EP0603278A1

EP0603278A1 - Indole derivatives as 5-alpha-reductase inhibitor

Info

Publication number: EP0603278A1
Application number: EP92919507A
Authority: EP
Inventors: Satoshi 1-1-17-202 Saganakadai 8-chome OKADA; Kozo Sawada; Natsuko Kayakiri; Yuki Saitoh; Hirokazu Tanaka; Masashi 2-2-8-1205 Shinmachi Hashimoto
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1991-09-11
Filing date: 1992-09-09
Publication date: 1994-06-29
Also published as: WO1993005019A1; CA2118697A1; JPH07501790A

Abstract

L'invention se rapporte à des dérivés d'indole représentés par la formule suivante (I), ou à un sel de ces dérivés, qui sont utiles comme inhibiteur de la testostérone 5alpha-réductase.The invention relates to indole derivatives represented by the following formula (I), or to a salt of these derivatives, which are useful as a testosterone 5alpha-reductase inhibitor.

Description

DESCRIPTION

INDOLE DERIVATIVES AS 5-alpha-reductase Inhibitor.

Technical Field

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

Disclosure of the Invention

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

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

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

Still further object of the present invention is to provide a use of said indole derivatives or a pharmaceutically acceptable salt thereof as a medicament such as testosteron 5α-reductase inhibitor useful for treating or preventing testosteron 5 -reductase mediated diseases such as alopecia, acnes, prostatism, and the like in human being or animals. The indole derivatives of the present invention are novel and can be represented by the formula (I) :

wherein R is aryl which may have suitable substituent(s), 2 R is carboxy(lower)alky1 or protected

^•carboxy(lower)alkyl, 3 R is hydrogen, lower alkyl or halogen,

X is -0- or -NH- and n is integer of 1 to 6, with proviso that when n is 1, then X is NH, and when n is 3, then (^c _nH_2n) is trimethylene or methylethylene.

According to the present invention, the object compound (I) and a salt thereof can be prepared by the following processes.

Process 1

(ID or a salt thereof f

or a salt thereof

Process 2

Elimination of the carboxy-protective group

(lb) or a salt thereof Process 3

(I) or a salt thereof

wherein R , R², *³, X and n are each as defined above, „2 is protected carboxy(lower)alkyl.

R ,, is carboxy(lower)alkyl, and

1 and W2 are each acid residue.

With regard to the compound (I) o.f the present invention, it is to be noted that there may be one or more stereoisomeric pairs due to the presence of one or more asymmetric carbon atom(s) and these isomers or a mixture thereof are included within a scope of the compound (I) of the present invention. The starting compound (II), (III) and (IV) can be prepared by the following methods, the details of which are shown in Preparations mentioned below, or a conventional manner.

Method A-(l)

(VI) or a salt thereof

Reduction

(Ha) or a salt thereof

Method A-(2)

(VII) or a salt thereof Elimination of the hydroxy protective group

(lib) or a salt thereof

Method B

- H

(VIII) or a salt thereof

of

⁽X⁾ or a salt thereof

(2) reduction (XI) or a salt thereof

conversion of hydroxy

(3) group to acid residue

(III) or a salt thereof

Method C

(XII) or a salt thereof

( IV) or a salt thereof

wherein R X, w and n are each as defined above.

R is protected hydroxy, and

3 W is an acid residue.

Suitable salts of the compounds (I) are conventional non-toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt^' such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), etc.; an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulf te, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid> etc.); and the like, and the preferable example thereof is an acid addition salt.

With respect to the salt of the object and starting compounds in Processes 1, 2 and 3, and Methods A, B and C, the suitable examples of the salts of these compounds 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 include within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" and "lower alkyl moiety" in the terms "carboxy(lower)alkyl" and "protected carboxy(lower)alkyl" may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atoms.

The term "halogen" means fluoro, chloro, bromo and iodo. Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bromo, iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and the like.

Suitable "aryl which may have suitable substituent(s)" may include a conventional group such as aryl (e.g. phenyl, naphthyl, etc.), substituted aryl, for example, lower alkylaryl, for example, lower alkylphenyl

(e.g. tolyl, xylyl, mesityl, cumenyl, isobutylphenyl, etc.), haloaryl, for example, halophenyl (e.g. chlorophenyl, etc.), and the like. Suitable "protected carboxy moiety" in the term

"protected carboxy(lower)alkyl" may include a conventionally protected carboxy such as an esterified carboxy group.

Suitable examples of the ester moiety of an "esterified carboxy" may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc. ) which may have at least one suitable substituent(s) , for example, lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)- acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, 1(or 2 or 3 or 4)-acetoxybutyl ester, l(or 2)-propionyl- oxyethyl 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, isobutyryloxymethyl ester, 2-ethγlbutyryloxymethyl ester,

3,3-dimethylbutyryloxymethyl ester, l(or 2)-pentanoyloxyethyl ester, etc.) lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy(lower)alkyl ester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(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-l,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-l,3-dioxol-4-yl)ethyl ester, etc.; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester, 4-me hoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc. ) ; aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc. ) ; phthalidyl ester; and the like.

Among the object compound (I), the preferred compound can be represented by the formula (I¹) shown below.

wherein

R is aryi which may have suitable substituent(s) [more preferably phenyl which may have suitable substituent(s) ; most preferably lower alkylphenyl] , 2 R is carboxy(lower)alkyl, or protected carboxy(lower)- alkyl [more preferably pharmaceutically acceptable esterified carboxy(lower)alkyl; most preferably lower alkoxycarbonyl(lower)alkyl3, X is -O- or -NH-, and n is integer of 1 to 6, with proviso that when n is 1, then X is NH.

Particularly, the preferred compound of the present invention can be represented by the following formula :

wherein R 1, R2, X and n are each as defined above.

In addition to the compound (I) of the present invention, the compound of the following formulae (A) and (B) is also novel, which can be prepared by similar methods as mentioned above or a conventional manner and is of use as a testosteron 5α reductase inhibitor.

wherein Z is methyl or ethyl, and- R 1 and R2 are each as defined above.

The processes 1 to 3 for preparing the object compound (I) of the present invention are explained in detail in the following. Process 1

The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof. This reaction is usually carried out in a solvent such as alcohol [e.g. methanol, ethanol, etc.], dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction. The reaction may be carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc. ], an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.3 an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], alkali metal hydride (e.g. sodium hydride, potassium hydride, etc. ) , tri(lower)alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridine or its derivative [e.g. picoline, lutidine, 4-dimethylaminopyridine, etc.], or the like. In case that the base to be used is liquid, it can also be used as a solvent.

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 (lb) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to elimination reaction of the carboxy protective group.

In the present elimination reaction, all conventional methods used in the elimination reaction of the carboxy protective group, for example, hydrolysis, reduction, elimination using Lewis acid, etc. are applicable. When the carboxy protective group is an ester, it can be eliminated by hydrolysis or elimination using Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.) , alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-one., 1,4-diazabicyclo[2.2.2]octane, l,5-diazabicyclo[5.4.0]undecene-5 or the like.

The hydrolysis using-a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

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 suitable be selected in accordance with the kind of the carboxy protective group and the elimination method.

The elimination using Lewis acid is preferable to eliminate substituted or unsubstituted ar(lower)alkyl ester and carried out by reacting the compound (Ig) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetrachloride, titanium tetrabromide, etc.), tin tetrahalide (e.g. tin tetrachloride, tin tetrabromide, etc.), aluminum halide (e.g. aluminum chloride, aluminum bromide, etc. ) , trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc÷) or the like. This elimination reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.) , alkylene halide (e.g. methylene chloride, ethylene chloride, etc. ) , diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof.

The reduction elimination can be applied preferably for elimination of the protective group such as halo(lower)alkyl (e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.) ester, ar(lower)alkyl (e.g. benzyl, etc.) ester or the like.

The reduction method applicable for the elimination reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or an inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc. ) ; and conventional catalytic reduction is the pressure of a conventional metallic catalyst (e.g. palladium carbon, Raney nickel, etc.). The reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.

Process 3

The object compound (I) or 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 Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.

The object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like. The object compound (I) thus obtained can be converted . o its salt by a conventional method.

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

In order to illustrate the usefulness of the object compounds (I), pharmacological activity of representative compounds of the present invention is shown below. [1] Test Compound :

(1) 4-[3-[4-[1-(4-Isobutylphenyl)hexyloxy]benzoyl]- indol-1-yl^]butyric acid

(2) 4-[3-[4-[l-(4-Isobutylphenyl)pentyloxy]benzoyl]- indol-l-yl]butyric acid

[2] Inhibitory activity on testosterone 5α-reductase in rats :

Test Methods

i) Materials

l,2,6,7-³H-Testosterone (85-105 Ci/mmol)

3 1,2,6,7- H-Testosterone (85-105 Ci/mmol) is a mixture

3 of 1,2,6,7- H-Testosterone and testosterone which includes 85-105 Ci of 1,2,6,7- 3H-testosterone per mmol of testosterone and is purchased from New

England Nuclear, Boston, Mass., U.S.A..

Aquazol-2 (Aquazol-2 Universal LSC Cocktail) :

Trademark, purchased from New England Nuclear, Boston, Mass., U.S.A.

ii) Preparation of prostatic testosterone 5α-reductase

Mature Spraque-Dawley male rats (7-8 weeks old) were sacrificed by diethyl ether. The ventral prostates were dissected to be free of their capsules and their combined volume was measured by displacement in several milliliters of ice-cold medium A (0.32 M sucrose, 0.1 mM dithiothreitol and 20 mM sodium phosphate, pH 6.5). Unless specified, all the following procedures were carried out at 0-4°C. The prostates were drained, minced, and then homogenized in 3-4 tissue volumes of medium A with Pyrex-glass homogenizer. The homogenate was fractioned by differential centrifugations at 3,000 g for 15 minutes. The resulting pellets were resuspended in medium A. The suspension (20-30 mg protein/ml) was stored at -80°C.

iii) Testosterone 5α-reductase assay

The reaction solution contains 1 mM dithiothreitol,

40 mM sodium phosphate pH 6.5, 50 μM NADPH,

1,2,6,7- 3H-testosterone/testosterone (2.2 x 10-9 M) and the suspension prepared above (0.8 mg of protein) in a total volume of 565 μl. Test Compound was added in 10 μl of 10% ethanol whereas control tubes received the same volume of 10% ethanol. The reaction was started with the addition of the enzyme suspension. After incubation at

37°C for 30 minutes, the reaction was extracted with 1 ml of ethyl acetate. Fifty μl of ethyl acetate phase was chromatogrpahed on a Merck silica plastic sheet Kieselgel

60 F₂₅₄, using ethyl acetate : cyclohexane (1:1) as the developing solvent system. The plastic sheet was air dried and cut the testosterone and the 5α-dihγdrotestosterone areas. The radioactivity was counted in 5 ml of Aquazol-2 in Packard scintillation counter (PACKARD TRI - CARB 4530), and an inhibitory ratio was calculated.

[3] Test Results

For therapeutic or preventive administration, the object compound (I) of the present invention [and also compounds (A) and (B)] are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable 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 solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, lotion and the like.

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, ethylene glycol, and the like. While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of disease or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 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 in treating diseases.

The following Preparations and Examples are given for the purpose of illustrating the present invention. Preparation 1

A solution of 3-nitrobenzoyl chloride (4.76 g) in dichloromethane (20 ml) was added to a suspension of aluminum chloride (3.42 g) in dichloromethane (50 ml) at ^' 25°C, and the mixture was stirred at the same temperature for an hour. A solution of indole (3.0 g) in dichloromethane (20 ml) was added to the mixture at 25°C. After stirring for an hour at 25°C, the reaction mixture was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was recrystallized from ethyl acetate to give 3-(^'3-nitrobenzoyl)indole (2.37 g) as pale red crystals. The mother liquid was purified by column chromatography on silica gel (20 g) with chloroform as eluent to give another crystals of 3-(3-nitrobenzoyl)indole (0.277 g) .

NMR (CDC1₃-CD₃0D, δ) : 7.21-7.35 (2H, m) , 7.42-7.55 (1H, m), 7.68-7.79 (2H, m), 8.13 (1H, dif-dd, J=7.5Hz), 8.24-8.35 (1H, m) , 8.40 (1H, dif-dd,

J=7.5Hz), 8.60 (1H, dif-d)

Preparation 2

A mixture of 3-(3-nitrobenzoyl)indole (2.09 g) , ethyl 4-bromobutyrate (1.614 g) and potassium carbonate (3.118 g) in N,N-dimethylformamide (20 ml) was stirred at 25°C overnight. The reaction mixture was poured into a mixture of ethyl acetate and IN hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give ethyl 4-[3-(3-nitrobenzoyl)indol-l-yϊ]butyrate (2.71 g) as colorless crystals. NMR (CDC1-., δ) : 1.20 (3H, t, J=7.5Hz), 2.12-2.40 (4H, m), 4.10 (2H, q, J=7.5Hz), 4.30 (2H, t, J=7.5Hz), 7.30-7.50 (3H, m) , 7.58 (1H, s), 7.70 (1H, t, J=8Hz), 8.27 (1H, dif-dd, J=7.5Hz), 8.35-8.48 (2H, m) , 8.68 (1H, dif-d)

Preparation 3

A mixture of ethyl 4-[3-(3-nitrobenzoyl)indol-l-yl]- butyrate (1.60 g) , IN aqueous sodium hydroxide (11 ml) and 1,4-dioxane (50 ml) was stirred at 25°C for 14 hours. After evaporation of the organic solvent, IN hydrochloric acid (20 ml) was added to the aqueous solution and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-[3-(3-nitrobenzoyl)indol-l-yl]butyric acid (1.28 g) as colorless crystals.

NMR (CDC1₃-CD₃0D, δ) : 2.10 (2H, m) , 2.35 (2H, t,

J=7.5Hz), 4.30 (2H, t, J=7.5Hz), 7.30-7.55 (3H, ), 7.60 (1H, s), 7.72 (1H, t, J=7.5Hz), 8.16

(1H, dif-dd, J=7.5Hz), 8.31-8.48 (2H, m) , 8.65 ^"(1H, dif-d)

Preparation 4 A mixture of 4-[3-(3-nitrobenzoyl)indol-l-yl]butyric acid (1.20 g) , 10% palladium on carbon (300 mg), methanol (12 ml) and 1,4-dioxane (12 ml) was stirred under hydrogen atmosphere (3 atm) at 25°C for 45 minutes. The mixture was filtered and the filtrate was evaporated to give 4-[3-(3-aminobenzoyl)indol-l-γl]butyric acid (982 mg) as yellow oil.

NMR (CDC1₃-CH₃0D, δ) : 2.15-2.45 (4H, m) , 4.32 (2H, t, J=7.5Hz), 6.97 (1H, m) , 7.15-7.60 (6H, m) , 7.72 (1H, s), 8.45 (1H, m) Preparation 5

Propionyl chloride (13.0 ml) was added to a suspension of aluminum chloride (20.0 g) in dichloromethane (200 ml) at 0°C. After the mixture was stirred at 0°C for 1 hour, isobutylbenzene (23.6 ml) was added to the mixture. The mixture was stirred at 0°C for 2 hours and poured into ice water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residual oil was distilled under reduced pressure to give 4'-isobutylpropiophenone as a colorless oil (24.4 g).

NMR (CDC1₃, δ) : 0.92 (6H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.90 (1H, m), 2.53 (2H, d, J=7Hz), 3.00 (2H, q, J=7Hz), 7.23 (2H, d, J=8Hz) , 7.90 (2H, d, J=8Hz)

Preparation 6

Sodium borohydride (4.72 g) was added to a solution of 2,2-dimethyl-4'-isobutylpropiophenone (22.7 g) in isopropyl alcohol (150 ml). The mixture was stirred at 50°C for 2 hours and poured into ice water. After acidified with 6N-hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated to give 2,2-dimethyl-l-(4-isobutylphenyl)- propanol as a colorless oil (21.6 g) .

NMR (CDC1₃, δ) : 0.90 (6H, d, J=7Hz), 0.92 (9H, s), 1.85 (1H, m), 2.45 (2H, d, J=7Hz), 4.38 (1H, s), 7.08 (2H, d, J=8Hz), 7.23 (2H, d, J=8Hz)

Preparation 7

The following compound was obtained according to a similar manner to that of Preparation 6.

l-(4-Isobutylphenyl)propanol as a colorless oil NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 0.89 (3H, t, J=7Hz), 1.6-2.0 (3H, m) , 2.47 (2H, d, J=7Hz), 4.57 (1H, t, J=7Hz), 7.13 (2H, d, J=8Hz), 7.25 (2H, d, J=8Hz)

Preparation 8

To a mixture of 2,2-dimethyl-l-(4-isobutylphenyl)- propanol (22.8 g) and carbon tetrabromide (61.8 g) in tetrahydrofuran (250 ml) was added triphenylphosphine (48.9 g) under nitrogen atmosphere at 0°C. The mixture was stirred at room temperature for 6 hours. After the white solid was filtered off, the filtrate was evaporated. n-Hexane (250 ml) was added to the residue and the precipitate was filtered off. The filtrate was evaporated and the residual oil was distilled under reduced pressure to give l-(l-bromoneopentyl)-4-isobutyl- benzene as a colorless oil (10.3 g) . bp : 120-125°C (0.2 mmHg)

NMR (CDC1₃, δ) : 0.90 (6H, d, J=7Hz), 1.05 (9H, s), 1.86 (1H, m), 2.45 (2H, d, J=7Hz), 4.85 (1H, s),

7.05 (2H, d, J=8Hz), 7.28 (2H, d, J=8Hz)

Preparation 9

The following compound was obtained according to a similar manner to that of Preparation 8.

1-(1-Bromopropyl)-4-isobutylbenzene

NMR (CDC1₃, δ) : 0.90 (6H, d, J=7Hz), 1.01 (3H, t,

J=7Hz), 1.7-2.0 (1H, m) , 2.0-2.4 (2H, m) , 2.45 (2H, d, J=7Hz), 4.89 (1H, t, J=7Hz), 7.11 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz)

Preparation 10

The following compound was obtained according to a similar manner to that of Preparation 1. -(4-Methoxybenzoyl)indole mp : 203-205°C

NMR (DMSO-dg, δ) : 3.70 (3H, s), 6.93 (2H, d,

J=8Hz), 7.00-7.19 (2H, m), 7.30-7.44 (1H, m) , 7.67 (2H, d), 7.31 (1H, s), 8.02-8.15 (1H, m)

Preparation 11

The following compounds were obtained according to a similar manner to that of Preparation 2.

(1) Ethyl 3-[3-(3-nitrobenzoyl)indol-l-yl]propionate mp : 102-103°C

NMR (CDC1₃, δ) : 1.20 (3H, t, J=7.5Hz), 2.88 (2H, t, J=6Hz), 4.13 (2H, q, J=7.5Hz), 4.53 (2H, t, J=6Hz), 7.3-7.5 (3H, m), 7.68 (1H, s), 7.70 (1H, t, J=7.5Hz), 8.4-8.5 (2H, m) , 8.62 (1H, t, J=2Hz)

(2) Ethyl 4-[3-(4-methoxybenzoyl)indol-l-yl]butyrate NMR (CDC1₃, δ) : 1.20 (3H, t, J=7.5Hz), 2.08-2.38

(4H, ), 3.38 (3H, s), 4.10 (2H, q, J=7.5Hz), 4.23 (2H, t, J=7.5Hz), 6.99 (2H, d, J=8Hz) , 7.28-7.48 (3H, m) , 7.58 (1H, s), 7.85 (2H, d, J=8Hz), 8.32-8.45 (1H, m)

Preparation 12

Aluminum chloride (3.3 g) was added to a solution of ethyl 4-[3-(3-methoxybenzoyl)indolyl-l-yl]butyrate (3.0 g) in a mixture of ethanethiol (10 ml) and dichloromethane (10 ml) at 0°C, and the mixture was stirred at 25°C for 1 hour. After evaporation of the solvent, IN hydrochloric acid and ethyl acetate were added to the residue. The mixture was stirred at 25°C for 30 minutes. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (100 g) eluting with chloroform to give ethyl 4-[3-(3-hydroxybenzoyl)indol-l-yl]butyrate (2.65 g) as an oil. NMR (CDC1₃, δ) : 1.22 (3H, t, J=7.5Hz), 2.22-2.38

(4H, m), 4.12 (2H, q, J=7.5Hz), 4.23 (2H, t, J=7.5Hz), 7.00-7.12 (1H, m) , 7.28-7.48 (6H, m) , 7.62 (1H, s), 8.35-8.46 (1H, m)

Preparation 13

The following compound was obtained according to a similar manner. to that of Preparation 12.

Ethyl 4-[3-(4-hydroxybenzoyl)indol-l-yl]butyrate mp : 129-131°C

NMR (CDC1₃, δ) : 1.20 (3H, t, J=7.5Hz), 2.08-2.40 (4H, m), 4.10 (2H, q, J=7.5Hz), 6.91 (2H, d, J=8.0Hz), 7.25-7.50 (3H, m) , 7.60 (1H, s), 7.75 (2H, d, J=8.0Hz), 8.30-8.42 (1H, m)

Preparation 14

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[3-(3-aminobenzoyl)indol-l-yl]propionate

NMR (CDC1₃, δ) : 1.18 (3H, t, J=7.5Hz), 2.86 (2H, t, J=6Hz), 4.10 (2H, q, J=7.5Hz), 4.49 (2H, t, J=6Hz), 6.90 (1H, dt, J=7.5, 2.5Hz), 7.1-7.4 (6H, m), 7.70 (1H, s), 8.4-8.5 (1H, m)

Preparation 15

To a suspension of aluminum chloride (6.67 g) in dichloromethane (70 ml) was added hexanoyl chloride (7.0 ml) at 0°C. After the mixture was stirred at 0°C for 15 minutes, isobutylbenzene (7.9 ml) was added to the mixture. The mixture was stirred at 0°C for 30 minutes and poured into ice water. The separated organic layer was washed with water, aqueous sodium bicarbonate and brine. The solution was dried over magnesium sulfate and^' evaporated to give 4^l-isobutylhexanophenone (10.52 g) as a colorless oil.

NMR (CDC1₃, δ) : 0.84-0.98 (9H, m), 1.30-1.43 (4H, m), 1.60-2.01 (3H, m) , 2.53 (2H, d, J=8.5Hz), 2.94 (2H, t, J=7Hz), 7.22 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz)

Preparation 16

The following compounds were obtained according to a similar manner to that of Preparation 15.

(1) 4'-Isobutylbutyrophenone

NMR (CDC1₃, δ) : 0.86-1.07 (9H, m), 1.67-2.01 (3H, m), 2.53 (2H, d, J=7Hz), 2.93 (2H, t, J=7.5Hz), 7.22 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz)

(2) 4'-Isobutylpentanophenone

NMR (CDC1₃, δ) : 0.85-1.00 (9H, m), 1.31-1.51 (2H, m), 1.60-2.01 (3H, m) , 2.53 (2H, d, J=7Hz), 2.95 (2H, t, J=7.5Hz), 7.22 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz)

(3) 4'-Isobutylheptanophenone

NMR (CDC1₃, δ) : 0.82-0.97 (9H, m), 1.18-1.47 (6H, m), 1.55-2.01 (3H, m) , 2.53 (2H, d, J=7Hz), 2.94 (2H, t, J=7.5Hz), 7.22 (2H, d, J=8Hz), 7.88 (2H, d, J=8Hz)

(4) 4'-Isobutyloctanophenone N NMMRR ((CCDDCC11₃₃,, δδ)) :: 00..8822--00..98 (9H, m), 1.20-1.46 (8H, m), 1.63-2.01 (3H, m) , 2.53 (2H, d, J=7Hz), 2.95 ( 2H, t, J=7 . 5Hz ) , 7 . 22 ( 2H, d, J=8Hz ) , 7. 88 ( 2H, d, J=8Hz )

Preparation 17 To a solution of 4'-isobutylhexanophenone (10.5 g) in 2-propanol (60 ml) was added sodium borohydride (2.05 g) , and the mixture was stirred at 50°C for 6 hours. The mixture was poured into ice water and acidified with 6N hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to give l-(4-isobutylphenyl)hexanol (9.32 g) as a colorless oil.

NMR (CDC1₃, δ) : 0.83-0.96 (9H, m) , 1.16-1.40 (6H, m), 1.60-1.96 (3H, m), 2.48 (2H, d, J=7Hz), 4.64

(1H, t, J=7Hz), 7.11 (2H, d, J=8.5Hz), 7.25 (2H, d, J=8.5Hz)

Preparation 18 The following compounds were obtained according to a similar manner to that of Preparation 17.

(1) 1-(4-Isobutylphenyl)butanol

NMR (CDC1₃, δ) : 0.86-0.98 (9H, m) , 1.16-1.97 (5H, m), 2.47 (2H, d, J=7Hz), 4.65 (1H, t, J=7Hz),

7.11 (2H, d, J=8Hz), 7.26 (2H, d, J=8Hz)

(2) 1-(4-Isobutylphenyl)pentanol

NMR (CDC1₃, δ) : 0.82-0.95 (9H, m) , 1.17-1.48 (4H, m), 1.60-1.97 (3H, m) , 2.47 (2H, d, J=7Hz), 4.63

(1H, t, J=7Hz), 7.11 (2H, d, J=8Hz), 7.25 (2H, d, J=8Hz)

(3) 1-(4-Isobutylphenyl) eptanol NMR (CDC1₃, δ) : 0.80-0.97 (9H, m) , 1.16-1.50 (8H, ) , 1. 58-1.97 ( 3H, m) , 2. 47 ( 2H, d, J=7Hz) , 4. 63 ( 1H, t, J=7Hz ) , 7 .11 ( 2H, d, J=8Hz ) , 7 .25 ( 2H, d, J=8Hz )

(4) l-(4-Isobutylphenyl)octanol

NMR (CDC1₃, δ) : 0.80-0.97 (9H, m) , 1.16-1.50 (10H, m), 1.60-1.97 (3H, m) , 2.47 (2H, d, J=7Hz), 4.63 (1H, t, J=7Hz), 7.12 (2H, d, J=8Hz), 7.26 (2H, d, J=8Hz)

Preparation 19

To a solution of l-(4-isobutylphenyl)hexan-l-ol (9.15 g) and carbon tetrabromide (25.9 g) in tetrahydrofuran (250 ml) was added triphenylphosphine (20.5 g) . The mixture was stirred at room temperature for 6 hours.

After the white solid was filtered off, the filtrate was evaporated. n-Hexane (300 ml) was added to the residue and the precipitate was filtered off. The filtrate was evaporated and the residual oil was distilled under reduced pressure to give l-(l-bromohexyl)-4- isobutylbenzene (3.52 g) as a colorless oil.

NMR (CDC1₃, δ) : 0.82-0.97 (9H, m) , 1.20-1.60 (8H, m), 1.74-1.97 (1H, m), 2.00-2.38 (2H, m), 2.46 (2H, d, J=7Hz), 4.96 (1H, t, J=7.5Hz), 7.10 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz)

Preparation 20

The following compounds were obtained according to a similar manner to that of Preparation 19.

(1) 1-(1-Bromobutyl)-4-isobutylbenzene

NMR (CDC1₃, δ) : 0.84-1.00 (9H, m) , 1.18-1.38 (5H, m), 2.46 (2H, d, J=7Hz), 4.99 (1H, t, J=7.5Hz), 7.10 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz) (2) 1-(1-Bromopentyl)-4-isobutylbenzene

NMR (CDC1₃, δ) : 0.80-0.94 (9H, m) , 1.15-1.55 (4H, m), 1.60-1.97 (3H, ) , 2.46 (2H, d, J=7Hz), 4.96 (1H, t, J=7.5Hz), 7.10 (2H, d, J=8Hz), 7.29 (2H,^' d, J=8Hz)

(3) 1-(1-(Bromoheptyl)-4-isobutylbenzene

NMR (CDC1₃, δ) : 0.81-0.97 (9H, m) , 1.16-1.55 (8H, ), 1.73-1.98 (1H, m) , 2.03-2.35 (2H, m) , 2.46 (2H, d, J=7Hz), 4.97 (1H, t, J=7.5Hz), 7.10 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz)

(4) 1-(1-Bromooctyl)-4-isobutylbenzene

NMR (CDC1₃, δ) : 0.82-1.06 (9H, m) , 1.18-1.55 (10H, m), 1.72-1.96 (1H, m) , 2.08-2.30 (2H, m), 2.45

(2H, d, J=7Hz), 4.97 (1H, t, J=7.5Hz), 7.10 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz)

Preparation 21 4'-Isobutylpentanophenone (2.1 g) was added to a solution of (+)-B-chlorodiisopinocampheylborane (3.57 g) in tetrahydrofuran (7 ml) at -25°C. After stirring for 5 hours, the solvent was removed and the residue was dissolved in ethyl ether (30 ml). To this solution was added diethanolamine (2 ml), and the mixture was stirred for 2 hours. The solid was filtered off and washed with ethyl ether. The combined filtrates were concentrated and the residue was chromatographed on silica gel (hexane:dichloromethane = 1:2) to give (R)-l-(4-isobutylphenyl)pentanol (635 mg) .

NMR (CDC1₃, δ) : 0.85-0.95 (3H, m) , 0.89 (6H, d,

J=7Hz), 1.2-1.5 (4H, m) , 1.6-2.0 (3H, m) , 2.45 (2H, d, J=7Hz), 4.63 (1H, t, J=7Hz), 7.11 (2H, d, J=8Hz), 7.25 (2H, d, J=8Hz) Preparation 22

(S)-l-(4-Isobutylphenyl)pentanol was obtained by reacting '-isobutylpentanophenone with (-)-B- chlorodiisopinocampheylborane according to a similar manner to that of Preparation 21.

NMR (CDC1₃, δ) : 0.85-0.95 (3H, m) , 0.89 (6H, d,

J=7Hz), 1.2-1.5 (4H, m) , 1.6-2.0 (3H, m) , 2.45 (2H, d, J=7Hz), 4.63 (1H, t, J=7Hz) , 7.11 (2H, d, J=8Hz), 7.25 (2H, d, J=8Hz)

Preparation 23

To a stirred solution of (R)-l-phenylbutanol (192 mg) in methylene chloride (10 ml) was added carbon tetrachloride (5 ml) and triphenylphosphine (494 mg) at 0°C. The mixture was heated at 50°C for 2 hours. After evaporation of the solvent, the residue was diluted with hexane and filtered through celite. The filtrate and washings were combined, evaporated in vacuo and chromatographed on silica gel to give (S)-l-chloro-l-phenylbutane (153 mg) .

NMR (CDC1₃, δ) : 0.93 (3H, t, J=7Hz), 1.2-1.6 (2H, m), 1.9-2.3 (2H, ) , 4.87 (1H, dd, J=8Hz and 7Hz), 7.25-7.45 (5H, m)

Preparation 24

(1) 1-Bromo-1-(4-isobutylphenyl)-3-methylbutane NMR (CDC1₃, δ) : 0.85-1.0 (12H, m) , 1.5-2.05 (4H, m), 2.47 (2H, d, J=7Hz), 5.06 (1H, t, J=8Hz), 7.11 (2H, d, J=8.5Hz), 7.30 (2H, d, J=8.5Hz)

(2) 1-Bromo-l-(4-isobutylphenyl)-4-methylpentane NMR (CDC1₃, δ) : 0.85-1.0 (12H, m) , 1.05-2.0 (4H, m), 2.05-2.4 (2H, m) , 2.46 (2H, d, J=7Hz), 4.93 (1H, t, J=7.5Hz), 7.11 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz)

Preparation 25

The following compounds were obtained with (-)-B- chlorodiisopinocampheylborane according to a similar manner to that of Preparation 21.

(1) (S)-l-(4-Isobutylphenyl)ethanol

NMR (CDC1₃, δ) : 0.90 (6H, d, J=7Hz), 1.51 (1H, d, J=7Hz), 1.87 (1H, m), 2.47 (2H, d, J=7Hz), 4.88 (1H, q, J=7Hz),^'7.13 (2H, d, J=8Hz), 7.28 (2H, d, J=8Hz)

(2) (S)-1-(4-Isobutylphenyl)propanol

NMR (CDC1₃, δ) : 0.85-1.0 (9H, m) , 1.6-1.95 (4H, m) , 2.47 (2H, d, J=7Hz), 4.57 (1H, t, J=7Hz), 7.12 (2H, d, J=8.5Hz), 7.26 (2H, d, J=8.5Hz)

Preparation 26

The following compounds were obtained according to a similar manner to that of Preparation 21.

(1) (R)-l-(4-Isobutylphenyl)ethanol

NMR (CDC1₃, δ) : 0.90 (6H, d, J=7Hz), 1.51 (1H, d, J=7Hz), 1.87 (1H, m), 2.47 (2H, d, J=7Hz), 4.88 (1H, q, J=7Hz), 7.13 (2H, d, J=8Hz), 7.28 (2H, d, J=8Hz)

(2) (R)-1-(4-Isobutylphenyl)propanol

NMR (CDC1₃, δ) : 0.85-1.0 (9H, m) , 1.6-1.95 (4H, m) , 2.47 (2H, d, J=7Hz), 4.57 (1H, t, J=7Hz), 7.12 (2H, d, J=8.5Hz), 7.25 (2H, d, J=8.5Hz) Preparation 27

The following compound was obtained according to a similar manner to that of Preparation 15.

4'-Isobutyl-3-methylbutyrophenone

NMR (CDC1₃, δ) : 0.91 (6H, d, J=7Hz) , 0.99 (6H, d, J=7Hz), 1.8-2.0 (1H, m) , 2.2-2.4 (1H, m), 2.53 (2H, d, J=7Hz), 2.82 (2H, d, J=7Hz) , 7.22 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz)

Preparation 28

To the solution of 4-methylvaleric acid (8.8 ml) in dichloromethane (50 ml) was added oxalyl chloride (6.4 ml) and several drops of N,N-dimethylformamide at 0°C. After the mixture was stirred at 0°C for 1 hour, the solvent was evaporated. The residue was dissolved in dichloromethane (100 ml), and then aluminum chloride (9.33 g) was added to the solution at 0°C. After the mixture was stirred at 0°C for 30 minutes, isobutylbenzene (9.4 ml) was added. The mixture was stirred at 0°C for 1 hour and poured into ice water. The organic layer was washed with water, aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give 4'-isobutyl-4-methylvalerophenone (15.56 g) as an oil. NMR (CDC1₃, δ) : 0.85-1.0 (12H, m) , 1.55-1.7 (3H, m), 1.8-2.0 (1H, m) , 2.53 (2H, d, J=7Hz), 2.9-3.0 (2H, m), 7.22 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz)

Preparation 29

The following compounds were obtained according to a similar manner to that of Preparation 17.

(1) 1-(4-Isobutylphenyl)-3-methylbutanol NMR (CDC1₃, δ) : 0.85-1.0 (12H, m) , 1.4-1.95 (4H, m) , 2. 47 ( 2H, d, J=7Hz ) , 4 . 72 ( 1H, t, J=7Hz ) , 7 . 12 ( 2H, d, J=8. 5Hz ) , 7. 25 ( 2H, d, J=8 . 5Hz )

(2) 1-(4-Isobutylphenyl)-4-methγlpentanol NMR (CDC1₃, δ) : 0.8-0.95 (12H, m) , 1.0-1.95 (6H, m), 2.47 (2H, d, J=7Hz), 4.60 (1H, t, J=7Hz), 7.11 (2H, d, J=8.5Hz), 7.25 (2H, d, J=8.5Hz)

Example 1 A mixture of ethyl 4-[3-(4-hγdroxybenzoyl)indol-l- yl]butyrate (176 mg), l-(l-bromohexyl)-4-isobutylbenzene (223 mg) and potassium carbonate (207 mg) in- N,N-dimethylformamide (4 ml) 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 0.5N hydrochloric acid. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (3:1) to give ethyl 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]^■ butyrate (279 mg) as an oil.

NMR (CDC1₃, δ) : 0.8-0.95 (9H, m) , 1.15-1.65 (9H, m), 1.7-2.35 (7H, m) , 2.45 (2H, d, J=7Hz), 4.09 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz),

5.14 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

Example 2

The following compounds were obtained according to a similar manner to that of Example 1.

(1) Ethyl 4-[3-[4-[l-(4-isobutγlphenyl)butoxy]benzoyl]- indol-1-yl]butyrate

NMR (CDC1₃, δ) : 0.8-1.05 (9H, m) , 1.20 (3H, t,

J=7Hz), 1.3-1.65 (2H, m) , 1.7-2.35 (7H, m) , 2.45 (2H, d, J=7Hz), 4.09 (2H, q, J=7Hz) , 4.23 (2H, t, J=7Hz), 5.17 (1H, dd, J=2Hz and 7Hz), 6.92

(2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

(2) Ethyl 4-[3-[4-[l-(4-isobutylphenyl)pentγloxy]- benzoyl]indol-l-yl]butyrate NMR (CDC1.₃, δ) : 0.8-1.0 (9H, m), 1.20 (3H, t,

J=7Hz), 1.3-1.65 (4H, m) , 1.75-2.35 (7H, m) , 2.45 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz) , 4.23 (2H, t, J=7Hz), 5.15 (1H, dd, J=2Hz and 7Hz),

6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

(3) Ethyl 4-[3-[4-[l-(4-isobutylphenyl)heptγloxy]- benzoyl]indol-1-yl]butyrate

NMR (CDC1₃, δ) : 0.8-0.95 (9H, m) , 1.15-1.65 (11H, m), 1.7-2.35 (7H, m), 2.45 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz), 4.13 (2H, t, J=7Hz), 5.15 (1H, dd, J=2Hz and 7Hz) , 6.92 (2H, d, J=9Hz), 7.11

(2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

(4) Ethyl 4-[3-[4-[l-(4-isobutylphenyl)octγloxy]- benzoyl]indol-l-yl]butyrate

NMR (CDC1₃, δ) : 0.8-0.95 (9H, m), 1.15-1.65 (13H, m), 1.7-2.35 (7H, m), 2.45 (2H d, J=7Hz), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.15 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz) , 7.11 {2H, d, J=8Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.74 ( 2H, d , J=9Hz ) , 8 . 3-8 . 4 ( 1H, m)

Example 3

To a solution of ethyl 4-[3-[4-[l-(4-isobutylphenyl)- hexyloxy]benzoyl]indol-l-yl]butyrate (270 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added IN aqueous solution of sodium hydroxide (1.5 ml) . The mixture was stirred at room temperature for 3 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-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol- l-yl]butyric acid (230 mg)^' as powder.

NMR (CDC1₃, δ) : 0.8-0.95 (9H, m) , 1.2-1.65 (6H, m) , 1.7-2.3 (5H, m) , 2.36 (2H, d, J=7Hz), 2.44 (2H, d, J=7Hz), 4.22 (2H, t, J=7Hz), 5.15 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.54 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

Example 4

The following compounds were obtained according to a similar manner to that of Example 3.

(1) 4-[3-[4-[l-(4-Isobutylphenyl)butoxy]benzoyl]indol-l- yl]butyric acid

NMR (CDC1₃, δ) : 0.8-1.05 (9H, m) , 1.3-1.65 (2H, m) , 1.7-2.3 (5H, m), 2.36 (2H, d, J=7Hz), 2.44 (2H, d, J=7Hz), 4.24 (2H, t, J=7Hz), 5.17 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.54 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

(2) 4-[3-[4-[l-(4-Isobutylphenyl)pentyloxy]benzoyl]- indol-l-yl]butyric acid NMR (CDC1₃, δ) : 0.8-1.0 (9H, m) , 1.25-1.6 (4H, m) , 1.75-2.3 (5H, m), 2.37 (2H, d, J=7Hz), 2.43 (2H, d, J=7Hz), 4.24 (2H, t, J=7Hz), 5.14 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.54 (1H, s), 7.73

(2H, d, J=9Hz), 8.3-8.4 (1H, m)

(3) 4-[3-[4-[l-(4-Isobutylphenyl)heptγloxy]benzoyl]- indol-1-γl]butyric acid NMR (CDC1₃, δ) : 0.8-0.95 (9H, m) , 1.15-1.65 (8H, m), 1.7-2.30 (5H, m) , 2.32-2.5 (4H, m) , 4.23 (2H_Λ t, J=7Hz), 5.15 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2-7.45 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

(4) 4-[3-[4-[l-(4-Isobutylphenyl)octyloxy]benzoyl]- indol-1-γl]butyric acid

NMR (CDC1₃, δ) : 0.8-0.95 (9H, m), 1.15-1.6 (10H, m), 1.7-2.28 (5H, m) , 2.32-2.5 (4H, m) , 4.24

(2H, t, J=7Hz), 5.15 (1H, dd, J=2Hz and 7Hz) , 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.54 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

Example 5

A mixture of ethyl 4-[3-(3-aminobenzoyl)indol-l-yl]- butyrate (176 mg), 1-(1-bromohexyl)-4-isobutylbenzene (233 mg) and diisopropylethylamine (194 mg) in dichloromethane (5 ml) was refluxed for 20 hours. The- reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (3:1) to give ethyl 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]- indol-l-yl]butyrate (155 mg) as an oil.

NMR (CDC1₃, δ) : 0.8-0.95 (9H, m) , 1.15-1.5 (9H, m) , 1.65-1.95 (3H, m) , 2.05-2.35 (4H, m) , 2.43 (2H, d, J=7Hz), 4.05-4.4 (6H, m) , 6.67 (1H, d,

J=8Hz), 6.95-7.5 (11H, m), 8.4-8.5 (1H, )

Example 6

The following compounds were obtained according to a similar manner to that of Example 5.

(1) Ethyl 4-[3-[3-[l-(4-isobutylphenyl)propylamino]- benzoγl]indol-l-yl]bύtγrate

NMR (CDC1₃, δ) : 0.85-1.0 (9H, m) , 1.21 (3H, t, J=7Hz), 1.7-2.0 (3H, m) , 2.1-2.35 (4H, m) , 2.45

(2H, d, J=7Hz), 4.0-4.35 (5H, m) , 6.68 (1H, d, J=8Hz), 7.0-7.5 (11H, m), 8.4-8.5 (1H, m)

(2) Ethyl 4-[3-[3-[l-(4-isobutylphenyl)butylamino]- benzoyl]indol-l-yl]butyrate

NMR (CDC1₃, δ) : 0.8-1.0 (9H, m) , 1.20 (3H, t,

J=7Hz), 1.25-1.5 (2H, m) , 1.65-1.95 (3H, m) , 2.05-2.35 (4H, m) , 2.43 (2H, d, J=7Hz), 4.0-4.4 (6H, m), 6.68 (1H, d, J=8Hz), 6.95-7.5 (11H, m) , 8.4-8.5 (1H, m)

(3) Ethyl 4-[3-[3-[l-(4-isobutylphenyl)pentylamino]- benzoyl]indol-1-γl]butyrate

NMR (CDC1₃, δ) : 0.8-0.95 (9H, m) , 1.15-1.5 (7H, m) , 1.65-1.95 (3H, m) , 2.05-2.35- (4H, m) , 2.43 (2H, d, J=7Hz), 4.05-4.4 (5H, m) , 6.68 (1H, d, J=8Hz), 7.0-7.5 (11H, m) , 8.4-8.5 (1H, m)

Example 7 To a solution of ethyl 4-[3-[3-l-(4-isobutylphenyl)- hexylamino]benzoyl]indol-l-γl]butyrate (150 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml) was added IN aqueous solution of sodium hydroxide (1 ml) . The mixture was stirred at room temperature for 3 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-[3-[l-(4-isobutylphenyl)hexylamino]benzoyϊ]- indol-1-yl]butyric acid (130 mg) as powder. NMR (CDC1₃, δ) : 0.75-0.95 (9H, m) , 1.15-1.5 (6H, m), 1.65-1.95 (3H, m), 2.05-2.25 (2H, m), 2.3-2.45 (4H, m) , 4.05-4.8 (5H, m) , 6.67 (1H, d, J=8Hz), 6.95-7.5 (11H, m), 8.4-8.5 (1H, m)

Example 8

The following compounds were obtained according to a similar manner to that of Example 7.

(1) 4-[3-[3-[l-(4-Isobutylphenyl)propyla ino]benzoyl]- indol-1-yl]butyric acid

NMR (DC1₃, δ) : 0.8-1.0 (9H, m), 1.7-1.95 (3H, m),

2.05-2.5 (6H, m), 4.05-4.3 (3H, m) , 6.68 (1H, d, J=8Hz), 7.0-7.5 (11H, m) , 8.4-8.5 (1H, m)

(2) 4-[3-[3-[l-(4-Isobutylphenyl)butylamino]benzoyl]- indol-l-γl]butγric acid

NMR (CDC1₃, δ) : 0.8-1.05 (9H, m), 1.2-1.55 (2H, m), 1.65-1.95 (3H, m) , 2.1-2.5 (6H, m) , 4.1-4.5 (4H, m), 6.68 (1H, d, J=8Hz) , 6.95-7.5 (11H, m) , 8.4-8.5 (1H, m)

(3) 4-[3-[3-[l-(4-Isobutylphenyl)pentylamino]benzoyl]- indol-1-yl)butyric acid

NMR (CDC1₃, δ) : 0.8-0.95 {9H, m) , 1.2-1.45 (4H, m) , 1.7-1.95 (3H, m), 2.1-2.5 (6H, m), 4.05-4.4 (3H, ) , 6 . 68 ( 1H, d, J=8Hz ) , 7 . 0-7 . 5 ( 11H, m) , 8 . 4-8. 5 ( 1H, m)

Example 9 To a mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol- l-yl]butyrate (275 mg) , (R)-l-(4-isobutylphenyl)pentanol (179 mg) and triphenylphosphine (213 mg) in a mixture of tetrahydrofuran and toluene (1:4, 10 ml) was added diethyl azodicarboxylate (0.13 ml) at -25°C. After stirring for 1 hour, the reaction mixture was concentrated in vacuo. The concentrate was chromatographed on silica gel using hexane and ethyl acetate (3:1) to give ethyl (S)-4-[3-[4-[l-(4- isobutylphenyl)pentyloxy]benzoyl]indol-l-yl]butyrate (279 mg) . NMR (CDC1₃, δ) : 0.89 (6H, d, J=7Hz), 0.8-0.95 (3H, m), 1.20 (3H, t, J=7Hz), 1.3-1.65 (4H, m) , 1.75-2.35 (7H, m) , 2.45 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.15 (1H, dd, J=5, 7Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.74

(2H, d, J=9Hz), 8.34 (1H, m)

Example 10

Ethyl (R)-4-[3-[4-[l-(4-isobutylphenyl)pentyloxy]- benzoyl]indol-l-yl]butyrate was obtained by reacting ethyl 4-[3-(4-hydroxybenzoyl)indol-l-yl]butyrate with (S)-l-(4-isobutylphenyl)pentanol according to a similar manner to that of Example 9.

NMR (CDC1₃, δ) : 0.89 (6H, d, J=7Hz), 0.8-0.95 (3H, m), 1.20 (3H, t, J=7Hz), 1.3-1.65 (4H, m) ,

1.75-2.35 (7H, m) , 2.45 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.15 (1H, dd, J=5Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.34 (1H, ) Example 11

(1) (S)-4-[3-[4-[l-(4-Isobutγlphenyl)pentyloxy]benzoyl]- indol-1-yl]butyric acid

NMR (CDC1₃, δ) : 0.89 (6H, d, J=7Hz), 0.85-0.95 (3H, m), 1.25-1.6 (4H, m) , 1.75-2.3 (5H, m), 2.37 (2H, t, J=7Hz), 2.43 (2H, d, J=7Hz), 4.24 (2H, t, J=7Hz), 5.14 (1H, dd, J=5Hz and 7Hz), 6.92

(2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2-7.45 (5H, m), 7.54 (1H, s), 7.73 (2H, d, J=9Hz), 8.33 (1H, m) [α]^⁵ : -61.0° (C=1.0, chloroform)

(2) (R)-4-[3-[4-[1-(4-Isobutylphenyl)pentyloxy]benzoyl]- indol-1-yl]butyric acid

NMR (CDC1₃, δ) : 0.89 (6H, d, J=7Hz), 0.85-0.95 (3H, m), 1.25-1.6 (4H, m), 1.75-2.3 (5H, m), 2.37 (2H, t, J=7Hz), 2.43 (2H, d, J=7Hz), 4.24 (2H, t, J=7Hz), 5.14 (1H, dd, J=5Hz and 7Hz) , 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2-7.45 (5H, m), 7.54 (1H, s), 7.73 (2H, d, J=9Hz), 8.33 (1H, m) L^α^^{5 :} +62.4° (C=0.5, chloroform)

Example 12

(1) Ethyl 4-[3-[4-[l-(4-isobutγlphenyl)-3-methylbutoxy]- benzoyl]indol-l-yl]butγrate

NMR (CDC1₃, δ) : 0.85-1.05 (12H, m), 1.20 (3H, t, J=7Hz), 1.5-2.35 (8H, m), 2.45 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz) , 4.23 (2H, t, J=7Hz) , 5.23 ( 1H, dd, J=4Hz and 7Hz ) , 6 . 93 ( 2H, d, J=9Hz ) , 7 .11 ( 2H, d, J=8.5Hz ) , 7 .2-7 .45 ( 5H, m) , 7 .53 ( 1H, s ) , 7 .73 ( 2H, d, J=9Hz ) , 8. 3-8 . 4 ( 1H, )

(2) Ethyl 4-[3-[4-[l-(4-isobutylphenyl)-4-methyl- pentyloxy]benzoyl]indol-1-y1]butyrate NMR (CDC1₃, δ) : 0.85-1.0 (12H, m) , 1.15-1.7 (8H, m), 1.75-2.35 (7H, m) , 2.45 (2H, d, J=7Hz), 4.09 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.12 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.11

(2H, d, J=8.5Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

Example 13 To a stirred solution of ethyl 4-[3-(4-hydroxy- benzoyl)indol-l-yl]butyrate (131 mg) in N,N-dimethylformamide (1.5 ml) was added (S)-l-chloro- 1-phenylbutane (153 mg) and powdered potassium carbonate (254 mg) , and the mixture was heated at 60°C for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate and washings were combined, washed with water and brine, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel (hexane:ethyl acetate = 2:1) to give ethyl- (R)-4-[3-[4-(l-phenylbutoxy)benzoyl]indol-l-yl]butyrate (91 mg).

NMR (CDC1₃, δ) : 0.98 (3H, t, J=7Hz), 1.20 (3H, t, J=7Hz), 1.25-2.4 (8H, m), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.19 (1H, dd, J=7Hz and 5Hz), 6.93 (2H, d, J=9Hz), 7>2-7.45 (8H, m) ,

7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.36 (1H, m)

Example 14

The following compounds were obtained according to a similar manner to that of Example 9 or 10. (1) Ethyl (S)-4 [3-[4-(l-phenylbutoxy)benzoyl]indol-l- yl]butyrate

NMR (CDC1₃, δ) : 0.98 (3H, t, J=7Hz), 1.20 (3H, t, J=7Hz), 1.25-2.4 (8H, m) , 4.10 (2H, g, J=7Hz), 4.23 (2H, t, J=7Hz), 5.19 (1H, dd, J=7Hz and

5Hz), 6.93 (2H, d, J=9Hz), 7.2-7.45 (8H, m) , 7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.36 (1H, m)

(2) Ethyl (R)-4-[3-[4-[l-(4-isobutylphenyl)butoxy]- benzoyl]indol-1-yl]butyrate

NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 0.97 (3H, t, J=7Hz), 1.20 (3H, t, J=7Hz), 1.3-2.1 (7H, m) , 2.1-2.4 (4H, m), 2.45 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.16 (1H, dd, J=6Hz and 8Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m), 7.52 (1H, s), 7.73 (2H, d, J=9Hz), 8.36 (1H, m)

(3) Ethy (S)-4-r3-[4-[l-(4-isobutylphenyl)butoxy]- benzoyl]indol-l-yl3butyrate

NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 0.97 (3H, t, J=7Hz), 1.20 (3H, t, J=7Hz), 1.3-2.1 (7H, m) , 2.1-2.4 (4H, m), 2.45 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.16 (1H, dd, J=6Hz and 8Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.52 (1H, s), 7.73 (2H, d, J=9Hz), 8.36 (1H, m)

(4) Ethyl (R)-4-[3-[4-[l-(4-isobutylphenyl)ethoxy3- benzoyl]indol-l-yl]butyrate

NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.67 (3H, d, J=7Hz), 1.85 (1H, m) , 2.1-2.4 (4H, m), 2.46 (2H, d, J=7Hz), 4.11 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.39 (1H, q, J=7Hz), 6.94 (2H, d, J=9Hz), 7.12 (2H, d. J=8Hz ) , 7. 2-7. 45 ( 5H, m) , 7 . 53 ( 1H, s ) , 7 .75 ( 2H, d, J=9Hz ) , 8. 36 ( 1H, m)

(5) Ethyl (S)-4-[3-[4-[l-(4-isobutylphenyl)ethoxy]- benzoyl]indol-l-yl]butyrate

NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.67 (3H, d, J=7Hz), 1.85 (1H, m) , 2.1-2.4 (4H, m), 2.46 (2H, d, J=7Hz), 4.11 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.39 (1H, q, J=7Hz), 6.94 (2H, d, J=9Hz), 7.12 (2H, d,

J=8Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.75 (2H, d, J=9Hz), 8.36 (1H, m)

(6) Ethyl (S)-4-[3-[4-[l-(4-isobutylphenyl)propoxy]- benzoyl]indol-l-yl]butyrate

NMR (CDC1₃, δ) : 0.89 (6H, d, J=6Hz), 1.02 (3H, t,

J=7Hz), 1.20 (3H, t, J=7Hz), 1.7-2.35 (7H, m) ,

2.45 (2H, d, J=7Hz), 4.09 (2H, q, J=7Hz), 4.23

(2H, t, J=7Hz), 5.09 (1H, t, J=7Hz), 6.93 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

(7) Ethyl (R)-4-[3-[4-[l-(4-isobutylphenyl)propoxy]- benzoyl]indol-l-yl]butyrate

NMR (CDC1₃, δ) : 0.89 (6H, d, J=7Hz), 1.02 (3H, t,

J=7Hz), 1.20 (3H, t, J=7Hz), 1.7-2.35 (7H, m) ,

2.45 (2H, d, J=7Hz), 4.09 (2H, q, J=7Hz), 4.23

(2H, t, J=7Hz), 5.09 (1H, t, J=7Hz) , 6.93 (2H, t, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

Example 15 The following compounds were obtained according to a similar manner to that of Example 3.

(1) (R)-4-[3-[4-(l-Phenylbutoxy)benzoyl3indol-l-yl3- butyric acid

NMR (CDC1₃, δ) : 0.96 (3H, t, J=7Hz), 1.2-2.3 (6H, m), 2.37 (2H, t, J=7Hz), 4.24 (2H, t, J=7Hz), 5.18 (1H, dd, J=5Hz and 7Hz), 6,91 (2H, d, J=9Hz), 7.2-7.45 (8H, m) , 7.53 (1H, s), 7.72 (2H, d, J=7Hz), 8.33 (1H, m)

(2) (S)-4-[3-[4-(1-Phenylbutoxy)benzoyl indol-l-yl3- butyric acid

NMR (CDC1₃, δ) : 0.96 (3H, t, J=7Hz), 1.2-2.3 (6H, ), 2.37 (2H, t, J=7Hz), 4.24 (2H, t, J=7Hz), 5.18 (1H, dd, J=5Hz and 7Hz), 6.91 (2H, d,

J=7Hz), 7.2-7.45 (8H, m) , 7.53 (1H, s), 7.72 (2H, d, J=7Hz), 8.33 (1H, m)

(3) (R)-4-[3-[4-[l-(4-Isobutylphenyl)butoxy3benzoyl]- indol-1-yl]butyric acid

NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 0.96 (3H, t, J=7Hz), 1.2-2.3 (7H, m) , 2.38 (2H, t, J=7Hz), 2.44 (2H, d, J=7Hz), 4.23 (2H, t, J=7Hz), 5.16 (1H, dd, J=5Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.33 (1H, m)

(4) (S)-4-[3-[4-[l-(4-Isobutylphenyl)butoxy3benzoyl]- indol-1-yl]butyric acid NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 0.96 (3H, t,

J=7Hz), 1.2-2.3 (7H, m), 2.38 (2H, t, J=7Hz) , 2.44 (2H, d, J=7Hz), 4.23 (2H, t, J=7Hz), 5.16 (1H, dd, J=5Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.33 (1H, m) (5) (R)-4-[3-[4-[l-(4-Isobutylphenyl)ethoxy3benzoyl]- indol-l-yl]butyric acid NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 1.63 (3H, d,

J=7Hz), 1.72 (1H, m), 2.16 (2H, m) , 2.35 (2H, t, J=7Hz), 2.44 (2H, d, J=7Hz), 4.19 (2H, t,

J=7Hz), 5.36 (2H, q, J=7Hz), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.25-7.4 (5H, m) , 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.32 (1H, m)

(6) (S)-4-[3-[4-[l-(4-Isobutylphenyl)ethoxy]benzoyl]- indol-1-yl]butyric acid NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz) , 1.63 (3H, d,

J=7Hz), 1.72 (1H, m), 2.16 (2H, m) , 2.35 (2H, t, J=7Hz), 2.44 (2H, d, J=7Hz), 4.19 (2H, t, J=7Hz), 5.36 (2H, q, J=7Hz), 6.92 (2H, d,

J=9Hz), 7.11 (2H, d, J=8Hz), 7.25-7.4 (5H, m) , 7.53 (1H, s), 7.74 (2H, d, J=9Hz), 8.32 (1H, )

(7) 4-[3-[4-[1-(4-Isobutylphenyl)-3-methylbutoxy]- benzoyl]indol-l-yl]butyric acid

NMR (CDC1₃, δ) : 0.85-1.05 (12H, m) , 1.5-1.7 (1H, m), 1.75-2.28 (5H, m) , 2.32-2.5 (4H, m) , 4.23 (2H, t, J=7Hz), 5.22 (1H, dd, J=4Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8.5Hz), 7.2-7.45 (5H, m) , 7.54 (1H, s), 7.72 (2H, d,

J=9Hz), 8.3-8.4 (1H, m)

(8) 4-[3-[4-[1-(4-Isobutylphenyl)-4-methylpentyloxy]- benzoyl3indol-l-yl3butyric acid NMR (CDC1₃, δ) : 0.85-1.0 (12H, m) , 1.15-1.7 (3H, m), 1.75-2.28 (5H, ), 2.32-2.5 (4H, m) , 4.23 (2H, t, J=7Hz), 5.11 (1H, dd, J=2Hz and 7Hz), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8.5Hz), 7.2-7.45 (5H, m) , 7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m) (9) (S)-4-t3-[4-[1-(4-Isobutylphenyl)propoxy3benzoyl]- indol-1-yl]butyric acid

NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz) , 1.00 (3H, t, J=7Hz), 1.7-2.3 (5H, m) , 2.3-2.5 (4H, m) , 4.24 (2H, t, J=7Hz), 5.09 (1H, t, J=7Hz), 6.73 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

(10) (R)-4-[3-[4-[l-(4-Isobutylphenyl)propoxy]benzoyl]- indol-1-yl]butyric acid

NMR (CDC1₃, δ) : 0.88 (6H, d, J=7Hz), 1.00 (3H, t, J=7Hz), 1.7-2.3^' (5H, m) , 2.3-2.5 (4H, ), 4.24 (2H, t, J=7Hz), 5.09 (1H, t, J=7Hz), 6.73 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.2-7.45 (5H, m), 7.53 (1H, s), 7.73 (2H, d, J=9Hz), 8.3-8.4 (1H, m)

Claims

C L A I S

1. A compound of the formula :

wherein R is aryl which may have suitable substituent(s) , R 2 is carboxy(lower)alkyl or protected carboxy(lower)alkyl, 3 R is hydrogen, lower alkyl or halogen,

X is -O- or -NH- and n is integer of 1 to 6, with proviso that when n is 1, then X is NH, and when n is 3, then (^c _n ^H ₂ ) is trimethylene or methylethylene, or pharmaceutically acceptable salt thereof.

2. A compound of claim 1, which is represented by the formula :

wherein R 1, R2, n and X are each as defined above.

A compound of claim 2, wherein R is phenyl which may have suitable substituent(s) , and 2 R is carboxy(lower)alkyl or esterified carboxy(lower)alkyl.

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

wherein R is lower alkylphenyl,

2 R is carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl, and n is integer of 2 to 6.

5. A compound of claim 4, which is selected from the group consisting of :

4-[3-f4-[l-(4-isobutylphenyl)pentyloxy]benzoyl]- indol-1-yl]butyric acid, and 4-[3-[4-[l-(4-isobutylphenyl)hexyloxy]benzoyl3- indol-l-yl3butyric acid.

6. A compound of claim 5, which is R or S configuration of 4-[3-[4-[l-(4-isobutylphenyl)pentyloxy]benzoyl - indol-l-yl]butyric acid.

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

wherein R is lower alkylphenyl, 2 R is carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl, and n is integer of 1 to 6.

8. A process for preparing a compound of the formula

wherein R is aryl which may have suitable substituent(s) , 2 R is carboxy(lower)alkyl or protected carboxy(lower)alkyl, 3 R is hydrogen, lower alkyl or halogen,

X is -O- or -NH- and n is integer of 1 to 6, with proviso that when n is 1, then X is NH, and when n is 3, then (CJH ) .is trimethylene or methylethylene, or a salt thereof, which comprises

(1) reacting a compound of the formula :

wherein R 2 , R3 and X are each as defined above, or a salt thereof, which a compound of the formula

wherein R and n are each as defined above, and ι W is acid residue, or a salt thereof to give a compound of the formula

wherein R 1 , R2 , R 3 , X and n are each as defined above , or a salt thereof, or

(2) subjecting a compound of the formula :

wherein R1, R3, X and n are each as defined above, and 2 Rc_L is protected carboxy(lower)alkyl, or a salt thereof to elimination reaction of the carboxy protective group to give a compound of the formula :

wherein R 1, R3, X and n are each as defined above, and

R ,.2 i.s carboxy(lower)alkyl, or a salt thereof, or

reacting a compound of the formula :

wherein R 1, R3, X and n are each as defined above, or a salt thereof, with a compound of the formula :

\T - R'

2 wherein R is as defined above, and 2 W is acid residue, or a salt thereof, to give a compound of the formula :

wherein R 1, R2 , R3 , X and n are each as defined above , or a salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

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

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

12. Use of compound of claim 1 or pharmaceutically acceptable salt thereof as a testosteron 5α-reductase inhibitor.

13. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.