). ] The compound of Claim 1 represented by these. 3. In the general formula [Ib], embedded image[In the formula, R^4bIs a hydrogen atom, C₁-C₈Alkyl, C₁-C₆Al
Coxy, C₃-C₇Cycloalkyl, C₂-C₆Alkenyl, α also
Preferably β-naphthyl, 2,3 or 4-pyridyl, 2 if
Ku-thienyl, 2 or 3-furyl, fluoro,
Chloro, bromo,(R^6b, R^7b, R^8bAre independently hydrogen and C₁-C₈Archi
Le, C₁-C₈Alkoxy, C₁-C ₃Alkylthio, chloro, bu
Lomo, Fluoro, -NR³¹R³²(R³¹, R³²Each independently C
₁-C₃It is alkyl. ), Chloromethyl, trichlorometh
Chill, trifluoromethyl, trifluoromethoxy,
Lichloromethoxy, difluoromethoxy, phenoxy,
Benzyloxy, hydroxy, trimethylsilyl oki
Ci, diphenyl-tert-butylsilyloxy, hydroxy
Methyl or -O (CH₂) nOR³³(R³³Is hydrogen or C₁-C₃Al
Means kill and n means 1, 2 or 3. )Means
Then R^8bR is hydrogen when is ortho to each other^6b, R
^7b, Together-OC (R³⁴) (R³⁵) O- (R³⁴, R³⁵Is independent
Hydrogen or C₁-C₃Means alkyl. ) Means
Also, R^7b, R^8bWhen both are hydrogen, R^6bIs(R³⁶Is hydrogen, C₁-C_FourAlkyl, C₁-C₃Alkoxy, trif
Luoromethyl, chloro, bromo or fluoro
It )) Or the phenyl group is C₁-C_FourAlkyl, C₁-
C₃Substituted by alkoxy, fluorine, chlorine or bromine
Optional phenyl-C₂-C₃Means alkenyl
Or C₁-C₃Alkoxy, naphthyl or1 and C selected from₁-C₈Alkyl 0, 1 or
C replaced by two ₁-C₃Means alkyl; R^5b
Is a nitrogen atom at the 1- or 2-position of the pyrazolopyridine ring
Is bound and this R^5bIs hydrogen, C₁-C₈Alkyl, not one
C substituted by 3 fluorine atoms₁-C ₃Alkyl, C
₃-C₇Cycloalkyl, α or β-naphthyl, 2,3 also
4-pyridyl, 2 or 3-thienyl, 2 or
Is 3-furyl orOr C₁-C₃Alkoxy, hydroxy,
Naphthyl or embedded image1 and C selected from₁-C₈Alkyl 0, 1 or
C replaced by two ₁-C₃Means alkyl. ]
The compound according to claim 1, which is represented by: 4. A compound represented by the formula [Ic]:[In the formula, R^4c, R^5cAre independently hydrogen and C₁-C₈Archi
Le, C₂-C₆Alkenyl, C₃-C₇Cycloalkyl, C₁-C₆A
Lucoxy, fluoro, chloro, bromo,(R^6c, R^7c, R^8cAre independently hydrogen and C₁-C_FourArchi
Le, C₁-C₃Alkoxy, C₃-C ₇Cycloalkyl, triflu
Means oromethyl, fluoro, chloro and bromo
It ), 2,3 or 4-pyridyl, 2 or 5-
Pyrimidyl, 2 or 3-thienyl, 2 or 3-
Frill,, -NR³⁷R³⁸(R³⁷, R³⁸Are independently hydrogen and C₁-C_FourAl
Kill,(j means 1, 2 or 3) or R³⁷, R³⁸But
Together- (CH₂) k-(k means 3, 4 or 5
It )) Is meant;And C₁-C₈Substituted with 0, 1 or 2 alkyls
C₁-C₃Means alkyl or α or β naphthyl
Do you want; R^4cAnd R^5cTogether C₁-C_FourAlkyl, C₃-C₇
From 0 for cycloalkyl, fluoro, chloro or bromo
3 pieces, andC substituted with 0 to 1 of₂-C₆Means alkylene
Or- (CHR³⁹) p-A- (CHR⁴⁰) q- (p and q are 0, 1, and
2 or 3, and A is -C (R ⁴¹) = C (R⁴²)-(R⁴¹, R⁴²Is
Hydrogen or C₁-C₃Means alkyl. ), -O-, -S-
Or -N (R⁴³)-(R⁴³Is hydrogen, C₁-C_FourAlkyl,) Means R³⁹, R⁴⁰Are each independently hydrogen or C₁-C_Four
Means alkyl. ) Or-CH = CH-means CH = CH-
It ] The compound of Claim 1 represented by these. 5. In formula [Ia], R ³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-. Pentyl, 1,2-dimethylpentyl, n-
Hexyl, n-heptyl, n-octyl, vinyl, n-
Propenyl, i-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,2-dimethyl-
1-propenyl, c-propyl, c-butyl, c-hexyl, 1-methylcyclopropyl, 2-methylcyclopropyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3
-Chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dichlorophenyl, 3-trifluoromethylphenyl, benzyl, 4-
Means chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 2-phenethyl, 1-methylbenzyl; when R ^5a and R ^6a both represent hydrogen, R ^4a represents hydrogen, 5-fluoro, 6-fluoro , 7-fluoro, 8-fluoro, 5-chloro, 6-chloro, 7-chloro, 8-chloro, 5-bromo, 6-bromo, 7-bromo, 8-bromo, 5-methyl, 6-methyl, 7 -Methyl, 8-methyl, 5-methoxy, 6-methoxy, 7-methoxy, 8-methoxy, 5-trifluoromethyl, 6-
Trifluoromethyl, 7-trifluoromethyl, 8-trifluoromethyl, 6-trifluoromethoxy, 6-difluoromethoxy, 8-hydroxyethyl, 5-hydroxy, 6-hydroxy, 7-hydroxy, 8-hydroxy, 6- Means ethyl, 6-n-butyl or 7-dimethylamino; when R ^6a is hydrogen, R ^4a and R ^5a together form 6-chloro-8-methyl, 6-bromo-7
-Methoxy, 6-methyl-7-chloro, 6-chloro-8
-Hydroxy, 5-methyl-2-hydroxy, 6-methoxy-7-chloro, 6-chloro-7-methoxy, 6-hydroxy-7-chloro, 6-chloro-7-hydroxy,
6-chloro-8-bromo, 5-chloro-6-hydroxy, 6-bromo-8-chloro, 6-bromo-8-hydroxy, 5-methyl-8-chloro, 7-hydroxy-8-
Chloro, 6-bromo-8-hydroxy, 6-methoxy-
7-methyl, 6-chloro-8-bromo, 6-methyl-8
-Bromo, 6,7-difluoro, 6,8-difluoro,
6,7-methylenedioxy, 6,8-dichloro, 5,8
-Dimethyl, 6,8-dimethyl, 6,7-dimethoxy,
6,7-diethoxy, 6,7-dibromo or 6,8-
Means dibromo; R ^4a , R ^5a and R ^{6a taken} together are 5,7-dimethoxy-8-hydroxy, 5,8-dichloro-6-hydroxy, 6,7,8-trimethoxy,
6,7,8-trimethyl, 6,7,8-trichloro, 5
-Fluoro-6,8-dibromo or 5-chloro-6,
It means 8-dibromo. The compound according to claim 1, which is represented by: 6. In the general formula [Ib], R ³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-. Pentyl, 1,2-dimethylpentyl, n-
Hexyl, n-heptyl, n-octyl, vinyl, n-
Propenyl, i-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,2-dimethyl-
1-propenyl, c-propyl, c-butyl, c-hexyl, 1-methylcyclopropyl, 2-methylcyclopropyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3
-Chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dichlorophenyl, 3-trifluoromethylphenyl, benzyl, 4
-Chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 2-phenethyl, 1-methylbenzyl; ^R4b is hydrogen, methyl, ethyl, n-propyl, i-
Propyl, n-butyl, i-butyl, sec-butyl, ter
t-butyl, cyclopropyl, cyclohexyl, phenyl, 2,3 or 4-fluorophenyl, 2,3 or 4-chlorophenyl, 2,3 or 4-bromophenyl, 2,3 or 4-tolyl, 2,3 Or 4
-Methoxyphenyl, 2,3 or 4-trifluoromethylphenyl, 2,3 or 4-chloromethylphenyl, 3 or 4-ethoxyphenyl, 4- (2-methylbutyl) phenyl, 4-n-heptylphenyl, 4
-N-octylphenyl, 4-n-pentylphenyl,
4-n-hexylphenyl, 4-n-propylphenyl, 4-n-butylphenyl, 4-tert-butylphenyl, 4-n-butoxyphenyl, 4-n-pentyloxyphenyl, 4-n-hexyloxyphenyl , 4-n
-Heptyloxyphenyl, 4-n-octyloxyphenyl, 4-phenoxyphenyl, 4-biphenyl, 4
-Trichloromethoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-
Difluorophenyl, 3,4-difluorophenyl,
2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,
4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,5-bis (trifluoromethyl) phenyl,
Means 3,4-methylenedioxyphenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2,4,6-triisopropylphenyl;
R ^5b is a group bonded to the nitrogen atom at the 1-position of the pyrazolopyridine ring, and is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-
Butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclohexyl, benzyl, 2-chlorobenzyl, 2-hydroxybenzyl, 3-trifluoromethylbenzyl, 2-phenylethyl, phenyl, 2,3
Or 4-chlorophenyl, 2,3 or 4-bromophenyl, 2,3 or 4-fluorophenyl,
2,3 or 4-tolyl, 2,3 or 4-trifluoromethylphenyl, 3 or 4-methoxyphenyl, 2-hydroxyphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-
Dichlorophenyl, 3,4-dichlorophenyl, 3,5
-Dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trichlorophenyl, 2,4-difluorophenyl, 3,5-bis (trifluoromethyl) phenyl, 3-chloro-4-tolyl, 3- Chloro-6-tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-
5-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-chlorophenyl, 2
-Chloro-4-trifluoromethylphenyl, 3-fluoro-6-tolyl, α-naphthyl, 2-pyridyl, 3-
Methyl-5-trifluoromethyl-2-pyridyl, 4-
It means pyridyl or 2,6-dichloro-4-pyridyl. The compound according to claim 1, which is represented by: 7. In the general formula [Ic], R ³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-. Pentyl, 1,2-dimethylpentyl, n-
Hexyl, n-heptyl, n-octyl, vinyl, n-
Propenyl, i-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,2-dimethyl-
1-propenyl, c-propyl, c-butyl, c-hexyl, 1-methylcyclopropyl, 2-methylcyclopropyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3
-Chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dichlorophenyl, 3-trifluoromethylphenyl, benzyl, 4-
Means chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 2-phenethyl, 1-methylbenzyl; R ^4c and R ^5c are independently hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl. , I-butyl, sec-
Butyl, tert-butyl, n-pentyl, 1,2-dimethylpentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclopropylmethyl, vinyl, 1-methylvinyl, 1-propenyl, allyl, 1-methyl-
1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-ethylvinyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1- Ethyl-1-propenyl, 1-
Ethyl-2-propenyl, 1-methyl-1-butenyl,
Means 1-methyl-2-butenyl, 2-methyl-1-butenyl, 1-i-propylvinyl, 1-methyl-1-pentenyl, phenyl; R ^4C and R ^{5C taken} together are ethylene, trimethylene , Tetramethylene, pentamethylene, methyltetramethylene, chlortetramethylene,
It means phenyltetramethylene. The compound according to claim 1, which is represented by: 8. (E) -3,5-dihydroxy-7-
[2'-Cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl] -6-heptic acid, its sodium salt, 1/2 calcium salt, its methyl ester, ethyl ester, n- A compound in which propyl ester, i-propyl ester and its carboxylic acid are condensed with a hydroxy group at the 5-position to form a lactone. 9. (E) -3,5-Dihydroxy-7-
[6′-Cyclopropyl-4 ′-(4 ″ -fluorophenyl) -1 ′, 3′-dimethylpyrazolo [3,4-b]
Pyridin-5'-yl] -6-heptic acid, its sodium salt, 1/2 calcium salt, its methyl ester, ethyl ester, n-propyl ester, i-propyl ester and its carboxylic acid have a hydroxy group at the 5-position. A compound that is condensed with lactone to form a lactone. 10. (E) -3,5-dihydroxy-7-
[6'-cyclopropyl-3'-ethyl-4 '-(4 "
-Fluorophenyl) -2'-methylthieno [2,3-
b] pyridin-5'-yl] -6-heptinoic acid, its sodium salt, 1/2 calcium salt, its methyl ester, ethyl ester, n-propyl ester, i-propyl ester and its carboxylic acid are in the 5-position. A compound that condenses with a hydroxy group to form a lactone. 11. An antihyperlipidemic agent, which comprises the compound represented by the general formula [I] according to claim 1. 12. An anti-hyperlipoproteinemic agent comprising the compound represented by the general formula [I] according to claim 1. 13. An anti-atherosclerotic agent comprising the compound represented by the general formula [I] according to claim 1.