WO1994026710A1

WO1994026710A1 - INDOLE DERIVATIVES AS TESTOSTERONE 5α-REDUCTASE INHIBITORS

Info

Publication number: WO1994026710A1
Application number: PCT/JP1994/000738
Authority: WO
Inventors: Satoshi Okada; Kozo Sawada; Akio Kuroda; Shinya Watanabe; Hirokazu Tanaka
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-05-17
Filing date: 1994-05-02
Publication date: 1994-11-24
Also published as: JPH07509256A; GB9310092D0

Abstract

A compound of formula (I), wherein R1 is an optionally protected carboxy(lower)alkyl, R2 is a hydrogen, a lower alkyl or a halogen, R3 is a hydrogen or an optionally substituted lower alkyl, X is a methylene, -O- or -NH-, and R4 is a cycloalkyl, a nitro or a lower alkoxy and R5 is a hydrogen or a lower alkyl, or R?4 and R5¿ are linked together to form a tetramethylene, or a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a testosterone 5α-reductase inhibitor and effective for testosterone 5α-reductase-mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism), androgenic alopecia (or male-pattern baldness), acne (e.g. acne vulgaris, pimple), other hyperandrogenisms, and the like.

Description

INDOLE DERIVATIVES AS TESTOSTERONE 5 O -REDUCTASE INHIBITORS

Technical Field

The present invention relates to novel indole derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to novel indole derivatives and pharmaceutically acceptable salts thereof, which have pharmacological activities such as inhibitory activity on testosterone 5a.-reductase, to a process for the preparation thereof, to a pharmaceutical composition containing the same, and to a use of the same as a medicament.

Background Art

It has hitherto been known that indole derivatives are effective for testosterone 5a-reductase-mediated diseases. However, a testosterone 5α-reductase inhibitor with stronger effects has been demanded.

Disclosure of Invention

Accordingly, one object of the present invention is to provide novel indole derivatives and pharmaceutically acceptable salts thereof, which are useful as a testosterone 5a- reductase inhibitor.

Another object of the present invention is to provide a process for the preparation of said indole derivatives or salts thereof.

A further object of the present invention is to provide a pharmaceutical composition containing, as an active ingredient, said indole derivative or a pharmaceutically acceptable salt thereof.

A still further object of the present invention is to provide use of said indole derivatives or pharmaceutically acceptable salts thereof as a medicament such as a testosterone 5β-reductase inhibitor useful for treating or preventing testosterone 5a-reductase-mediated diseases such as alopecia, acnes and prostatism in human being or animals.

Indole derivatives of the present invention are novel and can be represented by the formula (I):

H

wherein R¹ is an optionally protected carboxy( lower)alkyl, R² is a hydrogen, a lower alkyl or a halogen, R³ is a hydrogen or an optionally substituted lower alkyl,

X is a methylene, -0- or -NH-, and R⁴ is a cycloalkyl, a nitro or a lower alkoxy and R⁵ is a hydrogen or a lower alkyl, or R⁴ and R⁵ are linked together to form a tetramethylene. According to the present invention, the object compound (I) and a salt thereof can be prepared by the following processes. Process 1

(ID (III) or a salt thereof or a salt thereof

H

⁽I) or a salt thereof

Process 2

hereof

or a salt thereof

H

(I) or a salt thereof

Process 3

Elimination of the carboxy-protective group

(I-a) or a salt thereof

(I-b) or a salt thereof Process 4

of a salt thereof

H

(I) or a salt thereof

wherein each of R¹ , R^z , R³ , R⁴ , R⁵ and X is as defined above,

R¹, is a protected carboxy( lower)alkyl,

Ri is a carboxy( lower)alkyl ,

W¹ is a leaving group, and

W² and W³ are each an acid residue.

Suitable salts of the compound (I) are conventional, non- toxic, pharmaceutically acceptable salts, and include salts with base or acid addition salts. There are exemplified salts with inorganic bases such as alkali metal salts (e.g. sodium salt, potassium salt, cesium salt), alkaline earth metal salts (e.g. calcium salt, magnesium salt) and ammonium salts; salts with organic bases such as organic a ine salts (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt); inorganic acid addition salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate); organic carboxylic or sulfonic acid addition salts (e.g. formate, acetate, trifluoroacetate, aleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate) ; and salts with basic or acidic amino acids (e.g. arginine, aspartic acid, glutamic acid). The preferable salts are acid addition salts.

Suitable examples of the salts of the compounds (I-a), (I-b), (II), (III), (IV), (V), (VI) and (VII) in Processes 1 to 4 are to be referred to those as exemplified for the object compound (I).

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are detailedly as follows:

The term "lower" means that the number of carbon atom is from 1 to 6, preferably 1 to 4, unless otherwise indicated. "Carboxy( lower)alkyl" is a carboxyalkyl whose alkylene chain is lower alkylene.

Suitable "lower alkylene" of "optionally protected carboxy- (lower)alkyl" includes straight or branched bivalent lower alkanes such as methylene, ethylene, trimethylene, tetra- methylene, pentamethylene, hexa ethylene and propylene. Suitable "carboxy( lower)alkyl " includes carboxy ethyl , carboxyethyl , carboxypropyl , carboxybutyl , carboxypentyl and carboxyhexyl . Preferred is carboxy(Cι -C₄ ) alkyl and the most preferred is 3-carboxypropyl .

Suitable "protected carboxy" of "protected carboxy( lower)- alkyl" includes commonly protected carboxy such as esterified carboxyl groups.

Suitable examples of the ester moiety of "esterified carboxy" include, for instance, lower alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester) which may have one or more suitable substituents such as lower alkanoyloxy( lower)alkyl ester [e.g. acetoxy ethyl ester, propionyloxy ethyl ester, butyryloxymethyl ester, valeryloxy ethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)-acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, l(or 2 or 3 or 4)-acetoxybutyl ester, l(or 2)-propionyloxyethyl ester, l(or 2 or 3)-propionyloxypropyl ester, l(or 2)-butyryloxyethyl ester, l(or 2)-isobutyryloxyethyl ester, l(or 2)-pivaloyloxyethyl ester, l(or 2)-hexanoyloxyethyl ester, 3,3-dimethylbutyryloxymethyl ester, l(or 2)-pentanoyl- oxyethyl ester], lower alkanesulfonyl ( lower)alkyl ester [e.g. 2-mesylethyl ester], mono(or di or tri )-halo( lower)alkyl ester [e.g. 2-iodoethyl ester, 2, 2, 2-trichloroethyl ester], lower alkoxycarbonyloxy( lower)alkyl ester [e.g. methoxycarbonyloxy- methyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyl- oxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxy- carbonyloxyethyl ester], phthal idyl idene( lower)alkyl ester, or (5-lower alkyl-2-oxo-l, 3-dioxol-4-yl )( lower)alkyl ester [e.g. (5-methyl-2-oxo-l,3-dioxol-4-yl )methyl ester, (5-ethyl-2-oxo- 1, 3-dioxol-4-yl )methyl ester, (5-propyl-2-oxo-l, 3-dioxol-4-yl )- ethyl ester]; lower alkenyl ester [e.g. vinyl ester, allyl ester]; lower alkynyl esters [e.g. ethynyl ester, propynyl ester]; ar( lower)alkyl esters which may have one or more suitable substituents [e.g. benzyl ester, 4-methoxybenzyl ester, 4-ni trobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl Jmethyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-tert-butylbenzyl ester]; aryl esters which may have one or more suitable substituents [e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester]; and phthalidyl ester.

Preferable examples of the esterified carboxy as mentioned above include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxy- carbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , pentyloxy- carbonyl, tert-pentyloxycarbonyl , hexyloxycarbonyl , 1-cyclo- propylethoxycarbonyl ) .

Suitable "lower alkyl" includes straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl, preferable ones having 1 to 4 carbon atoms. Suitable "lower alkoxy" includes straight or branched ones having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy tert- pentyloxy, hexyloxy and 1-cyclopropylethoxy.

The term "halogen" means fluoro, chloro, bromo and iodo.

Suitable "substituent" of "substituted lower alkyl" includes halogens as mentioned above, and lower alkoxys as mentioned above.

Suitable "cycloalkyl" includes straight or branched ones having 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo- hexylmethyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl, preferable ones having 3 to 8 carbon atoms.

Suitable "leaving group" includes hydroxyl, and reactive groups derived from hydroxyl.

Suitable "reactive group derived from hydroxyl" includes acid residues.

Suitable "acid residue" includes halogen (e.g. fluoro, chloro, bromo, iodo) and acyloxy (e.g. acetoxy, tosyloxy, mesyloxy).

Particularly, the preferred embodiments of R¹ , R² , R³ , R⁴ , R⁵ and X are as follows:

R¹ : carboxy( lower)alkyl and lower alkoxycarbonyl ( lower)alkyl

R² : hydrogen R³ : hydrogen, lower alkyl, trihalo( lower)alkyl and lower alkoxy( lower)alkyl R⁴ : cycloalkyl, nitro and lower alkoxy

R⁵ : hydrogen and lower alkyl

X : -0- and

R⁴ and R⁵ : tetramethylene, which is formed by linking together

Most preferable compounds of the compound (I) are represented by the following formula:

wherein R¹ is a carboxy( lower)alkyl,

R³ is a lower alkyl or a trihalo( lower)alkyl , and R⁴ is a cycloalkyl having 3 to 8 carbon atoms.

The processes 1 to 4 for preparing the object compound (I) of the present invention are explained^' in detail in the fol lowing. Process 1

The object compound (I) and a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.

Suitable salts of the compounds (II) and (III) can be referred to the ones as exemplified for the compound (I).

This reaction is usually carried out in a solvent such as an alcohol [e.g. methanol, ethanol], dichloromethane, benzene, N, N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene or any other solvent which does not adversely affect the reaction. These solvents may be used alone or upon mixing with one another.

In this reaction, when W¹ in the compound (III) is an acid residue, the reaction may be carried out in the presence of an inorganic or organic base. Examples of the base are alkali metal hydroxides [e.g. sodium hydroxide, potassium hydroxide], alkali metal carbonates [e.g. sodium carbonate, potassium carbonate], alkali metal bicarbonates [e.g. sodium bicarbonate, potassium bicarbonate], alkali metal hydrides [e.g. sodium hydride, potassium hydride], tri (lower)alkylamines [e.g. tri- methylamine, triethylamine, di isopropylethylamine], and pyridine and its derivatives [e.g. picoline, lutidine, 4-dimethylamino- pyridine]. In case where the base to be used is a liquid, it can also be used as a solvent.

When W¹ in the compound (III) is hydroxyl, this reaction is usually carried out in the presence of a conventional condensing agent. Examples of the condensing agent are N,N' -dicyclohexyl- carbodi imide; N-cyclohexyl-N' -morphol inoethylcarbodi imide; N-cyclohexyl-N' -(4-diethylaminocyclohexyl )carbodi imide; N,N' - diethylcarbodi imide; N,N' -di isopropylcarbodi imide; N-ethyl-N'- (3-dimethylaminopropyl )carbodi imide; N,N' -carbonylbis(2-methyl- imidazole); pentamethyleneketene-N-cyclohexyl imine; diphenyl- ketene-N-cyclohexyl imine; ethoxyacetylene; 1-alkoxy-l-chloro- ethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate] ; a combination of triarylphosphine [e.g. triphenylphosphine] or tri ( lower)alkylphosphine [e.g. triethyl- phosphine], and di ( lower)alkyl azodicarboxylate [e.g. diethyl azodicarboxylate] ; 2-ethyl-7-hydroxybenzisoxazol ium salt; 2-ethyl-5-(m-sulfophenyl ) isoxazol ium hydroxide intramolecular salt ; l-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N- dimethylformamide with thionyl chloride; phosgene; trichloro- methyl chloroformate; and phosphorus oxychloride.

The reaction temperature is not critical, and the reaction can be carried out under cooling, at room temperature or under warming or heating. Process 2

The object compound (I) and a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.

This reaction can be carried out in substantially the same manner as in Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction temperature] are to be referred to those as explained in Process 1. Process 3

The object compound (I-b) and a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to an elimination reaction of the carboxy-protective group. In the present elimination reaction, all conventional methods used for the elimination of the carboxy-protective group, for example, hydrolysis, reduction, elimination using a Lewis acid, etc. are applicable. When the carboxy-protective group is an ester, it can be eliminated by hydrolysis or elimination using a Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable base includes, for example, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate), alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate), alkali metal acetates (e.g. sodium acetate, potassium acetate), alkaline earth metal phosphates (e.g. magnesium phosphate, calcium phosphate), and alkali metal hydrogen phosphates (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate); and organic bases such as trialkylamines (e.g. trimethylamine, triethylamine), picoline, N-methylpyrrol idine, N-methylmorphol ine, and 1,5-diazabicyclo- [4.3.0]non-5-one, 1, 4-diazabicyclo[2.2.2]octane, and 1,5- diazabicyclo[5.4.0]undecene-5. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid). The present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical, and it may be selected suitably in accordance with the kind of carboxy- protective group and elimination method to be employed.

The elimination using a Lewis acid is preferable for eliminating a substituted or unsubsti tuted ar( lower)alkyl ester, and carried out by reacting the compound (I-a) or a salt thereof with a Lewis acid. Examples of the Lewis acid are boron trihalides (e.g. boron trichloride, boron trifluoride) , titanium tetrahalides (e.g. titanium tetrachloride, titanium tetrabromide), tin tetrahalides (e.g. tin tetrachloride, tin tetrabromide) , aluminum halides (e.g. aluminum chloride, aluminum bromide), and trihaloacetic acids (e.g. trichloro- acetic acid, trifluoroacetic acid). This elimination reaction is preferably carried out in the presence of a cation trapping agent (e.g. anisole, phenol) and is usually carried out in a solvent such as nitroalkane (e.g. ni tromethane, ni troethane), alkylene halide (e.g. methylene chloride, ethylene chloride), diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction.

These solvents may be used alone or upon mixing with one another.

A reduction elimination can be preferably conducted for eliminating protective group such as halo( lower)alkyl (e.g. 2-iodoethyl, 2, 2, 2-trichloroethyl ) ester, and ar( lower)alkyl (e.g. benzyl) ester.

The reduction applicable for the elimination reaction includes the reduction using a combination of a metal (e.g. zinc, zinc amalgam) or a salt of chromium compound (e.g. chromous chloride, chromous acetate) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid); and a conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g. palladium carbon, Raney nickel ).

The reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming. Process 4

The object compound (I) and a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.

This reaction can be carried out in substantially the same manner as in Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction temperature] are to be referred to those as explained in Process 1.

The starting compounds (IV) and (VI) include novel compounds which can be prepared by the following methods or in a conventional manner. The details of the following methods and conventional ones are shown in Preparation Examples to be mentioned below. Method A-(l)

(VIII) (IX) or a salt thereof or a salt thereof

(X) or a salt thereof

Method A-(2)

(X) (V) or a salt thereof or a salt thereof

H

(VI) or a salt thereof Method B

(VIII) (XI) or a salt thereof or a salt thereof

(IV) or a salt thereof

wherein R¹ , R² , R³ , R⁴ , R⁵ , X, W² and W³ are each as defined above, and W⁴ and W⁵ are each an acid residue.

Methods A and B can be carried out in a conventional manner.

The object compound (I) of the present invention can be isolated and purified in a conventional manner such as extraction, precipitation, fractional crystallization, recrystall ization, or chromatography.

The object compound (I) thus obtained can be converted to its salt by a conventional method.

The object compound (I) of the present invention is useful as a testosterone 5α-reductase inhibitor and effective for testosterone 5a-reductase-mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism), androgenic alopecia (or male- pattern baldness), acne (e.g. acne vulgaris, pimple), other hyperandrogenis , and the like.

For therapeutic or preventive administration, the object compound (I) of the present invention is used in the form of a conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable, substantially non-toxic carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration. The pharmaceutical preparation may be in a solid form such as tablet, granule, powder or capsule, or a liquid form such as solution, suspension, syrup, emulsion, lemonade or lotion.

If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly-used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, and ethylene glycol.

While the dosage of the compound (I) may vary depending upon age and conditions of patients, the kind of diseases or conditions, the kind of the compound (I) to be used, etc. In general, amounts between about 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used for treating diseases.

The following Preparation Examples and Examples are given for the purpose of illustrating the present invention.

Preparation Example 1 [Step 1] : To a solution of pentanoyl chloride in methylenechloride was added aluminum chloride, and the mixture was reacted and then added with cyclohexylbenzene. The mixture was reacted at 0°C for an hour, was added with water, and was extracted with methylene chloride. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate and evaporated in vacυo. The residue was chromatographed on silica gel to give 4' -cyclohexylvalero- phenone. ^JH-NMR (CDCla. δ ) : 0.96 (t, 3H, J=7Hz), 1.15 - 1.55 (m, 7H),

1.6 - 2.0 (m, 7H), 2.45 - 2.65 (m, 1H), 2.94 (t, 2H, J=7Hz), 7.28 (d, 2H, J=9Hz), 7.89 (d, 2H, J=9Hz) [Step 2] : To a solution of the 4' -cyclohexylvalerophenone in methanol was added sodium borohydride at room temperature while stirring, and the mixture was reacted for 30 minutes. Then, an aqueous solution of potassium biphosphate was added thereto and concentrated in vacuo. The residue was extracted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel to give l-(4-cyclohexylphenyl )pentanol .

^JH-NMR (CDCls. δ ) : 0.89 (t, 3H, J=7Hz), 1.1 - 1.55 (m, 9H),

1.6 - 2.0 ( , 8H), 2.4 - 2.6 (m, 1H), 4.55 - 4.7 (m, 1H),

7.1 - 7.35 (m, 4H)

Preparation Example 2

The procedure of steps 1 and 2 of Pre. Ex. 1 was repeated except that (cyclopropylmethyl )benzene was used in place of (cyclohexyl )benzene to give l-[4-(cyclopropylmethyl Jphenyl ]- pentanol . ^XH-NMR (CDCls. δ ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H),

0.8 - 1.1 (m, 4H), 1.15 - 1.5 (m, 4H), 1.6 - 1.95 (m, 3H),

2.55 (d, 2H, J=7Hz), 4.6 - 4.7 (m, 1H), 7.15 - 7.35 (m, 4H)

Preparation Example 3

[Step 1] : To a solution of benzylmagnesium chloride in diethyl ether was added cyclohexanone. • The mixture was stirred at room temperature for 30 minutes, and then aqueous ammonium chloride was added thereto. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel to give 1-benzylcyclohexanol . ^JH-NMR (CDC . ά ) : 1.2 - 1.7 (m, 11H), 2.75 (s, 2H),

7.15 - 7.4 (m, 5H)

[Step 2] : To a solution of the 1-benzylcyclohexanol in pyridine was added thionyl chloride at 0°C • The mixture was stirred at 0°C for 20 minutes, then poured into ice water and extracted with diethyl ether. The organic layer was washed with 0.5N hydrochloric acid, aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in a mixture of methanol and 1,4-dioxane, and palladium carbon was added. The mixture was stirred under hydrogen atmosphere (3 atm. ) at room temperature for 1.5 hours. Removal of catalyst and evaporation of solvent gave (cyclohexyl^¬ methyl )benzene. "H-NMR (CDCla. tf ) : 0.8 - 1.35 (m, 5H), 1.4 - 1.85 (m, 6H),

2.49 (d, 2H, J=7Hz), 7.05 - 7.35 ( , 5H)

[Step 3] : The procedure of steps 1 and 2 of Pre. Ex. 1 was repeated except that (cyclohexylmethyl )benzene was used in place of cyclohexylbenzene to give l-[4-(cyclohexylmethyl )phenyl ]- pentanol. ^XH-NMR (CDC1₃, <5 ) : 0.8 - 1.9 (m, 21H), 2.47 (d, 2H, J=7Hz),

4.63 (t, 1H, J=7Hz), 7.11 (d, 2H, < J=8.5Hz), 7.24 (d, 2H,

J=8.5Hz)

Preparation Example 4

[Step 1] : A mixture of 1-iodobutane and zinc-copper couple in benzene and N,N-dimethylformamide was stirred at room temperature for an hour and at 60°C for 3 hours. To the mixture was added a solution of tetrakis(triphenylphosphine)- palladium and 4-nitrobenzoyl chloride in benzene, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel to give 4' -ni trovalerophenone. ^>H-NMR (CDCls. δ ) : 0.98 (t, 3H, J=7Hz), 1.3 - 1.55 (m, 2H),

1.65 - 1.85 (m, 2H), 3.02 (t, 2H, J=7Hz), 8.12 (d, 2H,

J=9Hz), 8.32 (d, 2H, J=9Hz)

[Step 2] : The procedure of step 2 of Pre. Ex. 1 was repeated except that 4' -ni trovalerophenone was used in place of 4' -cyclohexylvalerophenone to give 1-(4-ni trophenyl )pentanol. ^XH-NMR (CDC1₃, <5 ) : 0.89 (t, 3H, J=7Hz), 1.2 - 1.5 (m, 4H),

1.6 - 1.9 (m, 2H), 2.04 (s, 1H), 4.80 (t, 2H, J=7Hz), 7.52 (d, 2H, J=9Hz), 8.21 (d, 2H, J=9Hz)

Preparation Example 5 [Step 1] : A mixture of 2-hydroxy-4-methylbenzoic acid, 1-iodobutane and potassium carbonate in N, N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel to give butyl 2-butoxy-4-methylbenzoate.

^XH-NMR (CDC1₃, <5 ) : 0.9 - 1.05 (m, 6H), 1.35 - 1.9 (m, 8H), 2.36 (s, 3H), 4.02 (t, 2H, J=7Hz), 4.28 (t, 2H, J=7Hz),

6.7 - 6.8 (m, 2H), 7.71 (d, 1H, J=8.5Hz)

[Step 2] : A mixture of the butyl 2-butoxy-4-methyl- benzoate, N-bromosuccinimide and a catalytic amount of benzoyl peroxide in carbon tetrachloride was refluxed for 2 hours. The reaction mixture was cooled to room temperature and filtered.

The filtrate was concentrated and the residue was chromatographed on silica gel to give butyl 4-(bromomethyl )-2- butoxybenzoate.

'H-NMR (CDCl-3, 5 ) : 0.9 - 1.05 (m, 6H), 1.35 - 1.9 (m, 8H),

4.05 (t, 2H, J=7Hz), 4.30 (t, 2H, J=7Hz), 4.45 (s, 2H),

6.9 - 7.0 (m, 2H), 7.74 (d, 2H, J=8.5Hz)

[Step 3] : A mixture of the butyl 4-(bromomethyl )-2-butoxy- benzoate and triphenylphosphine in toluene was refluxed for 14 hours. The mixture was cooled to room temperature and the white solid was filtered off and washed with ether to give (3-butoxy- 4-bυtoxycarbonylbenzyl )triphenylphosphonium bromide. ^-NMR (DMSO-dβ. δ ) : 0.8 - 1.0 (m, 6H), 1.25 - 1.7 (m, 8H),

3.50 (t, 2H, J=7Hz), 4.18 (t, 2H, J=7Hz), 5.21 (d, 2H,

J=16Hz), 6.60 (s, 1H), 6.71 (d, 1H, J=8Hz), 7.54 (d, 1H,

J=8Hz), 7.6 - 8.0 (m, 15H)

[Step 4] : To a suspension of the (3-butoxy-4-butoxy- carbonylbenzyl )triphenylphosphonium bromide in tetrahydrofuran was added potassium t-butoxide at room temperature. After an hour, acetone was added and the mixture was stirred at room temperature for 14 hours. The insoluble materials were filtered off and the^' filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 0.5N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel to give butyl 2-butoxy-4-(2-methyl-l-propenyl )benzoate. ^>H-NMR (CDCls. δ ) : 0.85 - 1.05 (m, 6H), 1.35 - 1.95 (m, 14H), 4.02 (t, 2H, J=7Hz), 4.28 (t, 2H, J=7Hz), 6.25 (s, 2H), 6.75 - 6.85 (m, 2H), 7.76 (d, 2H, J=8.5Hz) [Step 5] : To a mixture of the butyl 2-butoxy-4-(2-methyl- 1-propenyl )benzoate and palladium carbon in methanol was added ammonium formate. The mixture was stirred at room temperature for 20 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated to give butyl 2-butoxy-4-isobutylbenzoate. ^XH-NMR (CDC1₃, <5 ) : 0.85 - 1.05 (m, 12H), 1.35 - 2.0 (m, 9H), 2.48 (d, 2H, J=7Hz), 4.02 (t, 2H, J=7Hz), 4.29 (t, 2H, J=7Hz), 6.7 - 6.8 (m, 2H), 7.71 (d, 1H, J=8.5Hz) [Step 6] : To a solution of the butyl 2-butoxy-4-isobutyl- benzoate in tetrahydrofuran was added l.OM solution of lithium aluminum hydride in tetrahydrofuran at 0 °C and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added dropwise a mixture of tetrahydrofuran and water while cooling. The mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give 2-butoxy-4-isobutylbenzyl alcohol. ^XH-NMR (CDCls. δ ) : 0.85 - 1.05 (m, 9H), 1.4 - 1.6 ( , 3H), 1.7 - 2.0 (m, 3H), 2.46 (d, 2H, J=7Hz), 4.02 (t, 2H, J=7Hz), 4.66 (s, 2H), 6.6 - 6.75 (m, 2H), 7.14 (d, 1H, J=8Hz )

Preparation Example 6

[Step 1] : A mixture of 2-hydroxy-4-methylbenzoic acid, bromoethane and potassium carbonate in N, N-dimethylformamide was stirred at room temperature for 6 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed to give ethyl 2- ethoxy-4-methylbenzoate. ^XH-NMR (CDC . δ ) : 1.3 - 1.5 (m, 6H), 2.37 (s, 3H), 4.09 (q,

2H, J=7Hz), 4.35 (q, 2H, J=7Hz), 6.7 - 6.8 (m, 2H),

7.71 (d, 1H, J=8.5Hz)

[Step 2] : The procedure of steps 2 - 6 of Pre. Ex. 5 was repeated except that ethyl 2-ethoxy-4-methylbenzoate was used in place of butyl 2-butoxy-4-methylbenzoate to give 2-ethoxy-4- isobutylbenzyl alcohol. ^JH-NMR (CDCW. δ ) : 0.90 (d, 6H, J=7Hz), 1.45 (t, 3H, J=7Hz),

1.75 - 2.0 (m, 1H), 2.46 (d, 2H, J=7Hz), 4.09 (q, 2H,

J=7Hz), 4.67 (s, 2H), 6.65 - 6.75 (m, 2H), 7.14 (d, 1H,

J=8Hz)

Preparation Example 7

The procedure of steps 1 - 2 of Pre. Ex. 1 was repeated except that 5, 6, 7, 8-tetrahydronaphthalene was used in place of cyclohexylbenzene to give l-(5, 6, 7, 8-tetrahydro-2-naphthyl )- pentanol. 'H-NMR (CDCls. d ) = 0.89 (t, 3H, J=7Hz), 1.15 - 1.5 (m, 4H),

1.6 - 1.9 (m, 7H), 2.77 (br s, 4H), 4.58 (t, 1H, J=6.5Hz), 7.04 (s, 3H)

Preparation Example 8 [Step 1] : To a mixture of (cyclopropylmethyl )benzene and dichloromethyl methyl ether in dichloromethane was added 2M solution of titanium(IV) chloride in dichloromethane at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 15 minutes, then poured into ice water. The organic layer was separated and washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel to give 4-(cyclopropylmethyl )benzaldehyde. 'H-NMR (CDCl₃, c5 ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.65 (m, 2H), 0.9 - 1.2 ( , 1H), 2.63 (d, 2H, J=7Hz), 7.43 (d, 2H, J=8Hz), 7.82 (d, 2H, J=8Hz), 9.99 (s, 1H) [Step 2] : A solution of propylmagnesium bromide was prepared from diethyl ether, magnesium and 1-bromopropane in a usual manner. A solution of the 4-(cyclopropylmethyl )benz- aldehyde in an ether was added dropwise to the obtained Grinard solution and the mixture was stirred at 0°C for 30 minutes. Aqueous ammonium chloride was added to the reaction mixture and the organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel to give l-[4-(cyclopropylmethyl )- phenyl ]butanol. *H-NMR (CDCls. δ ) : 0.2 - 0.3 ( , 2H), 0.5 - 0.6 (m, 2H), 0.9 - 1.15 (m, 4H), 1.2 - 1.9 (m, 5H), 2.54 (d, 2H, J=7Hz),

4.6 - 4.7 (m, 1H), 7.15 - 7.4 (m, 4H)

[Step 3] : Chromium(VI) oxide was added portionwise to pyridine. After the mixture was stirred at room temperature for 30 minutes, l-[4-(cyclopropylmethyl )phenyl ]butanol was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the mixture was extracted with an ether. The obtained organic solution was washed with 0.5N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel to give 4-(cyclopropylmethyl )- butyrophenone. ^-N R (CDC1₃, <5 ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.6 (m, 2H),

0.9 - 1.15 ( , 4H), 1.65 - 1.9 (m, 2H), 2.60 (d, 2H,

J=7Hz), 2.94 (t, 2H, J=7.5Hz), 7.35 (d, 2H, J=8.5Hz),

7.90 (d, 2H, J=8.5Hz)

[Step 4] : The 4-(cyclopropylmethyl )butyrophenone was added to a solution of (+)-B-chlorodi isopinocampheylborane in tetra^¬ hydrofuran at -20 °C • After 5 hours, the solvent was removed and the residue was dissolved in diethyl ether. Diethanolamine was added, and the mixture was stirred at room temperature for an hour. The solid was filtered off and washed with diethyl ether, after which the filtrate was concentrated and the residue was chromatographed on silica gel to give (R)-l-[4-(cyclopropyl- methyl )phenyl ]butanol. ^XH-NMR (CDCls. δ ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.6 (m, 2H), 0.9 - 1.15 (m, 4H), 1.2 - 1.9 (m, 5H), 2.54 (d, 2H, J=7Hz), 4.6 - 4.7 ( , 1H), 7.15 - 7.4 (m, 4H)

Preparation Example 9 The procedure of steps 2 - 4 of Pre. Ex. 8 was repeated except that 1-bromobutane was used in place of 1-bromopropane to give (R)-l-[4-(cyclopropylmethyl )phenyl ]pentanol . 'H-NMR (CDC1₃, <5 ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H),

0.85 - 1.15 ( , 4H), 1.2 - 1.5 (m, 4H), 1.6 - 1.95 (m, 3H), 2.54 (d, 2H, J=7Hz), 4.6 - 4.7 ( , 1H), 7.15 - 7.4^' ( , 4H)

Preparation Example 10 [Step 1] : Cyclopropylmethyl benzene was reacted with 4, 4, 4-trifluorobutanoic acid, using aluminum chloride and oxalyl chloride in dichloromethane to give 4' -(cyclopropyl^¬ methyl )-4, 4, 4-trifluorobutyrophenone.

*H-NMR (CDC . ά ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H), 0.85 - 1.1 (m, 1H), 2.45 - 2.75 (m, 4H), 3.25 (t, 2H, J=7.5Hz), 7.38 (d, 2H, J=9Hz), 7.92 (d, 2H, J=9Hz) [Step 2] : The procedure of step 4 of Pre. Ex. 8 was repeated except that 4' -(cyclopropylmethyl )-4, 4, 4-trifluoro^¬ butyrophenone was used in place of 4-(cyclopropylmethyl )butyro- phenone to give l-[4-(cyclopropylmethyl )phenyl ]-4, , 4-trifluoro- butanol.

^JH-NMR (CDC . δ ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H), 0.85 - 1.1 ( , 1H), 1.8 - 2.4 (m, 5H), 2.57 (d, 2H, J=7Hz), 4.65 - 4.8 (m, 1H), 7.28 (s, 4H)

Preparation Example 11 [Step 1] : The procedure of steps 2 - 3 of Pre. Ex. 8 was repeated except that 1-bromomethane was used in place of 1- bromopropane to give 4-(cyclopropylmethyl )acetophenone. *H-NMR (CDCla. δ ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.65 (m, 2H),

2.55 - 2.65 (m, 3H), 7.36 (d, 2H, J=8.5Hz), 7.90 (d, 2H,

J=8.5Hz)

[Step 2] : To a mixture of the 4-(cyclopropylmethyl )aceto- phenone and chlorotrimethylsi lane in dichloromethane was added dropwise 1, 8-diazabicyclo[5, 4, 0]undec-7-ene. The mixture was refluxed for 14 hours and concentrated. Hexane was added to the residue and insoluble materials were filtered off. The filtrate was concentrated to give 4-(cyclopropylmethyl )-o(-trimethyl- si lyloxystyrene. ^JH-NMR (CDCl₃, <n : 0.15 - 0.3 (m, 11H), 0.45 - 0.6 (m, 2H),

2.54 (d, 2H, J=7Hz), 4.39 (d, 1H, J=1.5Hz), 4.88 (d, 1H,

J=1.5Hz), 7.21 (d, 2H, J=8.5Hz), 7.52 (d, 2H, J=8.5Hz)

[Step 3] : Boron trifluoride etherate was added to a solution of iodosobenzene in ethanol and the mixture was cooled to -70°C • To the mixture was added 4-(cyclopropylmethyl ) -a- trimethylsi lyloxystyrene, and the mixture was stirred at -70°C for 30 minutes. The temperature was slowly raised to room temperature, then water was added to the mixture and neutralized with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column to give 4' -(cyclopropylmethyl )-2-ethyoxyacetophenone. ^XH-NMR (CDCls.5 ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.65 (m, 2H), 0.9 - 1.15 ( , 1H), 1.30 (t, 3H, J=7Hz), 2.61 (d, 2H, J=7Hz), 3.66 (q, 2H, J=7Hz), 4.73 (s, 2H), 7.37 (d, 2H, J=8.5Hz), 7.89 (d, 2H, J=8.5Hz)

[Step 4] : The procedure of step 4 of Pre. Ex. 8 was repeated except that 4' -(cyclopropylmethyl )-2-ethoxyacetophenone was used in place of 4-(cyclopropylmethyl )butyrophenone to give (S)-l-[4-(cyclopropylmethyl Jphenyl ]-2-ethoxyethanol. ^>H-NMR (CDC . δ ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H), 0.85 - 1.1 (m, 1H), 2.54 (d, 2H, J=7Hz), 2.79 (d, 1H, J=1.5Hz), 3.35 - 3.7 ( , 4H), 4.8 - 4.95 (m, 1H), 7.2 - 7.35 (m, 4H)

Preparation Example 12 [Step 1] : The procedure of step 3 of Pre. Ex. 11 was repeated except that methanol was used in place of ethanol to give 4' -(cyclopropylmethyl )-2-methoxyacetophenone. ^XH-NMR (CDCla. δ ) ^: 0.2 - 0.3 (m, 2H), 0.5 - 0.65 ( , 2H), 0.9 - 1.15 (m, 1H), 2.60 (d, 2H, J=7Hz), 3.52 (s, 3H), 4.70 (s, 2H), 7.36 (d, 2H, J=8.5Hz), 7.88 (d, 2H, J=8.5Hz) [Step 2] : The procedure of step 4 of Pre. Ex. 8 was repeated except that the 4' -(cyclopropylmethyl )-2-methoxyaceto- phenone was used in place of 4-(cyclopropylmethyl )butyrophenone to give (S)-l-[4-(cyclopropylmethyl )phenyl ]-2-methoxyethanol . ^-NMR (CDCla.5 ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H), 0.85 - 1.1 (m, 1H), 2.54 (d, 2H, J=7Hz), 2.69 (d, 1H, J= 1 . 5Hz ) , 3. 35 - 3. 6 (m, 5H ) , 4. 8 - 4. 95 ( m, 1H ) , 7. 2 - 7. 35 ( m, 4H )

Example 1 Diethyl azodicarboxylate was added to a mixture of ethyl 4-[3-(4-hydroxybenzoyl )-l-indolyl ]butyrate (281 mg), l-(4-cyclo- hexylphenyl )pentanol obtained in Pre. Ex. 1 (217 mg) and tri- phenylphosphine in a mixture of tetrahydrofuran and toluene at 0°C • After the mixture was reacted for 2 hours, the reaction mixture was evaporated in vacuo and chromatographed on silica gel (hexane : ethyl acetate = 3 : 1 by volume as eluent) to give ethyl 4-[3-[4-[ l-(4-cyclohexylphenyl )pentyloxy]benzoyl ]- l-indolyl]butyrate (203 mg). ^XH-NMR (CDCla. fi ) : 0.92 (t, 2H, J=7Hz), 1.15 - 1.6 ( , 12H),

1.65 - 2.35 (m, 11H), 2.4 - 2.6 (m, 1H), 4.09 (q, 2H, J=7Hz), 4.24 (t, 2H, J=7Hz), 5.15 (dd, 1H, J=5Hz, 7.5Hz), 6.93 (d, 2H, J=9Hz), 7.17 (d, 2H, J=9Hz), 7..2 - 7.45 (m, 5H), 7.53 (s, 1H), 7.74 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 2 To a solution of ethyl 4-[3-[4-[l-(4-cyclohexylphenyl )- pentyloxy]benzoyl ]-l-indolyl ]butyrate obtained in Ex. 1 (188 mg) in a mixture of ethanol and 1,4-dioxane was added IN aqueous solution of sodium hydroxide. The mixture was stirred at room temperature for 2 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[3-[4-[l-(4-cyclohexylphenyl )- pentyloxy]benzoyl ]-l-indolyl ]butyric acid (163 mg).

*H-NMR (CDCla. fi ) : 0.91 (t, 3H, J=7Hz), 1.15 - 1.6 (m, 9H),

1.65 - 2.3 ( , 9H), 2.3 - 2.55 (m, 3H), 4.25 (t, 2H, J=7Hz), 5.13 (dd, 1H, J=5Hz, 7.5Hz), 6.92 (d, 2H, J=9Hz), 7.17 (d, 2H, J=9Hz), 7.2 - 7.45 (m, 5H), 7.54 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 ( , 1H)

Example 3 The procedure of Ex. 1 was repeated except that l-[4- (cyclopropylmethyl )phenyl ]ρentanol obtained in Pre. Ex. 2 was used in place of l-(4-cyclohexylphenyl )pentanol and the reaction was carried out for 3 hours instead of 2 hours to give ethyl 4-[3-[4-[l-[4-(cyclopropylmethyl )phenyl]pentyloxy]benzoyl ]-l- indolyl Ibutyrate. ^-NMR (CDCla. fi ) : 0.15 -0.25 (m, 2H), 0.5 - 0.6 (m, 2H),

0.85- 1.1 ( , 4H), 1.21 (t, 3H, J=7Hz), 1.3 - 1.6 (m, 4H), 1.75 - 1.35 (m, 6H), 2.54 (d, 2H, J=6.5Hz), 4.10 (q, 2H, J=7Hz), 4.24 (t, 2H, J=7Hz), 5.17 (dd, 1H, J=5.5Hz, 7.5Hz), 6.94 (d, 2H, J=9Hz), 7.2 - 7.45 (m, 7H), 7.54 (s, 1H), 7.74 (d, 2H, J=7Hz), 8.3 - 8.4 (m, 1H)

Example 4 The procedure of Ex. 2 was repeated except that ethyl 4-[3- [4-[ l-[4-(cyclopropylmethyl )phenyl ]pentyloxy]benzoyl ]-l-indolyl ]- butyrate obtained in Ex. 3 was used in place of ethyl 4-[3-[4- [ l-(4-cyclohexylρhenyl )pentyloxy]benzoyl 3-1-indolyl Ibutyrate to give 4-[3-[4-[ l-[4-(cyclopropylmethyl )phenyl ]pentyloxy]benzoyl ]- 1-indolyl ]butyric acid. ^XH-NMR (CDCla. fi ) : 0.15 - 0.25 (m, 2H), 0.5 - 0.6 (m, 2H),

0.8 - 1.1 (m, 4H), 1.25 - 1.65 (m, 4H), 1.75 - 2.3 (m, 4H), 2.38 (t, 2H, J=7Hz), 2.53 (d, 2H, J=6.5Hz), 4.25 (t, 2H, J=7Hz), 5.15 (dd, 1H, J=5.5Hz, 7.5Hz), 6.93 (d, 2H, J=9Hz),

7.2 - 7.45 (m, 7H), 7.53 (s, 1H), 7.72 (d, 2H, J=9Hz),

8.3 - 8.4 (m, 1H)

Example 5 The procedure of Ex. 1 was repeated except that l-[4- (cyclohexyl ethyl )phenyl ]pentanol obtained in Pre. Ex. 3 was used in place of l-(4-cyclohexylphenyl )pentanol and the reaction was carried out for an hour instead of 2 hours to give ethyl 4-[3-[4-[ l-[4-(cyclohexylmethyl )phenyl ]pentyloxy]benzoyl ]-l- indolyl ]butyrate.

^XH-NMR (CDCla. fi ) : 0.8 - 2.35 (m, 27H), 2.45 (d, 2H, J=7Hz), 4.09 (q, 2H, J=7Hz), 4.23 (t, 2H, J=7Hz), 5.15 (dd, 1H, J=5Hz, 8Hz), 6.93 (d, 2H, J=9Hz), 7.11 (d, 2H, J=8Hz),

7.2 - 7.45 (m, 5H), 7.53 (s, 1H), 7.73 (d, 2H, J=9Hz),

8.3 - 8.4 (m, 1H)

Example 6 The procedure of Ex. 2 was repeated except that ethyl 4-[3- [4-[ l-[4-(cyclohexylmethyl )phenyl ]pentyloxy]benzoyl ]-l-indolyl ]- butyrate obtained in Ex. 5 was used in place of ethyl 4-[3-[4- [ l-(4-cyclohexylphenyl )pentyloxy]benzoyl ]-l-indolyl ]butyrate to give 4-[3-[4-[ l-[4-(cyclohexylmethyl )phenyl ]pentyloxy]benzoyl ]- 1-indolyl ]butyric acid. ^JH-NMR (CDCla. fi ) : 0.8 - 2.5 (m, 26H), 4.24 (t, 2H, J=7Hz), 5.14 (dd, 1H, J=5Hz, 8Hz), 6.92 (d, 2H, J=9Hz), 7.10 (d, 2H, J=8Hz), 7.2 - 7.45 (m, 5H), 7.54 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 7 The procedure of Ex. 1 was repeated except that 1-( -ni tro^¬ phenyl )pentanol obtained in Pre. Ex. 4 was used in place of l-(4-cyclohexylphenyl )pentanol to give ethyl 4-[3-[4-[ l-(4- ni trophenyl )pentyloxy]benzoyl ]-l-indolyl Ibutyrate. ^XH-NMR (CDCl₃, fi ) : 0.92 (t, 3H, J=7Hz), 1.21 (t, 3H, J=7Hz), 1.3 - 1.6 (m, 4H), 1.75 - 2.35 (m, 6H), 4.09 (q, 2H, J=7Hz), 4.23 (t, 2H, J=7Hz), 5.29 (dd, 1H, J=5Hz, 7.5Hz), 6.89 (d, 2H, J=9Hz), 7.25 - 7.45 (m, 3H), 7.5 - 7.6 (m, 3H), 7.75 (d, 2H, J=9Hz), 8.23 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 8 The procedure of Ex. 2 was repeated except that ethyl 4-[3- [4-[ 1-(4-nitrophenyl )pentyloxy]benzoyl 3-1-indolyl ]butyrate obtained in Ex. 7 was used in place of ethyl 4-[3-[4-[ l-(4- cyclohexylphenyl )pentyloxy]benzoyl ]-l-indolyl ]butyrate to give 4-[3-[4-[ 1-(4-ni trophenyl )pentyloxy]benzoyl ]-l-indolyl ]butyric acid.

*H-NMR (CDCls. fi ) : 0.92 (t, 3H, J=7Hz), 1.25 - 1.6 (m, 4H), 1.75 - 2.3 (m, 4H), 2.38 (t, 2H, J=7Hz), 4.24 (t, 2H, J=7Hz), 5.28 (dd, 1H, J=5Hz, 7.5Hz), 6.88 (d, 2H, J=9Hz), 7.25 - 7.45 (m, 3H), 7.5 - 7.6 ( , 3H), 7.75 (d, 2H, J=9Hz), 8.20 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 9 The procedure of Ex. 1 was repeated except that 2-butoxy-4- isobutylbenzyl alcohol obtained in Pre. Ex. 5 was used in place of l-(4-cyclohexylphenyl )pentanol and the reaction was carried out for 5 hours instead of 2 hours to give ethyl 4-[3-[4-(2- butoxy-4-isobutylbenzyloxy)benzoyl 3-1-indolyl ]butyrate. ^JH-NMR (CDCl₃, fi ) : 0.85 - 1.05 (m, 9H), 1.22 (t, 3H, J=7Hz), 1.4 - 1.65 (m, 2H), 1.7 - 2.0 (m, 3H), 2.1 - 2.4 (m, 4H), 2.48 (d, 2H, J=7Hz), 4.0 - 4.2 (m, 4H), 4.27 (t, 2H, J=7Hz), 5.18 (s, 2H), 6.7 - 6.8 (m, 2H), 7.08 (d, 2H, J=9Hz), 7.25 - 7.5 (m, 4H), 7.59 (s, 1H), 7.85 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 10 The procedure of Ex. 2 was repeated except that ethyl 4-[3- [4-(2-butoxy-4-isobutylbenzyloxy)benzoyl ]-l-indolyl ]butyrate obtained in Ex. 9 was used in place of ethyl 4-[3-[4-[l-(4- cyclohexylphenyl )pentyloxy]benzoyl ]-l-indolyl Ibutyrate to give 4-[3-[4-(2-butoxy-4-isobutylbenzyloxy)benzoyl 3-1-indolyl ]butyric acid.

*H-NMR (CDCla. fi ) : 0.85 - 1.05 (m, 9H), 1.4 - 1.6 (m, 2H), 1.7 - 2.0 (m, 3H), 2.15 - 2.3 (m, 2H), 2.35 - 2.5 (m, 4H), 4.02 (t, 2H, J=7Hz), 4.27 (t, 2H, J=7Hz), 5.17 (s, 2H), 6.65 - 6.8 (m, 2H), 7.08 (d, 2H, J=9Hz), 7.25 - 7.45 (m, 4H), 7.59 (s, 1H), 7.84 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 11 The procedure of Ex. 1 was repeated except that 2-ethoxy-4- isobutylbenzyl alcohol obtained in Pre. Ex. 6 was used in place of l-(4-cyclohexylphenyl )pentanol to give ethyl 4-[3-[4-(2- ethoxy-4-isobutylbenzyloxy)benzoyl ]-l-indolyl Ibutyrate. ^>H-NMR (CDCla. fi ) : 0.92 (d, 6H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.42 (t, 3H, J=7Hz), 1.75 - 2.0 (m, 1H), 2.1 - 2.4 (m, 4H), 2.48 (d, 2H, J=7Hz), 4.0 - 4.2 ( , 4H), 4.27 (t, 2H, J=7Hz), 5.18 (s, 2H), 6.70 (s, 1H), 6.78 (d, 2H, J=8Hz), 7.09 (d, 2H, J=9Hz), 7.25 - 7.45 (m, 4H), 7.59 (s, 1H), 7.85 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 12 The procedure of Ex. 2 was repeated except that ethyl 4-[3- [4-(2-ethoxy-4-isobutylbenzyloxy)benzoyl ]-l-indolyl ]butyrate obtained in Ex. 11 was used in place of ethyl 4-[3-[4-[ l-(4- cyclohexylphenyl )pentyloxy]benzoyl ]-l-indolyl ]butyrate to give 4-[3-[4-(2-ethoxy-4-isobutylbenzyloxy)benzoyl ]-l-indolyl ]butyric acid.

*H-NMR (CDCla. fi ) : 0.92 (d, 6H, J=7Hz), 1.42 (t, 3H, J=7Hz), 1.75 - 2.0 ( , 1H), 2.1 - 2.3 (m, 2H), 2.35 - 2.5 ( , 4H), 4.08 (q, 2H, J=7Hz), 4.27 (t, 2H, J=7Hz), 5.17 (s, 2H), 6.68 (s, 1H), 6.76 (d, 1H, J=8Hz), 7.08 (d, 2H, J=9Hz), 7.25 - 7.45 ( , 4H), 7.59 (s, 1H), 7.84 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 13 The procedure of Ex. 1 was repeated except that l-(5, 6, 7, 8-tetrahydro-2-naphthyl )pentanol obtained in Pre. Ex. 7 was used in place of l-(4-cyclohexylphenyl )pentanol to give ethyl 4-[3-[4-[l-(5,6,7,8-tetrahydro-2-naphthyl)pentyloxy]- benzoyl ]-l-indolyl Ibutyrate.

^XH-NMR (CDCla. fi ) 0.90 (t, 3H, J=7Hz), 1.15 - 1.65 ( , 7H), 1.7 - 2.4 ( , 10H), 2.76 (br s, 4H), 4.10 (q, 2H, J=7Hz), 4.24 (t, 2H, J=7Hz), 5.10 (dd, 1H, J=5Hz, 8Hz), 6.93 (d, 2H, J=9Hz), 7.0 - 7.15 (m, 3H), 7.25 - 7.5 (m, 3H), 7.54 (s, 1H), 7.74 (d, 2H, J=9Hz), 8.3 - 8.4 ( , 1H)

Example 14 The procedure of Ex. 2 was repeated except that ethyl 4-[3- [4-[l-(5,6,7,8-tetrahydro-2-naphthyl )pentyloxy]benzoyl ]-l- indolyl Jbutyrate obtained in Ex. 13 was used in place of ethyl 4-[3-[4-[l-(4-cyclohexylphenyl )pentyloxy]benzoyl 3-1-indolyl ]- butyrate to give 4-[3-[4-[ l-(5, 6,7, 8-tetrahydro-2-naρhthyl )- pentyloxy]benzoyl ]-l-indolyl ]butyric acid.

^>H-NMR (CDCla. fi ) : 0.90 (t, 3H, J=7Hz), 1.2 - 1.65 (m, 4H), 1.7 - 2.3 (m, 8H), 2.38 (t, 2H, J=7Hz), 2.74 (br s, 4H), 4.24 (t, 2H, J=7Hz), 5.10 (dd, 1H, J=5Hz, 8Hz), 6.85 - 7.15 (m, 5H), 7.25 - 7.5 (m, 3H), 7.55 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 15 The procedure of Ex. 1 was repeated except that (R)-l-[4- (cyclopropylmethyl )phenyl ]butanol obtained in Pre. Ex. 8 was used in place of l-(4-cyclohexylphenyl )pentanol to give (S)-ethyl 4-[3-[4-[l-[4-(cyclopropylmethyl )phenyl ]butoxy]- benzoyl ]-l-indolyl Ibutyrate. ^JH-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.6 (m, 2H),

0.9 - 1.15 (m, 4H), 1.20 (t, 3H, J=7Hz), 1.3 - 1.65 (m, 2H), 1.7 - 2.35 ( , 6H), 2.53 (d, 2H, J=7Hz), 4.09 (q, 2H, J=7Hz), 4.23 (t, 2H, J=7Hz), 5.18 (dd, 1H, J=5Hz, 8Hz), 6.93 (d, 2H, J=9Hz), 7.2 - 7.45 (m, 7H), 7.53 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 16 The procedure of Ex. 2 was repeated except that (S)-ethyl 4-[3-[4-[ l-[4-(cyclopropylmethyl )phenyl ]butoxy]benzoyl ]-l- indolyl ]butyrate obtained in Ex. 15 was used in place of ethyl 4-[3-[4-[ l-(4-cyclohexylphenyl )pentyloxy]benzoyl 3-1-indolyl ]- butyrate to give (S)-4-[3-[4-[ l-[4-(cyclopropylmethyl )phenyl ]- butoxy]benzoyl ]-l-indolyl ]butyric acid. ^>H-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.6 (m, 2H),

0.85 - 1.1 (m, 4H), 1.3 - 1.65 (m, 2H), 1.7 - 2.3 ( , 4H), 2.38 (t, 2H, J=7Hz), 2.52 (d, 2H, J=7Hz), 4.22 (t, 2H, J=7Hz), 5.17 (dd, 1H, J=5Hz, 8Hz), 6.92 (d, 2H, J=9Hz), 7.15 - 7.45 (m, 7H), 7.53 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 17 The procedure of Ex. 1 was repeated except that (R)-l-[4- (cyclopropylmethyl )phenyl ]pentanol obtained in Pre. Ex. 9 was used in place of l-(4-cyclohexylphenyl )pentanol to give (S)-ethyl 4-[3-[4-[ l-[4-(cyclopropylmethyl )phenyl ]pentyloxy]- benzoyl 3-1-indolyl Ibutyrate. ^JH-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.6 (m. 2H),

0.85 - 1.1 (m, 4H), 1.20 (t, 3H, J=7Hz), 1.3 - 1.6 (m, 4H), 1.75 - 2.35 (m, 6H), 2.53 (d, 2H, J=7Hz), 4.09 (q, 2H, J=7Hz), 4.24 (t, 2H, J=7Hz), 5.17 (dd, 1H, J=5Hz, 8Hz), 6.93 (d, 2H, J=9Hz), 7.2 - 7.45 (m, 7H), 7.53 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 18 The procedure of Ex. 2 was repeated except that (S)-ethyl 4-[3-[4-[l-[4-(cyclopropylmethyl )phenyl ]pentyloxy]benzoyl 3-1- indolyl ]butyrate obtained in Ex. 17 was used in place of ethyl 4-[3-[4-[l-(4-cyclohexylphenyl )pentyloxy]benzoyl 3-1-indolyl ]- butyrate to give (S)-4-[3-[4-[ l-[4-(cyclopropylmethyl )phenyl ]- pentyloxy3benzoyl 3-1-indolyl ]butyric acid. ^XH-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.5 - 0.6 (m, 2H), 0.85 - 1.1 (m, 4H), 1.15 - 1.65 (m, 4H), 1.75 - 2.3 (m, 4H), 2.38 (t, 2H, J=7Hz), 2.52 (d, 2H, J=7Hz), 4.23 (t, 2H, J=7Hz), 5.15 (dd, 1H, J=5Hz, 8Hz), 6.92 (d, 2H, J=9Hz), 7.15 - 7.45 (m, 7H), 7.53 (s, 1H), 7.72 (d, 2H, J=9Hz), 8.3 - 8.4 ( , 1H)

Example 19 The procedure of Ex. 1 was repeated except that l-[4- (cyclopropylmethyl )phenyl 3-4, 4, 4-trifluorobutanol obtained in Pre. Ex. 10 was used in place of l-(4-cyclohexylphenyl )pentanol to give (S)-ethyl 4-[3-[4-[l-[4-(cyclopropylmethyl )phenyl ]- 4,4, 4-trifluorobutoxy]benzoyl 3-1-indolyl 3butyrate. ^XH-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H), 0.85 - 1.1 (m, 1H), 1.20 (t, 3H, J=7Hz), 2.05 - 2.45 (m, 8H), 2.54 (d, 2H, J=7Hz), 4.10 (q, 2H, J=7Hz), 4.25 (t, 2H, J=7Hz), 5.27 (t, 1H, J=6.5Hz), 6.93 (d, 2H, J=9Hz), 7.15 - 7.45 ( , 7H), 7.53 (s, 1H), 7.74 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 20 The procedure of Ex. 2 was repeated except that (S)-ethyl 4-[3-[4-[l-[4-(cyclopropylmethyl )phenyl ]-4, 4, 4-tri fluorobutoxy]- benzoyl ]-l-indolyl ibutyrate obtained in Ex. 19 was used in place of ethyl 4-[3-[4-[ l-(4-cyclohexylphenyl )pentyloxy]benzoyl ]-l- indolyl Ibutyrate to give (S)-4-[3-[4-[ l-[4-(cyclopropylmethyl )- phenyl ]-4, 4, 4-trifluorobutoxy]benzoyl ]-l-indolyl Jbutyric acid. *H-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H), 0.85 - 1.1 (m, 1H), 2.05 - 2.45 (m, 8H), 2.53 (d, 2H, J=7Hz), 4.24 (t, 2H, J=7Hz), 5.24 (t, 1H, J=6.5Hz), 6.91 (d, 2H, J=9Hz), 7.15 - 7.45 (m, 7H), 7.53 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 21 The procedure of Ex. 1 was repeated except that (S)-1-[4- (cyclopropylmethyl )phenyl ]-2-ethoxyethanol obtained in Pre. Ex. 11 was used in place of l-(4-cyclohexylphenyl )pentanol to give (R)-ethyl 4-[3-[4-[ l-[4-(cyclopropylmethyl )phenyl 3-2-ethoxy- ethoxy3benzoyl 3-1-indolyl ibutyrate. ^XH-NMR (CDCl₃, fi ) : 0.2 - 0.3 (DI, 2H), 0.45 - 0.6 (m, 2H),

0.85 - 1.1 (m, 1H), 1.15 - 1.3 ( , 6H), 2.1 - 2.35 (m, 4H), 2.53 (d, 2H, J=7Hz), 3.5 - 3.95 (m, 4H), 4.10 (q, 2H, J=7Hz), 4.23 (t, 2H, J=7Hz), 5.42 (dd, 1H, J=3.5Hz, 8Hz), 6.98 (d, 2H, J=9Hz), 7.15 - 7.45 (m, 7H), 7.52 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 ( , 1H) Example 22 The procedure of Ex. 2 was repeated except that (R)-ethyl 4-[3-[ -[l-[4-(cyclopropylmethyl )phenyl ]-2-ethoxyethoxy]- benzoyl ]-l-indolyl Ibutyrate obtained in Ex. 21 was used in place of ethyl 4-[3-[4-[ l-(4-cyclohexylphenyl )pentyloxy]benzoyl ]-l- indolyl Ibutyrate to give (R)-4-[3-[4-[ l-[4-(cyclopropylmethyl )- phenyl ]-2-ethoxyethoxy]benzoyl ]-l-indolyl ]butyric acid. ^JH-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H),

0.85 - 1.1 (m, 1H), 1.22 (t, 3H, J=7Hz), 2.1 - 2.25 (m, 2H), 2.37 (t, 2H, J=7Hz), 2.52 (d, 2H, J=7Hz), 3.5 - 3.95 (m, 4H),

4.22 (t, 2H, J=7Hz), 5.42 (dd, 1H, J=3.5Hz, 8Hz), 6.97 (d, 2H, J=9Hz), 7.15 - 7.45 (m, 7H), 7.52 (s, 1H), 7.72 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 23 The procedure of Ex. 1 was repeated except that (S)-l-[4- (cyclopropylmethyl )phenyl ]-2-methoxyethanol obtained in Pre. Ex. 12 was used in place of l-(4-cyclohexylphenyl )pentanol to give (R)-ethyl 4-[3-[4-[l-[ -(cyclopropylmethyl )phenyl ]-2-methoxy- ethoxylbenzoyl -1-indolyl ibutyrate. ^XH-NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 ( , 2H),

1.20 (t, 3H, J=7Hz), 2.1 - 2.35 ( , 4H), 2.53 (d, 2H, J=7Hz), 3.48 (s, 3H), 3.6 - 3.9 (m, 2H), 4.10 (q, 2H, J=7Hz),

4.23 (t, 2H, J=7Hz), 5.43 (dd, 1H, J=3.5Hz, 8Hz), 6.98 (d, 2H, J=9Hz), 7.2 - 7.45 (m, 7H), 7.53 (s, 1H), 7.73 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Example 24 The procedure of Ex. 2 was repeated except that (R)-ethyl 4-[3-[4-[ 1-[4-(cyclopropylmethyl )phenyl ]-2-methoxyethoxy - benzoyl ]-l-indolyl Ibutyrate obtained in Ex. 23 was used in place of ethyl 4-[3-[4-[ l-(4-cyclohexylphenyl )pentyloxy]benzoyl 3-1- indolyl Ibutyrate to give (R)-4-[3-[4-[ l-[4-(cyclopropylmethyl )- phenyl ]-2-methoxyethoxy3benzoyl ]-l-indolyl ]butyric acid.

-HH-_NMR (CDCla. fi ) : 0.2 - 0.3 (m, 2H), 0.45 - 0.6 (m, 2H),

0.85 - 1.1 ( , 1H), 2.1 - 2.3 (m, 2H), 2.37 (t, 2H, J=7Hz), 2.52 (d, 2H, J=7Hz), 3.47 (s, 3H), 3.6 - 3.9 (m, 2H), 4.22 (t, 2H, J=7Hz), 5.42 (dd, 1H, J=3.5Hz, 8Hz), 6.97 (d, 2H, J=9Hz), 7.2 - 7.45 (m, 7H), 7.52 (d, 2H, J=9Hz), 8.3 - 8.4 (m, 1H)

Claims

X is a methylene, -0- or -NH-, and

R⁴ is a cycloalkyl, a nitro or a lower alkoxy and

R⁵ is a hydrogen or a lower alkyl, or

R⁴ and R⁵ are linked together to form a tetramethylene, or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein

R¹ is a carboxy( lower)alkyl or a lower alkoxycarbonyl- ( lower)alkyl ,

R² is a hydrogen,

R³ is a hydrogen, a lower alkyl, a trihalo(lower)alkyl or a lower alkoxy( lower)alkyl,

X is -0-, and

R⁴ is a cycloalkyl, a nitro or a lower alkoxy and

R⁵ is a hydrogen or a lower alkyl, or R⁴ and R⁵ are linked together to form a tetramethylene.

3. A compound of claim 2, which is represented by the formula

wherein R¹ is a carboxy( lower)alkyl ,

4. A process for preparing a compound of the formula (I)

H

wherein R¹ is an optionally protected carboxy( lower)alkyl , R² is a hydrogen, a lower alkyl or a halogen, R³ is a hydrogen or an optionally substituted lower alkyl,

X is a methylene, -0- or -NH-, and

R⁴ is a cycloalkyl, a nitro or a lower alkoxy and R⁵ is a hydrogen or a lower alkyl, or

R⁴ and R⁵ are linked together to form a tetramethylene, or a pharmaceutically acceptable salt thereof, which comprises:

(1) reacting a compound of the formula (II) :

H

wherein R¹ , R² and X are as defined above, or a salt thereof, with a compound of the formula (III)

wherein R³ , R⁴ and R⁵ are as defined above, and^" W¹ is a leaving group, or a salt thereof;

(2) reacting a compound of the formula (IV)

wherein R² and A are as defined above, or a salt thereof, with a compound of the formula (V;

wherein R¹ is as defined above, and

W² is an acid residue, or a salt thereof ;

(3) subjecting a compound of the formula (I-a) :

wherein R² , R³ , R⁴ , R⁵ and X are as defined above, and

R¹, is a protected carboxy( lower)alkyl, or a salt thereof, to an elimination reaction of the carboxy- protective group to give a compound of the formula (I-b) :

wherein R² , R³ , R⁴ , R⁵ and X are as defined above, and R\ is a carboxy( lower)alkyl, or a salt thereof; or

(4) reacting a compound of the formula (VI) :

H

wherein R¹ and R² are as defined above, and

W³ is an acid residue, or a salt thereof, with a compound of the formula (VII)

wherein R³ , R⁴ , R⁵ and X are as defined above, and W³ is an acid residue, or a salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in association with pharmaceutically acceptable carriers or excipients.

6. A method for treating or preventing testosterone 5α.-reductase-mediated diseases, which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human being or animals.

7. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as a medicament.

8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as a testosterone 5β-reductase inhibitor.

9. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable carriers or excipients.