WO1995011898A1

WO1995011898A1 - Condensed pyridine type mevalonolactone intermediate and process for its production

Info

Publication number: WO1995011898A1
Application number: PCT/JP1993/001551
Authority: WO
Inventors: Tamejiro Hiyama; Tatsuya Minami; Yoshinobu Yanagawa; Yoshio Ohara
Original assignee: Nissan Chemical Industries Ltd.; Sagami Chemical Research Center
Priority date: 1992-05-12
Filing date: 1993-10-27
Publication date: 1995-05-04

Abstract

The present invention provides a synthetic condensed pyridine type mevalonolactone intermediate of formula (1), wherein Z is (a) or (b), each of R?9a and R9b¿ is a hydroxyl-protecting group, and R10 is methyl, ethyl, propyl, isopropyl, tert-butyl, tetrahydropyranyl, allyl, benzyl, triphenylmethyl, trimethylsilyl or tert-butyldimethylsilyl. The intermediate is useful for producing a 7-position substituted (E, 3R, 5S)-3,5-dihydroxy-6-heptenoic acid or its 1,5-lactone or its enantiomer which has an activity as an HMG-CoA reductase inhibitor and which is useful as a hypercholesterolemia therapeutic agent.

Description

SPECIFICATION CONDENSED PYRIDINE TYPE MEVALONOLACTONE INTERMEDIATE AND PROCESS FOR ITS PRODUCTION TECHNICAL FIELD

The present invention relates to a novel intermediate for a condensed pyridine type mevalonolactone derivative which is a HMG-CoA reductase inhibitor and which is useful as a hypercholesterolemia therapeutic agent or as an arteriosclerosis therapeutic agent, and a process for its production as well as a novel condensed pyridine derivative useful as the starting material thereof.

BACKGROUND ART Heretofore, a condensed pyridine type mevalonolactone derivative has been synthesized by stepwisely eκrending the side chain of a condensed pyridine ring moiety, as disclosed in European Patent No. 535548 or Japanese Patent Application No. 257870/1991. (Scheme 1) Scheme 1

acceptable salt)

(1-4)

This method provides a relatively good yield in each step, but has drawbacks such that it is cumbersome including many steps, special conditions (an extremely low temperature, a borane reactant) are reguired to control the steric configuration of two hydroxyl groups (a syn-form is highly active), since the side chain is stepwisely extended, and a highly sophisticated asymmetrical synthetic method is reguired or an inefficient optical resolution has to be carried out to obtain an optically active substance (a (3R,5S)-form is highly active) .

DISCLOSURE OF THE INVENTION

The present invention provides a novel process developed to solve such problems of the conventional method and a novel intermediate useful for the process.

A condensed pyridine type mevalonolactone intermediate of the formula (1)

(1)

wherein ring X is a benzene ring, a substituted benzene ring or a substituted 5- or 6-membered heteroaromatic ring, each of R¹ and R² which are independent of each other, is hydrogen, C^_g alkyl, C₃_₇ cycloalkyl, C_1-3 alkoxy, butoxy, i-butoxy, sec-butoxy, tert-butoxy, _R ²⁰ _R ²ⁱ _N_ (_Wherein each of R²⁰ and R²¹ which are independent of each other, is hydrogen or C_1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -0(CH₂)_eOR²² (wherein R²² is hydrogen or C_1-3 alkyl, and e is 1, 2, or 3); or R¹ and R² together form -CH=CH-CH=CH- or methylenedioxy, when they are at the o-position to each other;

R³ is hydrogen, _λ__Q alkyl, C₂_₆ alkenyl, C₃_₇

_ '^R? cycloalkyl, C₅_₇ cycloalkenyl or —<>Λ (wherein R⁷ is hydrogen, C-^._g alkyl, C^_g alkoxy, _λ_₃ alkylthio, chloro, bromo, fluoro, chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy or

hydroxymethyl); or C₁_₃ alkyl substituted by one

(wherein R⁷ is as defined above) and zero, one or two C _ alkyl;

(each of R^9a and R^9b represents a hydroxyl-protecting group and is independently methoxymethyl, 2- methoxyethoxymethyl, tetrahydropyranyl, 4- methoxytetrahydropyranyl, 1-ethoxyethyl, 1-methyl-l- methoxyethyl, allyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, or R^9a and R^9b together form isopropylidene, cyclopentylidene, cyclohexylidene or benzylidene; and

R¹⁰ is methyl, ethyl, propyl, isopropyl, tert-butyl, tetrahydropyranyl, allyl, benzyl, triphenylmethyl, trimethylsilyl or tert-butyldimethylsilyl), can be produced by reacting a condensed pyridine derivative of the formula (2) :

wherein ring X, R¹, R² and R³ are as defined above:

Y is P⁺R^1;LR¹²R¹³Hal^~ or P( )R¹⁴R¹⁵ (wherein each of R¹¹, R¹² and R¹³ which are independent of one another, is methyl, ethyl, propyl, isopropyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, methylphenyl, pentafluorophenyl or benzyl, each of R¹⁴ and R¹⁵ which are independent of each other, is methyl, ethyl, propyl, isopropyl, butyl, 2-chloroethyl, 2,2,2- trifluoroethyl, phenyl, methoxyphenyl, methylphenyl, pentafluorophenyl, benzyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2- trifluoroethoxy, phenoxy, methoxyphenyloxy, methylphenyloxy, pentafluorophenyloxy or benzyloxy, or

R¹⁴ and R¹⁵ together form a 5- or 6-membered ring, Hal is chlorine, bromine or iodine, and is O or S, with a base to form an anion, which is then condensed with a compound of the formula (3):

wherein R^9a, R^9b and R¹⁰ are as defined above.

Especially when Y in the formula (2) is P(0)Ph₂, the yield of the condensation reaction and the stereo selectivity (trans-selectivity) will be excellent, and the compound of the formula (1) can be obtained in good yield and with a high purity. (Scheme 2) Scheme 2

_.(2) (vm^< (l)

The intermediate of the formula (1) is a novel compound, and it is a useful intermediate which can easily be led to a condensed pyridine type mevalonolactone derivative (I) which is a HMG-CoA reductase inhibitor and which is useful as a hypercholesterolemia therapeutic agent or as an arteriosclerosis therapeutic agent, stepwisely or in a single step by hydrolyzing R^9a and R^9b which are hydroxyl-protecting groups, and R¹⁰ which is an ester. (In the formulas, (I-l) represents a condensed pyridine type mevalonic acid ester, (1-2) represents a condensed pyridine type mevalonic acid, (1-5) represents a pharmaceutically acceptable salt of the condensed pyridine type mevalonic acid, and (1-3) represents a condensed pyridine type mevalonolactone.) (Scheme 3) Scheme 3

(1) (I-l)

hydrolysis

C 1-5 ) (R =pharmaceutically acceptable salt)

lactonization

These compounds respectively have four stereoisomerε depending upon the steric configurations of hydroxyl groups of the compound of the formula (3) to be used, and they can be produced by the process of the present invention.

The compound of the formula (2) is also novel, and it can be synthesized from a conventional intermediate in accordance with Scheme 4. Scheme 4

( NI ) (DO

(2) The hydroxyl group of the compound of the formula (VI) is treated by a halogenating agent such as PBr₃ to obtain a halogenated compound of the formula (IX). When the halogenated compound is reacted with PR¹¹R¹²R¹³ (wherein R¹¹, R¹² and R¹³ are as defined above), a phosphonium salt (a compound of the formula (2) wherein Y is P⁺R¹¹R¹²R¹³Hal^_) can be obtained. When the halogenated compound is subjected to an Arbusow reaction with PR¹⁴R¹⁵(WR¹⁶) (wherein R¹⁴, R¹⁵ and W are as defined above, and R¹⁶ is methyl, ethyl, propyl, isopropyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, methylphenyl, pentafluorophenyl or benzyl), or the above-mentioned phosphonium salt is hydrolyzed, a compound of the formula (2) wherein Y is P(W)R¹ R¹⁵ (wherein R¹ , R¹⁵ and W are as defined above) can be prepared.

The compound of the formula (3) can be synthesized by the method of Scheme 5.

Scheme 5

protection O?

-_*- ( 3 ) (racemate)

O O Y reduction transesterification

protection ⁰

0-. — ( 3 ) (Optical isomer)

The condensation reaction of the condensed pyridine derivative of the formula (2) with the aldehyde compound of the formula (3) is carried out by withdrawing a hydrogen atom adjacent to Y in the formula (2) by means of a base in an anhydrous inert solvent to form an anion, which is then reacted with the aldehyde compound of the formula (3) .

The inert solvent may, for example, be an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether type solvent. Preferred is an ether type solvent such as diethyl ether, 1,2-diethoxyethane, 1,2-dimethoxyethane or tetrahydrofuran. Further, as a stabilizer for the anion, a polar solvent such as hexamethylphosphoric acid triamide, dimethylsulfoxide or dimethylimidazolidone, may be employed, as the case requires.

The base may, for example, be a sodium compound such as sodium hydride or sodium amide, a potassium compound such as tert-butoxypotassium, a lithium compound such as butyl lithium or phenyl lithium, or an amide lithium compound such as 2,2,6,6-tetramethylpiperidide lithium.

The reaction temperature varies to some extent depending upon the substrate. However, it is from -78 to_. 30°C at the time of the addition of the base, and the reaction with the aldehyde is conducted at a temperature of from -70°C to the refluxing temperature of the solvent.

The compound of the formula (1) thus synthesized, can readily be led to a condensed pyridine type mevalonolactone derivative (I) by the method of the above-mentioned Scheme 3. The condensed pyridine type mevalonolactone intermediate of the formula (1) as the compound of the present invention includes compounds of the formulas (la), (lb) and (lc):

Further, the condensed pyridine type mevalonolactone intermediate of the formula (2) as the compound of the present invention includes compounds of the formulas (2a), (2b) and (2c):

(2a7 (2b; (2c)

As the substituents of the above compounds, the following substituents may be mentioned. In any compounds, substituents R¹, R², R³, Z and Y are as defined above.

Each of R¹ and R² is preferably hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert- butyl, pentyl, i-pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, propoxy, i-propoxy, butoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy or hydroxymethyl.

R³ is preferably hydrogen, methyl, ethyl, propyl, i- propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, i- pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, vinyl, 1-propenyl, 1-methylvinyl, 1-methyl-l-propenyl, 2-methyl- 1-propenyl, 1,2-dimethyl-l-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 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- clorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 2-phenethyl or 1-methylbenzyl. In the quinoline type compounds of the formula (la) and (2a), each of R^4a, R^5a and R^6a which are independent of one another, is hydrogen, C-^_g alkyl, C₃_₇ cycloalkyl, C_λ_₃ alkoxy, butoxy, i-butoxy, sec-butoxy, R²⁶R²⁷N- (wherein R²⁶ and R²⁷ which are independent of each other, s hydrogen or C_λ_₃ alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or - 0(CH₂)_mOR²⁸ (wherein R²⁸ is hydrogen or C_λ_₃ alkyl, and m is 1, 2 or 3) ; or

R ^a and R^5a together form -CH=CH-CH=CH-; or

R^4a and R^5a together form -OC(R²⁹) (R³⁰)O- (wherein each of R²⁹ and R³⁰ which are independent of each other, is hydrogen or C_1-3 alkyl) when they are at the o- position to each other.

The following substituents may be mentioned as preferred substituents for R^4a, R^5a and R^6a.

Namely, when both R^5a and R^6a are hydrogen, R ^a is preferably 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-trifluoromethox , 6-difluoromethoxy, 8-hydroxyethyl, 5-hydroxy, 6-hydroxy, 7-hydroxy, 8- hydroxy, 6-ethyl, 6-butyl or 7-dimethylamino. When R^6a is hydrogen, R ^a and R^5a may together represent 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-methox , 6-hydroxy-7~chloro, 6-chloro-7-hydroxy, 6-chloro-8-bromo, 5-chloro-6-hydroxy, 6-bromo-8-chloro, 6-bromo-8-hydrox , 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-dimethox , 6,7-diethoxy, 6,7- dibromo or 6,8-dibromo.

Further, R^4a, R^5a and R^6a may together represent 5,7- dimethoxy-8-hydroxy, 5,8-dichloro-6-hydroxy, 6,7,8- trimethoxy, 6,7,8-trimethy1, 6,7,8-trichloro, 5-fluoro- 6,8-dibromo or 5-chloro-6,8-dibromo.

Quinoline compounds of the formulas (la) and (2a) wherein R¹ is p-fluoro, each of R², R ^a, R^5a and R^6a is hydrogen, and R³ is cyclopropyl, are preferred.

In the pyrazolopyridine type compounds of the formulas (lb) and (2b), R ^b is hydrogen, C_1-8 alkyl, C_1-6 alkoxy, C₃_₇ cycloalkyl, C₂_₆ alkenyl, a- or ^-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, fluoro, chloro, bromo,

(wherein each of R^6b, R^7b and R^8b

which are independent of one another, is hydrogen, C-^_g alkyl, C^_g alkoxy, C_1-3 alkylthio, chloro, bromo, fluoro, -NR³¹R³² (wherein each of R³¹ and R³² which are independent of each other, is C_λ_₃ alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -0(CH₂)_nOR³³ (wherein R³³ is hydrogen or C_λ_₃ alkyl, and n is 1, 2 or 3), or when R^8b is hydrogen, R^6b and R^7b together form -OC(R³⁴) (R³⁵)0- when they are at the o-position to each other (wherein each of R³⁴ and R³⁵ which are independent of each other, is hydrogen or C_1-3 alkyl group), or when R^7b and R^8b are simultaneously hydrogen, R^6b is (wherein R,3^J6^b is hydrogen, C₁_₄ alkyl,

C_λ_₃ alkoxy, trifluoromethyl, chloro, bromo or fluoro), phenyl-C₂_₃ alkenyl wherein the phenyl group may be substituted by C₁_₄ alkyl, C_λ_₃ alkoxy, fluorine, chlorine or bromine, or C₁_₃ alkyl substituted by one member selected from C₁_₃ alkoxy, naphthyl and

(wherein R^6b, R^7b and R^8b are as

defined above) and zero, one or two C_λ_₈ alkyl;

R^5b is bonded to nitrogen atom at the 1- or 2- position of the pyrazolopyridine ring, and such R^5b is hydrogen, _±__Q alkyl, C_1-3 alkyl substituted by from one to three fluorine atoms, C₃_₇ cycloalkyl, a- or β- naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3- furyl or

( wherein R^6b , R^7b and R^8b are as def ined

above ) ; or

C₁_₃ alkyl substituted by one member selected f rom C₁_₃ alkoxy , hydroxy , naphthyl and

( wherein R^6b , R^7b and R^{8 b} are as def ined

above) and by zero, one or two C^_g alkyl.

R¹, R², R³ and Z are as defined with respect to the formula (1) .

The following substituents may be mentioned as preferred substituents for R ^b and R^5b.

Namely, R^4b is preferably hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-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-heptylphenyl, 4-octylphenyl, 4- pentylphenyl, 4-hexylphenyl, 4-propylphenyl, 4- butylphenyl, 4-tert-butylphenyl, 4-butoxyphenyl, 4- pentyloxyphenyl, 4-hexyloxyphenyl, 4-heptyloxyphenyl, 4- octyloxyphenyl, 4-phenoxyphenyl, 4-biphenyl, 4- trichloro ethoxyphenyl, 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, 3,4- methylenedioxyphenyl, 2,4,6-trimethoxyphenyl, 3,4,5- trimethylphenyl or 2,4,6-triisopropylphenyl.

R^5b is preferably a group bonded to the nitrogen atom at the 1-position of the pyrazolopyridine ring and is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec- butyl, tert-butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclohexyl, benzyl, 2-chlorobenzyl, 2-hydroxybenzyl, 3- trifluoro ethylbenzyl, 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(trifluoromethylJphenyl, 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-pyridyl or 2,6-dichloro-4- pyridyl.

Pyrazolopyridine compounds of the formulas (lb) and (2b) wherein R¹ is p-fluoro, R² is hydrogen, each of R^4b and R^5b is methyl and R³ is cyclopropyl, are preferred.

In the pyrazolopyridine type compounds of the formulas (lc) and (2c), each of R^4c and R^5c which are independent of each other, is hydrogen, C₁_₈ alkyl, C₂_₆ alkenyl, C₃_₇ cycloalkyl, C_χ_₆ alkoxy, fluoro, chloro, bromo,

(wherein each of R^6c, R^7c and R^8c which

are independent of one another, is hydrogen, C₁_₄ alkyl, C₁_₃ alkoxy, C₃_₇ cycloalkyl, trifluoromethyl, fluoro, chloro and bromo), 2-, 3- or 4-pyridyl, 2- or 5- pyrimidyl, 2- or 3-thienyl, 2- or 3-furyl,

(wherein R^6c is as defined above),

-NR³⁷R³⁸ (wherein each of R³⁷ and R³⁸ which are independent of each other, is hydrogen, C₁_ alkyl,

(wherein j is 1, 2 or 3, and R^6c

is as defined above), or R³⁷ and R³⁸ together form -(CH₂)_k- (wherein k is 3, 4 or 5)), C₁_₃ alkyl substituted by _R6c

— (s (wherein R^6c is as defined above), and by

zero, one or two C_α_₃ alkyl, or a- or /3-naphthyl; or R^4c and R^5c together form C₂_₆ alkylene substituted by from zero to three members selected from C_1-4 alkyl, C₃_₇ cycloalkyl, fluoro, chloro and bromo and by zero or one member selected from

(wherein R⁶ is as defined above), or

-(CHR³⁹)_p-A-(CHR ⁰)_g- (wherein each of p and q is 0, 1, 2 or 3, A is -C(R⁴¹)=C(R⁴²)- (wherein each of R⁴¹ and R⁴² is hydrogen or C_χ_₃ alkyl), -0-, -S- or -N(R⁴³)- (wherein R⁴³ is hydrogen, C_1-4 alkyl, or

(wherein R^6c and j are as defined

above)), and each of R³⁹ and R⁴⁰ which are independent of each other, is hydrogen or C_1-4 alkyl) or -CH=CH-CH=CH-. The following substituents may be mentioned as preferred substituents for R ^c and R^5c.

Namely, each of R^4c and R^5c which are independent of each other, is preferably hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, 2- methylcyclohexyl, cycloheptyl, cyclopropylmethyl, vinyl, 1-methylvinyl, 1-propenyl, allyl, 1-methyl-l-propenyl, 1- methyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 1- ethylvinyl, 1,2-dimethyl-l-propenyl, l,2-dimethyl-2- propenyl, 1-ethyl-l-propenyl, l-ethyl-2- propenyl, 1-methyl-l-butenyl, l-methyl-2-butenyl, 2- methyl-1-butenyl, 1-i-propylvinyl, 1-methyl-l-pentenyl or phenyl; or

R^4c and R^5c together form ethylene, trimethylene, tetramethylene, pentamethylene, methyltetramethylene, chlorotetramethylene or phenyltetramethylene.

Thienopyridine compounds of the formula (lc) and (2c) wherein R¹ is p-fluoro, R² is hydrogen, R ^c is ethyl, R^5c is methyl and R³ is cyclopropyl, are preferred. BEST MODE FOR CARRYING OUT THE INVENTION

REFERENCE EXAMPLE 1

Preparation of methyl (3R^* ,5S^*,6E)-7~phenyl-3,5- dihydroxy-6-heptenoate

Diethylmethoxyborane (1.07 ml, 8.13 mmol) was added at -78°C to a THF (20 ml)/methanol (5.0 ml) solution of methyl (E)-7-phenyl-3,5-dioxo-6-heptenoate (2.00 g, 8.12 mmol), and the mixture was stirred for 15 minutes to room temperature. The mixture was again cooled to -78°C, and sodium borohydride (1.54 g, 40.7 mmol) was added thereto. Then, the reaction mixture was stirred at -78°C for 4 hours and from -78°C to room temperature for 8 hours. Acetic acid (2.0 ml) was added to terminate the reaction, and the reaction mixture was poured into a saturated sodium hydrogencarbonate aqueous solution and extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over sodium sulfate and concentrated. The residue was dissolved in methanol (10 ml) and then concentrated. This operation was repeated 10 times, and the organic boron compound was decomposed and distilled off. The product was purified by column chromatography (hexane:ethyl acetate = 2:1) to obtain methyl (3R*,5S*,6E)-7-phenyl-3,5-dihydroxy-6-heptenoate (1.16 g, 56%).

Rf = 0.08 (hexane:ethyl acetate = 2:1)

IR(CHC1₃): 3475, 3005, 1720, 1490, 1435, 1205, 1110, 1070, 1030, 775,

730 cm"¹.

¹H-NMR(CDC1₃): δ 7.38(d, J=7.2 Hz, 2H), 7.31(t, J=7.2 Hz, 2H), 7.24(π,

J=7.2, 1.3 Hz, IH), 6.62(d, J=15.7 Hz, IH), 6.21(dd, J=15.7, 6.4 Hz, IH),

4.59(m,lH), 4.43(m, IH), 3.74(s, IH), 3.72(s, 3H), 3.24(s, IH), 2.54(dd,

J=19.8, 16.5 Hz, IH), 2.52(dd, J=17.4, 16.5 Hz, IH), 1.80(dt, J=14.3, 9.4

Hz, IH), 1.73(dt, J=14.3, 3.1 Hz, IH).

MS (m/z) 250(M⁺, 2.5), 232(M⁺-H₂0, 3.5), 218(4), 215(4), 200(15),

158(60), 104(100).

REFERENCE EXAMPLE 2

Preparation of methyl (3R^*,5S^*,6E)-7-phenyl-3,5- isopropylidenedioxy-6-heptenoate

Methyl ( 3R* , 5S^* , 6E ) -7-phenyl-3 , 5-dihydroxy-6- heptenoate ( 1 . 10 g , 4 . 39 mmol ) obtained in Reference Example 1 and p-toluenesulfonic acid (50 mg, catalytic amount) were dissolved in acetone dimethylacetal (10.0 ml), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and a sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated. The product was purified by column chromatography (hexane:ethyl acetate = 10:1) to obtain methyl

(3R^*,5S^*,6E)-7-phenyl-3,5-isopropylidenedioxy-6- heptenoate (1.17 g, 92%) as colorless oil. Rf = 0.78 (hexane:ethyl acetate = 2:1)

IR(CHC1₃): 3000, 1735, 1440, 1380, 1200, 1160, 10S5, 1030, 770, 740 cm^"1.

¹H-NMR(CDC1₃): δ 7.37(d, J=7.2 Hz, 2H), 7.29(t, J=7.2 Hz, 2H), 7.24(tt, J=7.2, 1.3 Hz, IH), 6.60(d, J=15.9 Hz, IH), 6.16(dd, J=15.9, 6.2 Hz, IH), 4.57(m,lH), 4.40(m, IH), 3.70(s, 3H), 2.60(dd, J=15.6, 6.9 Hz, IH), 2.52(dd, J=15.6, 6.2 Hz, IH), 1.74(dt, J=12.3, 2.5 Hz, IH), 1.54(s, 3H), 1.45(s, 3H), 1.40(dd, J=11.4, 10.2 Hz, IH).

MS (m/z) 290(M⁺, 3), 232(M⁺-C0₉Me, 4), 215(15), 158(50), 104(100).

REFERENCE EXAMPLE 3

Preparation of methyl (3R^* ,5S^*)-6-oxo-3, 5- isopropylidenedioxy-6-heptenoate

- 25 -

Methyl (3R^*,5S^*,6E)-7~phenyl-3,5-isopropylidenedioxy- 6-heptenoate (340 mg, 1.17 mmol) obtained in Reference Example 2 was dissolved in ethanol (50 ml), and the solution was cooled to -78°C. A gas mixture of ozone and oxygen supplied from an ozone-generator, was introduced, and the introduction was continued until the reaction solution turned blue. Then, nitrogen gas was introduced to remove excess ozone gas. Then, dimethylsulfide (1.0 ml) was added thereto. The reaction mixture was stirred at room temperature for 12 hours and concentrated. The product was purified by column chromatography (hexane:ethyl acetate = 3:1) to obtain methyl (3R",5S^X)- 6-0x0-3,5-isopropylidenedioxy-6-heptenoate (210 mc, 83%) as colorless crystals. Rf = 0.14 (hexane:ethyl acetate = 2:1)

IR(CHC1₃):2950, 1735, 1435, 1380, 1080, 1030, 775, 730 cm.-¹ _. ¹H-NMR(CDC1₃): S 9.58(s, IH), 4.38(m, IH), 4.33(m, IH), 3.70(s_, 3H_), 2.58(dd, J=15.8, 7.0 Hz, IH), 2.44(dd, J=15.8, 6.0 Hz, IH)_, 1.86₍d_t, J=12.9, 2.7 Hz, IH), 1.50(s, 3H), 1.46(s, 3H), 1.35(dt, J=12.0, 12_.0 Hz_, IH).

MS (m/z) 201(M⁺-Me, 24), 129(31), 97(36), 59(100). REFERENCE EXAMPLE 4

Preparation of methyl (3S, 5R, 6E)-7-phenyl-3 , 5-dihvdroxy- 6-heotenoate

(4S)-4,7,7-trimethyl-3-exo-(l- naphthyl)bicyclo[2.2.1]heptan-2-exo-yl (3S,5R,6E)-7- phenyl-3,5-dihydroxy-6-heptenoate (210 mg, 0.42 mmol) prepared in accordance with a literature [J. Org. Chem. , 56_, 5752 (1991)] was dissolved in methanol, and a IM sodium hydroxide aqueous solution (0.2 ml) was added thereto. The mixture was stirred at room temperature for 12 hours. Then, methanol was removed under reduced pressure. The residue was diluted with water, and (4S)- 4,7,7-trimethy1-3-exo-(1-naphthyl)bicyclo[ 2.2.1]heptan-2- exo-ol was extracted with diethyl ether. The aqueous layer was acidified with hydrochloric acid, and the carboxylic acid was extracted with diethyl ether. The organic layer was treated with a diethyl ether solution of diazomethane to form a methyl ester. Acetic acid was added to consume excess diazomethane, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, then dried over anhydrous magnesium sulfate and concentrated. The product was purified by column chromatography

(hexane:ethyl acetate = 2:1) to obtain methyl (3S,5R,6E)- 7-phenyl-3,5-dihydroxy-6-heptenoate (92 mg, 87%) as colorless oil. Rf = 0.08 (hexane:ethyl acetate = 2:1)

IR(CHC1₃): 3475, 3005, 1720, 1490, 1435, 1205, 1110, 1070, 1030, 775, 730 cm^"1. ^IH- MR(CDC1₃): δ 7.38(d, J=7.2 Hz, 2H), 7.31(t, J=7.2 Hz, 2H), 7.24(t_t, J=7.2 Hz, 1.3, IH), 6.62(d, J = 15.7 Hz, IH), 6.21(dd, J=15.7, 6.4 Hz, IH), 4.59(m,lH), 4.43(m, IH), 3.74(s, IH), 3.72(s, 3H), 3.24(s, IH), 2.54(dd, J=19.8, 16.5 Hz, IH), 2.52(dd, J=17.4, 16.5 Hz, IH), l.S0(dt, J=14.3, 9.4 Hz, IH), 1.73(dt, J=14.3, 3.1 Hz, IH). MS (m/z) 250(M⁺, 2.5), 232(M^÷-H₂0, 3.5), 218(4), 215(4), 200(15), 158(60), 104(100).

HRMS Calcd. for C₁₄H_lg0₄; M⁺ 250.1222, found m/z 250.1224. [*]_D ²⁰+8.23° (c 1.19, CHC1₃)

REFERENCE EXAMPLE 5 Preparation of methyl (3S,5R,6E)-7-phenyl-3,5- isopropylidenedioxy-6-heptenoate

Methyl (3S,5R,6E)-7-phenyl-3,5-dihydroxy-6-heptenoate (90 mg, 0.36 mmol) obtained in Reference Example 4 and p- toluenesulfonic acid (5 mg, catalytic amount) were dissolved in acetone dimethylacetal (1.0 ml). The reaction mixture was stirred at room temperature for 6 hours. Then, the mixture was diluted with diethyl ether, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and a sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated. The product was purified by column chromatography (hexane:ethyl acetate = 10:1) to obtain methyl (3S,5R,6E)-7-phenyl-3,5- isopropylidenedioxy-6-heptenoate (97 mg, 92%) as colorless oil.

Rf = 0.78 (hexane:ethyl acetate = 2:1)

IR(CHC1₃): 3000, 1735, 1440, 1380, 1200, 1160, 1085, 1030, 770, 740 cm^"1. ¹H-NMR(CDC1₃): δ 7.37(d, J=7.2 Hz, 2H), 7.29(t, J=7.2 Hz, 2H), 7.24(tt, J=7.2, 1.3 Hz, IH), 6.60(d, J=15.9 Hz, IH), 6.16(dd, J = 15.9, 6.2 Hz, IH), 4.57(m,lH), 4.40(m, IH), 3.70(s, 3H), 2.60(dd, J=15.6, 6.9 Hz, IH), 2.52(dd, J=15.6, 6.2 Hz, IH), 1.74(dt, J=12.3, 2.5 Hz, IH), 1.54(s, 3H), 1.45(s, 3H), 1.40(dd, J=l 1.4, 10.2 Hz, IH).

MS (m/z) 290(M⁺, 3), 232(M⁺-C0₂Me, 4), 215(15), 158(50), 104(100). Milli MS Calcd. for C₁₇H₂₂0₄ M⁺; 290.1498, found m/z; 290.1496. [ ]_D ²⁰ +6.66^* (c 1.11, CHC1₃)

REFERENCE EXAMPLE 6

Preparation of methyl (3S,5R)-6-oxo-3,5- isopropylidenedioxy-6-heptenoate

Methyl (3S,5R,6E)-7-phen l-3,5-isopropylidenedioxy-6- heptenoate (120 mg, 0.41 mmol) obtained in Reference Example 5 was dissolved in methanol (20 ml), and the solution was cooled to -78°C. A gas mixture of ozone and oxygen supplied from an ozone generator, was introduced, and the introduction was continued until the reaction solution turned blue. Then, nitrogen gas was introduced to remove excess ozone gas, and dimethyl sulfide (0.5 ml) was added thereto. The reaction mixture was stirred at room temperature for 12 hours and concentrated. The product was purified column chromatography (hexane:ethyl acetate = 3:1) to obtain methyl (3S,5R)-6-oxo-3,5- isopropylidenedioxy-6-heptenoate (49 mg, 90%) as colorless oil. Rf = 0.14 (hexane:ethyl acetate = 2:1)

IR(CHC1₃): 2950, 1735, 1435, 1380, 1080, 1030, 775, 730 cm^'1. ¹H-NMR(CDC1₃): δ 9.58(s, IH), 4.38(m,lH), 4.33(m, IH), 3.70(s, 3H), 2.58(dd, J=15.8, 7.0, IH), 2.44(dd, J=15.8, 6.0, IH), 1.86(dt, J=12.9, 2.7, IH), 1.50(s, 3H), 1.46(s, 3H), 1.35(dt, J=12.0. 12.0, IH). MS (m/z) 201(M⁺-Mε, 24), 129(31), 97(36), 59(100). [ a ]_D ²⁰=20.0θ^' (c 1.03, CHC1₃)

REFERENCE EXAMPLE 7

Preparation of 3-bromomethyl-2-cyclopropyl-4-(4- fluorophenyl)quinoline

Phosphorus tribromide (4.0 ml, 42.1 mmol) was added at room temperature to a toluene (40 ml)-methylene chloride (20 ml) solution of 2-cyclopropyl-3- hydroxymethyl-4-(4-fluorophenyl)quinoline (6.0 g, 20.5 mmol). The reaction mixture was stirred at room temperature for 3 hours and then poured into an aqueous sodium hydrogencarbonate solution to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (hexane:chloroform = 3:1) to obtain the desired product (6.54 g, 89%) as white crystals. Melting point: 140°C

^!H-NMR(CDC1₃): δ 7.97(d, J=8.9, IH), 7.62(dd, J=6.8. 1.6 Hz_, IH₎, 7.40(m, 6H), 4.59(s, 2H), 2.5l(m, IH), 1.41-1.37(m, 2H), 1.16-1.12₍m, 2H).

Triphenylphosphine (2.81 g, 10.7 mmol) was added to a toluene solution (50 ml) of 3-bromomethyl-2-cyclopropyl- 4-(4-fluorophenyl)-quinoline (4.00 g, 10.2 mmol) obtained in Reference Example 7, and the mixture was refluxed under heating for 5 hours. The formed solid was collected by filtration, washed with toluene and then dried to obtain {2-cyclopropyl-4-(4-fluorophenyl)- quinolin-3-yl}methyltriphenylphosphonium bromide (6.80 g, quantitative yield) as white powder. Melting point 245°C (decomposed)

IR(CHC1₃): 3300, 3050, 1600, 1520, 1495, 1440, 1320, 1220, 1150, 920, 840 cm^"1. ¹H-NMR(CDC1₃):^ 0.3-0.7 (m, 2H), 1.2-0.9 ( , 2H), 2.5-2.0 ( , IH)_, 5.5(d, 2H, 14.4Hz), 8.0-6.8(m, 23H).

EXAMPLE 2

Preparation of diethyl {2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}methylphosphonate

Triethyl phosphite (3.50 ml, 20.4 mmol) was added to a toluene solution (30 ml) of 3-bromomethyl-2- cyclopropyl-4-(4-fluorophenyl)quinoline (4.00 g, 10.2 mmol) obtained in Reference Example 7, and the reaction mixture was refluxed under heating for 12 hours. The solvent was removed under reduced pressure, and the product was purified by column chromatography (hexane:ethyl acetate = 2:1) to obtain diethyl {2- cyclopropyl-4-(4-fluorophenyl-quinolin-3- yl}methylphosphonate (4.14 g, quantitative yield) as colorless crystals. Melting point: 89°C Rf = 0.09 (hexane:ethyl acetate = 5:1)

IR(CHC1₃) 2950, 1600, 1510, 1490, 1435, 1240, 1145, 1020, 970, 830 cm^"1 ¹H-NMR(CDC1₃): δ 8.95(d, J=8.4 Hz, IH), 7.59(dt, 7.0, 1.2 Hz, IH), 7.35-7.17(m, 6H), 4.01-3.84(m, 4H), 3.43(d, J=22.5 Hz, 2H), 2.67- 2.61(m, IH), 1.33-1.29(m, 2H), 1.19(t, J=7.0 Hz, 6H), 1.09(dd, J=8.0, 3.1 Hz, 2H).

MS (m/z) 413 (M⁺, 63 ), 385 (4), 356(4), 328 (5) , 276( 100) .

EXAMPLE 3

Preparation of diphenyl {2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}methylphosphine oxide

Diphenylethoxyphosphorane (1.30 g, 5.65 mmol) was added to a toluene solution (20 ml) of 3-bromomethyl-2- cyclopropyl-4-(4-fluorophenyl)quinoline (1.00 g, 2.80 mmol) obtained in Reference Example 7, and the reaction mixture was refluxed under heating for 12 hours. The solvent was removed under reduced pressure, and the product was purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain diphenyl {2- cyclopropyl-4-(4-fluorophenyl)quinolin-3- yljmethylphosphine oxide (1.38 g, quantitative yield) as colorless crystals. Melting point: 170°C Rf = 0.11 (hexane:ethyl acetate = 2:1)

IR(CHC1₃) 2950, 1605, 1510, 1490, 1435, 1210, 1110, 1025, 830 cm^'1 Η-NMR(CDC1₃): δ 7.95(d, J=S.3 Hz, IH), 7.57(t, J=7.2 Hz, IH), 7.51- 7.33(m, IH), 7.24(td, J=7.0. 1.2 Hz, IH), 7.05(d, J=S.4 Hz, IH), 6.99(d,

J=8.7 Hz, IH), 6.97(d, J=8.7 Hz, IH), 6.80(d, J=5.5 Hz, IH), 6.78(d, J=5.5 Hz, IH), 4.04(d, J=14.0 Hz, 2H), 2.61-2.55(m, IH), 1.24-1.20(m,

2H), 0.89(dd, J=8.8, 3.1 Hz, 2H).

MS (m/z) 477(M⁺, 3), 449(0.1), 352(4), 246(8), 201(50), 124(25), 77(100).

EXAMPLE 4

Preparation of methyl (3R^*,5S^*)-7-{2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate

6Z

t-Butyl lithium (0.15 ml, 1.60M pentane solution, 0.24 mmol) was added at -78°C to a THF solution (3.0 ml) of diethyl {2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- yl}methylphosphonate (100 mg, 0.24 mmol) obtained in Example 2, and the mixture was stirred at -78°C for 30 minutes. A THF solution (2.0 ml) of methyl (3R^*,5S^*)-6- oxo-3,5-isopropylidenedioxy-6-heptenoate (50 mg, 0.23 mmol) obtained in Reference Example 3, was added at -78°C, and reaction mixture was stirred for 3 hours from -78°C to 0°C and further stirred for 2 hours at room temperature. A saturated sodium hydrogencarbonate aqueous solution was added to terminate the reaction, and the reaction mixture was extracted with diethyl ether. The organic layer was washed with a sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (hexane:ethyl acetate = 10:1) to obtain methyl (3R^*,5S^*,6Z)-7-{2-cyclopropyl-4-(4- luorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate (14 mg, 12%) as colorless crystals and (6E)- form (31 mg, 29%) as colorless crystals. 6Z-form

Rf = 0.40 (hexane:ethyl acetate = 5:1)

IR(CHC1₃) : 3000, 1730, 1600, 1510, 1490, 1380, 1230, 1160, 1090, 840 cm"¹.

¹H-NMR(CDC1₃):5 7.96(d, J=8.2 Hz, IH), 7.62(dd, J=6.7, 1.5 Hz, IH),

7.37-7.15(m, 6H), 6.42(d, J=11.4 Hz, IH), 5.61(dd, J=11.4, 8.2 Hz, IH),

^'4.38-4.30(m, IH), 4.13-4.06(m, IH), 3.64(s, 3H), 2.48(dd, J=15.5, 6.8

Hz, IH), 2.46-2.41(m, IH), 2.29(dd, J=15.5, 6.3 Hz, IH), 1.46(s, 3H),

1.40-1.35(m, 4H), 1.37(s, 3H), 1.31-1.25(m, 2H), 1.04(dd, J=8.1, 3.3 Hz,

2H).

MS (m/z) 475(M⁺, 6), 416(8), 400(5), 344(21), 288(100), 275(43)

6E-form Melting point: 133°C

Rf = 0.33 (hexane:ethyl acetate = 5:1) IR₍CHC ₎ : 3000_, 1730, 1605, 1510, 1490, 1380, 1230^, 1160^, 1090^, 840 cm

¹H-NMR₍CDC1₃₎: δ 7.95(d, J=8.4 Hz, IH), 7.58(dd, J=6.6, 1.6 Hz^, IH⁾, 7.37-7.15₍m, 6H), 6.55(dd, J=16.3, 1.2 Hz, IH), 5.57⁽dd, J=16.3, 6.1 Hz, IH)_, 4.38-4.33(m, IH), 4.32-4.25(m, IH), 3.71(s, 3H), 2.54⁽dd, J=15.6, 6.7 Hz_, IH), 2.43(m, IH), 2.35(dd, J=15.6. 6.4 Hz, IH), 1.46(s. 3H)^, 1.40-1.35(m, 4H₎, 1.37(s, 3H), 1.31-1.25(m, 2H), 1.04⁽dd^, J=8^.1^, 3.3 Hz^,

2H).

MS (m/z): 475(M⁺, 6), 416(8), 400(5), 344(21), 288(100^), 275(43).

EXAMPLE 5

Preparation of methyl (3R^*,5S^*,6E)-7-{2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate

A THF solution (6 ml) of diphenyl {2-cyclopropyl-4- (4-fluorophenyl-3-yl}methylphosphine oxide (115 mg, 0.24 mmol) obtained in Example 3, was cooled to -78°C. Then, butyl lithium (0.16 ml, 0.26 mmol) was added thereto, and the mixture was stirred for 30 minutes. A THF solution (2.0 ml) of methyl (3R*,5S*)-6-oxo-3,5- isopropylidenedioxy-6-heptenoate (50 mg, 0.23 mmol) obtained in Reference Example 3 was stirred at -78°C for 4 hours, and then the temperature was raised to room temperature overnight with stirring. The mixture was treated in the same manner as in Example 4 to obtain methyl (3R^*,5S*,6E)-7-{2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate (71 mg, 64%) as colorless crystals. The E/Z ratio was 99:1 as measured by ¹H-NMR.

The melting point, Rf, IR, ^-NM and MS agreed to 6E-form of Example 4. EXAMPLE 6

Butyl lithium (0.16 ml, 1.62M hexane solution, 0.26 mmol) was added at -78°C to a THF solution (2.0 ml) of 2,2,6,6-tetramethylpiperidine (37 mg, 0.26 mmol), and the mixture was stirred at -78°C for 15 minutes. A THF solution (4.0 ml) of diphenyl {2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}methylphosphine oxide (115 mg, 0.24 mmol) obtained in Example 3, was added thereto at -78°C, and the mixture was stirred at room temperature for 30 minutes. A THF solution (2.0 ml) of methyl

(3R^*,5S^*)-6-OXO-3,5-isopropylidenedioxy-6-heptenoate (50 mg, 0.23 mmol) obtained in Reference Example 3, was added thereto at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was treated in the same manner as in Example 4 to obtain methyl (6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin- 3-yl}-3,5-isopropylidenedioxy-6-heptenoate (84 mg, 76%) as colorless crystals. The E/Z ratio was 98:2 as measured by ^- MR.

The melting point, Rf, IR, ¹H-NMR and MS agreed to 6E-form of Example 4. EXAMPLES 7 to 10

Using the following amines instead of 2,2,6,6- tetramethylpiperidine in Example 6, the reaction was conducted in the same manner to obtain the following results.

Yield of

Examples Amines 6E-form (%) E/Z

7 Diisopropylamine 54 98:2

8 Bistri ethylsilylamine 47 98:2

9 Dicyclohexylamine 60 97:3

10 Isopropylcyclohexylamine 64 95:5

EXAMPLE 11

Preparation of methyl (3S,5R,6E)-7-{2-cyclopropyl-4-(4- fluorophenyl)cτuinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate

Butyl lithium (0.125 ml, 1.62M hexane solution, 0.20 mmol) was added at -78°C to a THF solution (2.0 ml) of 2,2,6,6-tetramethylpiperidine (29 mg, 0.20 mmol), and the mixture was stirred at -78°C for 15 minutes. A THF solution (4.0 ml) of diphenyl {2-cyclopropyl-4-(4- fluorophenyl)isoquinolin-3-yl}-methylphosphine oxide (98 mg, 0.20 mmol) obtained in Example 3, was added thereto at -78°C, and the mixture was stirred at room temperature for 30 minutes. Then, a THF solution (2.0 ml) of methyl (3S,5R)-6-0x0-3,5-isopropylidenedioxy-6-heptenoate (38 mg, 0.18 mmol) obtained in Reference Example 6, was added thereto at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. Then, a saturated sodium hydrogencarbonate aqueous solution was added to terminate the reaction, and the mixture was extracted with diethyl ether. The organic layer was washed with a sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated. The product was purified by column chromatography (hexanerethyl acetate = 5:1) to obtain methyl (3S,5R,6E)- 7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5- isopropylidenedioxy-6-heptenoate (62 mg, 74%) as colorless oil. The E/Z ratio was 98:2 as confirmed by ^LH-NMR .

[α]_D ²⁰ = 19.16° (c 0.96, CHC1₃)

Rf = 0.33 (hexane:ethyl acetate = 5:1)

IR(CHC1₃): 3000, 1730,1605, 1510, 1490, 1380, 1230, 1160, 1090, 840 cm"¹.

^IH-NMR(CDCl₃):^7.95(d, J=S.4Hz, IH), 7.58(dd, J=6.6, 1.6 Hz, IH),

7.37-7.15(m, 6H), 6.55(dd, J=16.3, 1.2 Hz, IH), 5.57(dd, J=16.3, 6.1 Hz,

IH), 4.38-4.33(m,lH), 4.32-4.25(m, IH), 3.71(s, 3H), 2.54(dd, J=15.6, 6.7Hz, IH), 2.43(m,lH), 2.35(dd, J=15.6, 6.4Hz, IH), 1.46(s,3H), 1.40- 1.35(m,4H), 1.37(s,3H), 1.3 l-1.25(m,2H), 1.04(dd, J=8.1, 3.3Hz, 2H). MS (m/z) 475(M⁺, 6), 416(8), 400(5), 344(21), 288(100), 275(43).^' HRMS(Calcd. for C₂₉H₃₀O₄NF; M⁺ 475.21^9, found m/z 475.2157.

EXAMPLE 12

6Z

Preparation of t-butyl ( 3R,5S)-7-{2-cyclopropyl-4-( 4- fluorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate

Butyl lithium (0.42 ml, 0.67 mmol) was added at -70°C to a THF solution (15 ml) of {2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}methyltriphenylphosphonium bromide obtained in Example 1, and the mixture was stirred at -78°C for 30 minutes. A THF solution (5 ml) of t-butyl (3R,5S)-6-oxo-3,5-isopropylidenedioxy-6- heptenoate (208 mg, 0.78 mmol) separately prepared, was added thereto at -78°C, and the mixture was stirred for 2 hours at -78°C and further overnight while raising the temperature to room temperature. The mixture was treated and purified in the same manner as in Example 4 to obtain t-butyl (3R,5S,6Z)-7-{2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate (140 mg, 40%) as colorless oil and 6E-form (200 mg, 58%) as colorless crystals. 6Z-form

Rf = 0.40 (hexane:ethyl acetate = 5:1)

IR(CHC1₃): 3450, 3000, 1720, 1595, 1560, 1510, 1490, 1380, 1310, 1260, 1220, 1200, 1160, 1100, 1030, 970, 950, 920, 840 cm"¹

¹H- MR(CDC1₃):<? 7.0-8. l(m, 8H), 6.4(d, J=llHz, IH), 5.6(dd, J=ll, 8Hz, IH), 3.7-4.2(m,2H), 2. l-2.7(m,3H), 0.8-1.7( , 21H).

MS (m/z) 518(M⁺H, 100), 462, 404, 386, 344, 316, 288, 274, 262, 220_, 173, 154, 136.

6E-form

Melting point: 46°C _D ²⁵ = +10.4° (c 1.0, CHC1₃)

Rf = 0.33 (hexane:ethyl acetate = 5:1) IR(-KBr): 3450, 3000, 1720, 1600, 1560, 1510, 1490, 1380, 1310, 1260, 1220, 1200, 1160, 1100, 1030, 970, 950, 920, 840 cm^"1.

¹H-NMR(CDCl₃):60MHz, 57-8(m,8H), 6.5(d, J=16Hz, IH), 5.5(dd, J=16, 6Hz, IH), 4.0-4.5(m, 2H), 2.2-2.6(m, 3H), 0.85-1.7(m, 21H). MS (m/z) 518(M⁺H, 100), 462, 404, 386, 344, 316, 288, 274, 262, 220, 173, 154, 136.

EXAMPLE 13

Preparation of t-butyl (3R,5S,6E)-7-{2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy-6- heptenoate

Butyl lithium (1.24 ml, 2.0 mmol) was added at 0°C to a THF solution (5 ml) of 2,2,6,6-tetramethylpiperidine (161 mg, 1.1 mmol), and the mixture was stirred for 15 minutes. The mixture was cooled to -78°C. Then, a THF solution (5 ml) of diphenyl {2-cyclopropyl-4-(4- fluorophenyl)isoquinolin-3-yl}methylphosphine oxide (419 mg, 0.86 mmol) obtained in Example 3, was added thereto, and the mixture was stirred for 30 minutes. Then, a THF solution (5 ml) of t-butyl (3R,5S)-6-oxo-3,5- isopropylidenedioxy-6-heptenoate (294 mg, 1.1 mmol) separately prepared, was added thereto, and the mixture was stirred for 4 hours at -78°C and then overnight to room temperature. The mixture was treated in the same manner as in Example 6 to obtain t-butyl (3R,5S,6E)-7-{2- cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5- isopropylidenedioxy-6-heptenoate (378 mg, 83%) as white crystals. The E/Z ratio was 95:5 as confirmed by high performance liquid chromatography.

The melting point, ! ]_D ²⁵, Rf, IR, ¹H-NMR and MS agreed to 6E-form of Example 12.

REFERENCE EXAMPLE 8

Preparation of (4R^*,6S^*)-6-{2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl-E-ethenyl}-4-hydroxy- ,4,5,6- tetrahydro-2H-pyran-2-one

A methyl chloride solution (2 ml) of trifluoroacetic acid (170 mg, 1.5 mmol) was added to a methylene chloride solution (5 ml) of methyl (3R^*,5S^*,6E)-7-{2-cyclopropyl- 4-( -fluorophenyl)quinolin-3-yl}-3,5-isopropylidenedioxy- 6-heptenoate (48 mg, 0.1 mmol) obtained in Example 5, and the mixture was stirred at room temperature for 24 hours. The reaction solution was cooled with ice, and then a 5% sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with methyl chloride. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate = 5:1) to obtain (4R^*,6S*)-6-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- yl-E-ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (30 mg, 75%) as white crystals. Melting point: 201°C

IR(CHC1₃): 3440, 3005, 1730, 1600, 1560, 1510, 1490, 1410, 1230, 1155, 1060, 970, 830, 730 cm^"1.

¹H-NMR(CDC1₃):5 1.03-1.08(m,2H), 1.30-1.40( , 2H), 1.56-1.60(m, IH), 1.78(m, IH), 2.38(m, IH), 2.60(ddd, J=7.4, 4.0, 1.5Hz, IH), 2.70(dd, J=13.0, 4.8 Hz, IH), 4.25(m, IH), 5.18 and 4.66(m, IH, ratio 64:36), 5.62(dd, J=16.1, 6.2Hz, IH), 6.72(dd, J=16.1, 1.4Hz, IH), 7.17-7.25(m, 4H), 7.30-7.37(m, 2H), 7.61(dd, 3=6. 1 , 2.1Hz, IH), 7.96(d, J=8.3Hz, IH). MS (m/z) 403(M⁺, 9), 316(11), 288(100), 274(12).

REFERENCE EXAMPLE 9

Preparation of (4R,6S)-6-{2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl-E-ethenyl)-4-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one

t-Butyl (3R,5S,6E)-7-{2-cycloropyl-4-(4- fluorophenyl)quinolin-3-yl}-3,5-isopropylideneoxy-6- heptenoate (259 mg, 0.5 mmol) obtained in Example 13, was reacted in the same manner as in Reference Example 8 to obtain (4R,6S)-6-{2-cyclopropyl-4-(4- fluorophenyl )quinolin-3-yl-E-ethenyl}-4-hydroxy-3 ,4,5,6- tetrahydro-2H-pyran-2-one (151 mg, 75%) as white crystals.

Melting point: 139°C [α]_D ²⁰ = +9.0° (c 1.0, CHC1₃)

Rf = 0.19 (hexane: ethyl acetate = 2:1)

IR(CHC1₃):3440, 3005, 1730, 1600, 1560, 1510, 1490, 1410, 1230, 1155, 1060, 970, 830, 730 cm^"1.

¹H-NMR(CDC1₃):5 1.03-1.08(m,2H), 1.30-1.40(m, 2H), 1.56-1.60(m, IH), 1.78(m, IH), 2.38(m, IH), 2.60(ddd, J=7.4, 4.0, 1.5Hz, IH), 2.70(dd, 1=13.0, 4.8 Hz, IH), 4.25(m, IH), 5.18 and 4.66(m, IH, ratio 64:36), 5.62(dd, J=16.1, 6.2Hz, IH), 6.72(dd, J=16.1, 1.4Hz, IH), 7.17-7.25(m, 4H), 7.30-7.37(m, 2H), 7.61(dd, J=6.1, 2.1Hz, IH), 7.96(d, J=8.3Hz, IH). MS (m/z) 403(M⁺, 9), 316(11), 288(100), 274(12).

INDUSTRIAL APPLICABILITY

The present invention provides a novel intermediate for a condensed pyridine type mevalonolactone derivative which is a HMG-CoA reductase inhibitor and which is useful as a hypercholesterolemia therapeutic agent or as an arteriosclerosis therapeutic agent and a process for its production as well as a novel condensed pyridine derivative useful as a starting material therefor.

Claims

CLAIMS :

1. A condensed pyridine type mevalonolactone intermediate of the formula (1):

wherein ring X is a benzene ring, a substituted benzene ring or a substituted 5- or 6-membered heteroaromatic ring, each of R¹ and R² which are independent of each other, is hydrogen, _λ_₈ alkyl, C₃_₇ cycloalkyl, C_1-3 alkoxy, butoxy, i-butoxy, sec-butoxy, tert-butoxy, R²⁰R²¹N- (wherein each of R²⁰ and R²¹ which are independent of each other, is hydrogen or C_1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -0(CH₂)_€OR²² (wherein R²² is hydrogen or C_χ_₃ alkyl, and is 1, 2, or 3); or R¹ and R² together form -CH=CH-CH=CH- or methylenedioxy, when they are at the o-position to each other;

R³ is hydrogen, C^_g alkyl, C₂_₆ alkenyl, C₃_₇

hydrogen, C-^_g alkyl, C₁_₈ alkoxy, C_λ_₃ alkylthio, chloro, bromo, fluoro, chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethox , difluoromethoxy, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy or

hydroxymethyl); or C₁_₃ alkyl substituted by one

(wherein R⁷ is as defined above) and zero, one or two

C_1-3 alkyl;

Z is

R¹⁰ is methyl, ethyl, propyl, isopropyl, tert-butyl, tetrahydropyranyl, allyl, benzyl, triphenylmethyl, trimethylsilyl or tert-butyldimethylsilyl).

2. The intermediate according to Claim 1, which is a guinoline type mevalonolactone intermediate of the formula (la)

wherein each of R ^a, R^5a and R^6a which are independent of one another, is hydrogen, C₂_₆ alkyl, C₃_₇ cycloalkyl, C_1-3 alkoxy, butoxy, i-butoxy, sec-butoxy, R²⁶R²⁷N-

( herein each of R²⁶ and R²⁷ which are independent of each other, is hydrogen or C_1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or

-0(CH₂)_mOR²⁸ (wherein R²⁸ is hydrogen or C_χ_₃ alkyl, and m is 1, 2, or 3) ; or

R^4a and R^5a together form -CH=CH-CH=CH-; or R^4a and R^5a together form -OC(R²⁹) (R³⁰)O- when they are at the o-position to each other (wherein each of R²⁹ and R³⁰ which are independent of each other, is hydrogen or C_1-3 alkyl); and

R¹, R², R³ and Z are as defined with respect to the formula (1) . 3. The intermediate according to Claim 1, which is a pyrazolopyridine type mevalonolactone intermediate of the formula (lb):

wherein R^4b is hydrogen, _λ_₈ alkyl, C_1-6 alkoxy, C₃_₇ cycloalkyl, C₂_₆ alkenyl, a- or /?-naphthyl, 2-, 3- or 4- pyridyl, 2- or 3-thienyl, 2- or 3-furyl, fluoro, chloro,

bromo , ( wherein each of R^6b , R^7b and R^8b

which are independent of one another, is hydrogen, C_±_₈ alkyl, _₈ alkoxy, C₁_₃ alkylthio, chloro, bromo, fluoro, -NR³¹R³² (wherein each of R³¹ and R³² which are independent of each other, is C_χ_₃ alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -0(CH₂)_nOR³³ (wherein R³³ is hydrogen or C₁_₃ alkyl, and n is 1, 2 or 3), or when R^8b is hydrogen, R^6b and R^7b together form -OC(R³⁴) (R³⁵)0- when they are at the o-position to each other (wherein each of R³⁴ and R³⁵ which are independent of each other, is hydrogen or C₁_₃ alkyl group), or when R^7b and R^8b are simultaneously hydrogen, R^6b is (wherein R³⁶ is hydrogen, C_1-4 alkyl,

C _₃ alkoxy, trifluoromethyl, chloro, bromo or fluoro), phenyl-C₂_₃ alkenyl wherein the phenyl group may be substituted by C_χ_₄ alkyl, C₁_₃ alkoxy, fluorine, chlorine or bromine, or C_λ_₃ alkyl substituted by one member selected from C₁_₃ alkoxy, naphthyl and

(wherein R ,6⁰b^D, R ,7^/b^D and R 8^Bb^D are as

defined above) and zero, one or two C₁_₈ alkyl;

R^5b is bonded to nitrogen atom at the 1- or 2- position of the pyrazolopyridine ring, and such R^5b is hydrogen, C₁_₈ alkyl, C₁_₃ alkyl substituted by from one to three fluorine atoms, C₃_₇ cycloalkyl, a- or β- naphthyl, 2-,

3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3- furyl or

(wherein R ,6^Db^D, R )7b^D and R 8⁰b^D are as defined

above) ; or

C₁_₃ alkyl substituted by one member selected from C₁_₃ alkoxy, hydroxy, naphthyl and (wherein R^6b, R^7b and R^8b are as defined

above) and zero, one or two C _₈ alkyl; and

R¹, R², R³ and Z are as defined with respect to the formula (1) .

4. The intermediate according to Claim 1, which is a thienopyridine type mevalonolactone intermediate of the formula (lc) :

wherein each of R^4c and R^5c which are independent of each other, is hydrogen, C₁_₈ alkyl, C₂_₅ alkenyl, C₃_₇ cycloalkyl, C-^_g alkoxy, fluoro, chloro, bromo,

(wherein each of R^6c, R^7c and R^8c which

are independent of one another, is hydrogen, C₁_ alkyl, C₁_₃ alkoxy, C₃_₇ cycloalkyl, trifluoromethyl, fluoro, chloro and bromo), 2-, 3- or 4-pyridyl, 2- or 5- pyrimidyl, 2- or 3-thienyl, 2- or 3-furyl, (wherein R^6c is as defined above),

-NR³⁷R³⁸ (wherein each of R³⁷ and R³⁸ which are independent of each other, is hydrogen, C₁_₄ alkyl,

(wherein j is 1, 2 or 3, and R^6c

is as defined above), or R³⁷ and R³⁸ together form -(CH₂)_k- (wherein k is 3, 4 or 5)), C₁_₃ alkyl substituted by

(wherein R^6c is as defined above), and

zero, one or two C_±_₃ alkyl, or a- or 5-naphthyl; or

R^4c and R^5c together form C₂_₆ alkylene substituted by from zero to three members selected from C_1-4 alkyl, C₃_₇ cycloalkyl, fluoro, chloro and bromo and zero or one member selected from

(wherein R^6c is as defined above), or

(CHR _? ^J3⁹9)_p-_A_a-_(_/CpH_WR_R ⁴4⁰0)'_q- (wherein each of p and q is 0, 1, 2 or 3, A is -C(R ¹)=C(R⁴²)- (wherein each of R⁴¹ and R⁴² is hydrogen or C_1-3 alkyl), -0-, -S- or -N(R⁴³)- (wherein R⁴³ is hydrogen, C₁_₄ alkyl, or

-(CH₂) (wherein R^6c and j are as defined

above)), and each of R³⁹ and R⁴⁰ which are independent of each other, is hydrogen or C_χ_₄ alkyl) or -CH=CH-CH=CH-; and

R¹, R², R³ and Z are as defined with respect to the formula (I) .

5. The quinoline type mevalonolactone intermediate according to Claim 2, wherein in the formula (la),

R³ is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, i-pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, vinyl, 1- propenyl, 1-methylvinyl, 1-methyl-l-propenyl, 2-methyl-l- propenyl, 1, 2-dimethyl-l-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 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 or 1-methylbenzyl; when R^5a and R^6a are simultaneously hydrogen, R^4a is 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-ethyl, 6-butyl or 7-dimethylamino; or when R^6a is hydrogen, R^4a and R^5a together represent 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-dibromo; or

R⁴ , R^5a and R^6a together represent 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-6,8-dibromo.

6. The pyrazolopyridine type mevalonolactone intermediate according to Claim 3, wherein in the formula (lb),

R³ is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, i-pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, vinyl, 1- propenyl, 1-methylvinyl, 1-methyl-l-propenyl, 2-methyl-l- propenyl, 1,2-dimethyl-l-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 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 or 1-methylbenzyl;

R ^b is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-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- heptylphenyl, 4-octylphenyl, 4-pentylphenyl, 4- hexylphenyl, 4-propylphenyl, 4-butylphenyl, 4-tert- butylphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4- hexyloxyphenyl, 4-heptyloxyphenyl, 4-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- di ethylphenyl, 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, 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, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert- butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclohexyl, benzyl, 2-chlorobenzyl, 2-hydroxybenzyl, 3- trifluoro ethylbenzyl, 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, c-naphthyl, 2-pyridyl, 3-methyl-5- trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-dichloro-4- pyridyl.

7. The thienopyridine type mevalonolactone intermediate according to Claim 4, wherein in the formula (lc), R³ is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, i-pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, vinyl, 1- propenyl, 1-methylvinyl, 1-methyl-l-propenyl, 2-methyl-l- propenyl, 1,2-dimethyl-l-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 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 or 1-methylbenzyl; each of R^4c and R^5c which are independent of each other, is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, 1,2- dimethylpentyl, hexyl, heptyl, octyl, cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, cycloheptyl, cyclopropylmethyl, vinyl, 1-methylvinyl, 1- propenyl, allyl, 1-methyl-l-propenyl, l-methyl-2- propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-ethylvinyl, 1,2-dimethyl-l-propenyl, l,2-dimethyl-2-propenyl, 1- ethyl-1-propenyl, l-ethyl-2-propenyl, 1-methyl-l-butenyl, l-methyl-2-butenyl, 2-methyl-l-butenyl, 1-i-propylvinyl, 1-methyl-l-pentenyl or phenyl; or

R ^c and R^5c together form ethylene, trimethylene, tetramethylene, pentamethylene, methyltetramethylene, chlorotetramethylene or phenyltetramethylene.

8. The quinoline type mevalonolactone intermediate according to Claim 2, wherein in the formula (la), R¹ is p-fluoro, each of R², R^4a, R^5a and R^6a is hydrogen, and R³ is cyclopropyl.

9. The pyrazolopyridine type mevalonolactone intermediate according to Claim 3, wherein in the formula (lb), R¹ is p-fluoro, R² is hydrogen, each of R^4b and R^5b is methyl, and R³ is cyclopropyl.

10. The thienopyridine type mevalonolactone intermediate according to Claim, 4, wherein in the formula (lc), R¹ is p-fluoro, R² is hydrogen, R ^c is ethyl, R^5c is methyl, and R³ is cyclopropyl.

11. A condensed pyridine derivative of the formula (2):

wherein ring X is a benzene ring, a substituted benzene ring or a substituted 5- or 6-membered heteroaromatic ring, each of R¹ and R² which are independent of each other, is hydrogen, C_λ_₈ alkyl, C₃_₇ cycloalkyl, C_1-3 alkoxy, butoxy, i-butoxy, sec-butoxy, tert-butoxy, _R ²⁰ _R ²ⁱ _N_ (_Wherein each of R²⁰ and R²¹ which are independent of each other, is hydrogen or C-^-_j alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -0(CH₂) OR²² (wherein R²² is hydrogen or C±-₃ alkyl, and £ is 1, 2, or 3); or R¹ and R² together form -CH=CH-CH=CH- or methylenedioxy, when they are at the o-position to each other;

R³ is hydrogen, C_λ_₈ alkyl, C₂_₆ alkenyl, C₃_₇

cycloalkyl hydrogen,

bromo, fluoro, chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy or

hydroxymethyl); or C₁_₃ alkyl substituted by one

(wherein R⁷ is as defined above) and zero, one or two C₁_₃ alkyl;

Y is P⁺R¹¹R¹²R¹³Hal^" or P(W)R¹⁴R¹⁵ (wherein each of R¹¹, R¹² and R¹³ which are independent of one another, is methyl, ethyl, propyl, isopropyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, methylphenyl, pentafluorophenyl or benzyl, each of R¹⁴ and R¹⁵ which are independent of each other, is methyl, ethyl, propyl, isopropyl, butyl, 2-chloroethyl, 2,2,2- trifluoroethyl, phenyl, methoxyphenyl, methylphenyl, pentafluorophenyl, benzyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2- trifluoroethoxy, phenoxy, methoxyphenyloxy, methylphenyloxy, pentafluorophenyloxy or benzyloxy, or R¹⁴ and R¹⁵ together form a 5- or 6-membered ring, Hal is chlorine, bromine or iodine, and is 0 or S.

12. The derivative according to Claim 11, which is a guinoline derivative of the formula (2a):

wherein each of R^4a, R^5a and R^6a which are independent of one another, is hydrogen, C_1-6 alkyl, C₃_₇ cycloalkyl, C_λ_₃ alkoxy, butoxy, i-butoxy, sec-butoxy, R²⁶R²⁷N- ( herein each of R²⁶ and R²⁷ which are independent of each other, is hydrogen or C_j__₃ alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -0 ( R₂ ) _mOR² (wherein R²⁸ is hydrogen or C_1-3 alkyl, and m is 1, 2, or 3) ; or

R^4a and R^5a together form -CH=CH-CH=CH-; or R ^a and R^5a together form -OC(R²⁹) (R³⁰)O- when they are at the o-position to each other (wherein each of R²⁹ and R³⁰ which are independent of each other, is hydrogen or C_χ_₃ alkyl); and

R¹, R², R³ and Y are as defined with respect to the formula ( 2) .

13. The derivative according to Claim 11, which is a pyrazolopyridine derivative of the formula (2b):

wherein R is hydrogen, C-^_g alkyl, C_λ_₆ alkoxy, C₃_₇ cycloalkyl, C₂_₆ alkenyl, a- or /?-naphthyl, 2-, 3- or 4- pyridyl, 2- or 3-thienyl, 2- or 3-furyl, fluoro, chloro,

bromo, (wherein each of R° 6^Db, R ,7^/Db and R ,8b

which are independent of one another, is hydrogen, C-^_g alkyl, C_j,_₈ alkoxy, C₁_₃ alkylthio, chloro, bromo, fluoro, -NR³¹R³² (wherein each of R³¹ and R³² which are independent of each other, is C₁_₃ alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethoxy, difluoromethox , phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -0(CH₂)_nOR³³ (wherein R³³ is hydrogen or

'1-3 alkyl, and n is 1, 2 or 3), or when R^8b is hydrogen, R^6b and R^7b together form -OC(R³ ) (R³⁵)0- when they are at the o-position to each other (wherein each of R³⁴ and R³⁵ which are independent of each other, is hydrogen or C₁_₃ alkyl group), or when R^7b and R^8b are simultaneously hydrogen, R^6b is

C_λ_₃ alkoxy, trifluoromethyl, chloro, bromo or fluoro), phenyl-C₂_₃ alkenyl wherein the phenyl group may be substituted by C_χ_₄ alkyl, C₁_₃ alkoxy, fluorine, chlorine or bromine, or C₁_₃ alkyl substituted by one member selected from C₁_₃ alkoxy, naphthyl and

(wherein R ,6^bb^D, R )7^/b^D and R 8⁸b^D are as

defined above) and zero, one or two C₁_₈ alkyl;

R 5b is bonded to nitrogen atom at the 1- or 2- position of the pyrazolopyridine ring, and such R^5b is hydrogen, C-^_g alkyl, C₁_₃ alkyl substituted by from one to three fluorine atoms, C₃_₇ cycloalkyl, a- or β- naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3- furyl or

(wherein R ,6b^D, R ,7b^D and R 8⁰b^D are as defined

above) ; or

C_χ_₃ alkyl substituted by one member selected from C₁_₃ alkoxy, hydroxy, naphthyl and

(wherein R^6b, R^7b and R^8b are as defined

above) and zero, one or two C-^_g alkyl; and

R¹, R², R³ and Y are as defined with respect to the formula (2) .

14. The derivative according to Claim 11, which is a thienopyridine derivative of the formula (2c):

wherein each of R^4c and R^5c which are independent of each other, is hydrogen, C-^_g alkyl, C₂_₆ alkenyl, C₃_₇ cycloalkyl, C₁_₆ alkoxy, fluoro, chloro, bromo,

(wherein each of R^6c, R^7c and R^8c which

are independent of one another, is hydrogen, C₁_₄ alkyl, C₁_₃ alkoxy, C₃_₇ cycloalkyl, trifluoromethyl, fluoro, chloro and bromo), 2-, 3- or 4-pyridyl, 2- or 5- pyrimidyl, 2- or 3-thienyl, 2- or 3-furyl, (wherein R^6c is as defined above),

-(CH₂)_j (wherein j is 1, 2 or 3, and R^6c

(wherein R^6c is as defined above), and

zero, one or two C₁_₃ alkyl, or a- or /9-naphthyl; or

R ^c and R^5c together form C₂_₆ alkylene substituted by from zero to three members selected from C₁_₄ alkyl, C₃_₇ cycloalkyl, fluoro, chloro and bromo and zero or one member selected from

(wherein R^6c is as defined above), or

-(CHR³⁹)_p-A-(CHR⁴⁰)_q- (wherein each of p and q is 0, 1, 2 or 3, A is -C(R ¹)=C(R⁴²)- (wherein each of R⁴¹ and R⁴² is hydrogen or C_χ_₃ alkyl), -0-, -S- or -N(R⁴³)- (wherein R⁴³ is hydrogen, C₁_₄ alkyl, or τ?^6c

-(CH₂)-—C. _/) (wherein R^6c and j are as defined above)), and each of R³⁹ and R⁴⁰ which are independent of each other, is hydrogen or C_1-4 alkyl) or -CH=CH-CH=CH-; and

R¹, R², R³ and Y are as defined with respect to the formula (2) .

15. The quinoline derivative according to Claim 12, wherein in the formula (2a),

R³ is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, i-pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, vinyl, 1- propenyl, 1-methylvinyl, 1-methyl-l-propenyl, 2-methyl-l- propenyl, 1, 2-dimethyl-l-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 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 or 1-methylbenzyl; when R^5a and R^6a are simultaneously hydrogen, R ^a is 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-ethyl, 6-butyl or 7-dimethylamino; or when R^6a is hydrogen, R^4a and R^5a together represent 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-dibromo; or

R^4a, R^5a and R^6a together represent 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-6,8-dibromo.

16. The pyrazolopyridine derivative according to Claim 13, wherein in the formula (2b), R³ is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, i-pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, vinyl, 1- propenyl, 1-methylvinyl, 1-methyl-l-propenyl, 2-methyl-l- propenyl, 1,2-dimethyl-l-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 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 or 1-methylbenzyl;

R^4b is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-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- heptylphenyl, 4-octylphenyl, 4-pentylphenyl, 4- hexylphenyl, 4-propylphenyl, 4-butylphenyl, 4-tert- butylphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4- hexyloxyphenyl, 4-heptyloxyphenyl, 4-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, 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, propyl, i-propyl, 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( rifluoromethyl)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-pyridyl or 2,6-dichloro-4- pyridyl.

17. The thienopyridine derivative according to Claim 14, wherein in the formula (2c),

R³ is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, i-pentyl, 1,2-dimethylpentyl, hexyl, heptyl, octyl, vinyl, 1- propenyl, 1-methylvinyl, 1-methyl-l-propenyl, 2-methyl-l- propenyl, 1,2-dimethyl-l-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 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 or 1-methylbenzyl; each of R^4c and R^5c which are independent of each other, is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, tert-butyl, pentyl, 1,2- dimethylpentyl, hexyl, heptyl, octyl, cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, cycloheptyl, cyclopropylmethyl, vinyl, 1-methylvinyl, 1- propenyl, allyl, 1-methyl-l-propenyl, l-methyl-2- propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-ethylvinyl, 1,2-dimethyl-l-propenyl, l,2-dimethyl-2-propenyl, 1- ethyl-1-propenyl, l-ethyl-2-propenyl, 1-methyl-l-butenyl, l-methyl-2-butenyl, 2-methyl-l-butenyl, 1-i-propylvinyl, 1-methyl-l-pentenyl or phenyl; or R^4c and R^5c together form ethylene, trimethylene, tetramethylene, pentamethylene, methyltetramethylene, chlorotetramethylene or phenyltetramethylene.

18. The quinoline derivative according to Claim 12, wherein in the formula (2a), R¹ is p-fluoro, each of R², R ^a, R^5a and R^6a is hydrogen, and R³ is cylcopropyl.

19. The pyrazolopyridine derivative according to Claim 13, wherein in the formula (2b), R¹ is p-fluoro, R² is hydrogen, each of R ^b and R^5b is methyl, and R³ is cyclopropyl.

20. The thienopyridine derivative according to Claim 14, wherein in the formula (2c), R¹ is p-fluoro, R² is hydrogen, R ^c is ethyl, R^5c is methyl, and R³ is cylcopropyl.

21. A process for producing a compound of the formula (1) as defined in Claim 1, which comprises reacting a compound of the formula (2) as defined in Claim 11 with a base to form an anion, which is then condensed with a compound of the formula (3):

(3). wherein each R^9a and R^9b is a hydroxyl-protecting group, and is independently methoxymethyl, 2- methoxyethoxymethyl, tetrahydropyranyl, 4- methoxytetrahydropyranyl, 1-ethoxyethyl, 1-methyl-l- methoxyethyl, allyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, or R^9a and R^9b together form isopropylidene, cyclopentylidene, cyclohexylidene or benzylidene; and

R¹⁰ is methyl, ethyl, propyl, isopropyl, tert-butyl, tetrahydropyranyl, allyl, benzyl, triphenylmethyl, trimethylsilyl or tert-butyldimethylsilyl.

22. A process for producing a compound of the formula (la) as defined in Claim 2, which comprises reacting a compound of the formula (2a) as defined in Claim 12, with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

23. A process for producing a compound of the formula (lb) as defined in Claim 3, which comprises reacting a compound of the formula (2b) as defined in Claim 13 with_. a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

24. A process for producing a compound of the formula (lc) as defined in Claim 4, which comprises reacting a compound of the formula (2c) as defined in Claim 14 with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

25. A process for producing a quinoline type mevalonolactone intermediate as defined in Claim 5, which comprises reacting a quinoline derivative as defined in Claim 15 with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

26. A process for producing a pyrazolopyridine type mevalonolactone intermediate as defined in Claim 6, which comprises reacting a pyrazolopyridine derivative as defined in Claim 16 with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

27. A process for producing a thienopyridine type mevalonolactone intermediate as defined in Claim 7, which comprises reacting a thienopyridine derivative as defined in Claim 17 with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

28. A process for producing a quinoline type mevalonolactone intermediate as defined in Claim 8, which comprises reacting a quinoline derivative as defined in Claim 18 with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

29. A process for producing a pyrazolopyridine type mevalonolactone intermediate as defined in Claim 9, which comprises reacting a pyrazolopyridine derivative as defined in Claim 19 with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.

30. A process for producing a thienopyridine type mevalonolactone intermediate as defined in Claim 10, which comprises reacting a thienopyridine derivative as defined in Claim 20 with a base to form an anion, which is then condensed with a compound of the formula (3) as defined in Claim 21.