WO1993016996A1

WO1993016996A1 - Indole derivatives as testosterone-5-alpha-reductase inhibitors

Info

Publication number: WO1993016996A1
Application number: PCT/JP1993/000201
Authority: WO
Inventors: Satoshi Okada; Kozo Sawada; Akio Kuroda; Shinya Watanabe; Hirokazu Tanaka
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1992-02-25
Filing date: 1993-02-18
Publication date: 1993-09-02
Also published as: JPH07503969A; GB9204024D0

Abstract

A compound of formula (I), wherein R1 is carboxy or protected carboxy, R2 is hydrogen, lower alkyl or halogen, R3 is aryl which may have suitable substituent(s), A is lower alkylene, X is methylene, -O- or -NH-, and Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R3 is alkyl, and a pharmaceutically acceptable salt thereof. The compound 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 malepattern baldness), acne (e.g. acne vulgaris, pimple, etc.), other hyperandrogenism, and the like.

Description

DESCRIPTION

INDOLE DERIVATIVES AS TESTOSTERONE-5-ALPHA-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 testosteron 5a-reductase and the like, to a 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 pharmaceutically acceptable salts thereof, which are useful as a testosteron 5a--reductase inhibitor.

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

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

A still further object of the present invention is to provide a use of said indole derivative or a pharmaceutically acceptable salt thereof as a medicament such as testosteron 5α- reductase inhibitor useful for treating or preventing testosteron 5ot-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 R¹ is carboxy or protected carboxy,

R^z is hydrogen, lower alkyl or halogen,

R³ is aryl which may have suitable substituent(s),

A is lower alkylene,

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

Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R³ is alkyl. 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

(I-a) or a salt thereof

Process 2

(IV) (V) or a salt thereof or a salt thereof

(I) or a salt thereof

Process 3

R² Elimination of the X-Y-R³ carboxy-protective

group

A-R¹,

(I-b) or a salt thereof

(I-C) or a salt thereof

Process 4

(VI) (VII) or a salt thereof or a salt thereof

(I-a) or a salt thereof

wherein R¹ , R² , R³ , A, X and Y are each as defined above,

Ri is protected carboxy,

X¹ is -0- or -NH-, ¹ is leaving group,

W² and ³ are each acid residue.

Suitable salts of the compounds (I) are conventional non- toxic, pharmaceutically acceptable salts 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, sulfate, 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 compounds (I-a) to (I-c), (II), (III), (IV), (V), (VI) and (VII) in Processes 1 to 4, 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 includes 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" 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.

Suitable "halogen" may include fluoro, chloro, bromo and iodo.

Suitable "lower alkylene" may include straight or branched bivalent lower alkane such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexa ethylene, propylene, and the like.

Suitable "lower alkylene substituted by lower alkoxy" may include lower alkylene as mentioned above, which is substituted by lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.). Specific examples of thus defined "lower alkylene substituted by lower alkoxy" may be methoxyethylene, ethoxyethylene, methoxypropylene, ethoxypropylene, and the like.

Suitable "lower alkenylene" may include one having 2 to 6 carbon atoms such as vinylene, propenylene, butenylene, pentenylene, hexenylene, and the like.

Suitable "lower alkynylene" may include one having 2 to 6 carbon atoms such as ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like.

Suitable "leaving group" may include hydroxy, reactive group derived from hydroxy, and the like.

Suitable "reactive group derived from hydroxy" may include acid residue and the like. 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 (e.g. tolyl, xylyl, mesityl, cumenyl, isobutylphenyl, etc. ), haloaryl (e.g. chlorophenyl, etc. ), and the like.

Suitable "alkyl" may include straight or branched one, having 1 to 20 carbon atom(s), preferably one having 6 to 17 carbon atoms.

Suitable "protected carboxy" may include 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, pivaloyloxy- methyl 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, isobutyryloxymethyl ester, 2- ethylbutyryloxymethyl 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, ethoxy- carbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1- ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(lower)alkyl ester, or (5-lower alkyl-2- oxo-1,3-dioxol-4-yl) (lower)alkyl ester (e.g. (5-meth l-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.); aryl(lower)alkyl ester which may have at least one suitable sub- stituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitro- benzyl 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, cu enyl ester, etc.); phthalidyl ester; and the like.

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

Particularly, the preferred embodiments of R¹ , R² , R³ , A, X and Y are as follows. R¹ is carboxy; or lower alkoxycarbonyl, more preferably C1-C4 alkoxycarbonyl

(e.g. methoxycarbonyl, ethoxycarbonyl, etc. ), R² is hydrogen, R³ is aryl which may be substituted by lower alkyl, more preferably phenyl substituted by C1-C4 alkyl (e.g. isobutylphenyl, etc.), A is lower alkylene, more preferably C1-C4 alkylene (e.g. ethylene, trimethylene, etc.), X is methylene, -0- or -NH-, and Y is lower alkylene substituted by lower alkoxy, more preferably

C1-C4 alkylene substituted by C1-C4 alkoxy (e.g. methoxyethylene, ethoxyethylene, methoxypropylene, ethoxypropylene, etc. ); lower alkenylene, more preferably

C₂-Cβ alkenylene (e.g. pentenylene, etc.); or lower alkynylene, more preferably C₂-C_β alkynylene (e.g. butynylene, etc. ), or Y-R³ is alkyl, more preferably C1-C20 alkyl, most preferably

C₆-Ci7 alkyl (e.g. hexyl, heptyl, undecyl, tridecyl, pentadecyl, heptadecyl, etc.). The processes 1 to 4 for preparing the object compound (I) of the present invention are explained in detail in the following. Process 1

The object compound (I-a) 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, toluene or any other solvent which does not adversely affect the reaction.

In this reaction, when W¹ in the compound (III) is acid residue, 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.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), trϊ (lower)alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridϊne or its derivative [e.g. picoline, lutidine, 4-dimethyl- aminopyridine, etc.], or the like. In case that the base to be used is liquid, it can also be used as a solvent.

When W¹ in the compound (III) is hydroxy, this reaction is usually carried out in the presence of a conventional condensing agent such as N,N' -dicyclohexylcarbodi imide; N-cyclohexyl-N' - morphol inoethylcarbodi imide; N-cyclohexyl-N' -(4-diethylamino- cyclohexyl )carbodi imide; N,N' -diethylcarbodi imide, N,N'-diiso- propylcarbodi imide; N-ethyl-N' -(3-di ethylaminopropyl)carbodi- imide, N,N' carbonyl-bis(2-methyl i idazole) ; pentamethylene- ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine; ethoxyacetylene; l-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxy- chloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc. ]; a combination of triarylphosphine [e.g. triphenylphosphine, etc. ] or tri(lower)- alkylphosphine [e.g. triethylphosphine, etc. ], and di(lower)- alkyl azodicarboxylate [e.g. diethyl azodicarboxylate, etc. ]; 2-ethyl-7-hydroxybenzisoxazol iu salt; 2-ethyl-5-(m-sulfo- phenyl )isoxazolium hydroxide intramolecular salt; l-(p-chloro- benzenesulfonyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylform- amide with thionyl chloride, phosgene, trichloromethyl chloro¬ formate, phosphorus oxychloride, etc. ; or the like.

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) 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. Process 3

The object compound (I-c) or a salt thereof can be prepared by subjecting the compound (I-b) or a salt thereof to elimination reaction of the caboxy-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 carbo¬ nate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phos- phate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phos¬ phate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methyl- orpholine, 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 aryl (lower)alkyl ester and carried out by reacting the compound (I-b) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetra- chloride, 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 nitro- alkane (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 in the presence 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 4

The object compound (I-a) or 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 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.

Some of the starting compounds (IV) and (VI) are new and can be prepared by the following methods or conventional manners, the details of which are shown in Preparations mentioned below, or a conventional manner. 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

(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 , A, X, Y, W² and W³ are each as defined above, and W⁴ and W⁵ are each 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, for example, extraction, precipitation, fractional crystallization, recrystall ization, chromatography, and the like.

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 testosteron 5a.-reductase inhibitor and effective to testosteron 5ø-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-[l-(4-Isobutylphenyl )-2-butynyloxy]benzoyl ]-indol- l-yl]butyric acid

(2) (E)-4-[3-[4-[l-(4-Isobutylphenyl)-3-pentenyloxy]benzoyl]- indol-1-yl Jbutyric acid

(3) 4-[3-[4-[l-(4-Isobutylphenyl)-2-ethoxyethoxy]benzoyl]- indol-1-yl ]butyric acid

[2] Inhibitory activity on testosterone 5a-reductase in rats Test Methods i) Materials l,2,6,7-³H-Testosterone (85-105 Ci/mmol) : l,2,6,7-³H-Testosterone (85-105 Ci/mmol) is a mixture of 1, 2, 6, 7-³H-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 iii) Testosterone 5β-reductase assay

The reaction solution contains 1 mM dithiothreitol, 40 mM sodium phosphate pH 6.5, 50 μM NADPH, 1,2,6,7- H- 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 chro atographed 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 5of- dihydrotestosterone 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 is used in the form of a 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, stearϊc 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 diseases 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 Example are given for the purpose of illustrating the present invention. Preparation 1

To a solution of (E)-l-(4-isobutylphenyl )-2-penten-l-one (840 mg) in toluene (15 ml) was added a solution of diisobutyl- aluminum hydride (1.0 M in toluene : 3.4 ml) at -78°C • After 2 hours, a solution of potassium sodium tartrate (1 M in water : 5 ml) was added and the resulting mixture was filtered through celite and washed with toluene. The combined filtrate and washings were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane : ethyl acetate = 9 : 1) to give (E)-l-(4- isobutylphenyl )-2-penten-l-ol (366 mg).

NMR (CDCla, δ ) '• 0.89 (6H, d, J=7Hz), 1.01 (3H, t, J=7Hz), 1.7 - 2.2 (3H, m), 2.48 (2H, d, J=7Hz), 5.14 (1H, ), 5.55 - 5.9 (2H, iff), 7.12 (2H, d, J=8Hz), 7.28 (2H, d, J=8Hz). Preparation 2

To a stirred solution of lithium bis(trimethylsilyl )amide (0.57 M in tetrahydrofuran; 20 ml) was added 4-isobutylaceto- phenone (1.0 g) in tetrahydrofuran (3 ml) at -20°C After 30 minutes, to the mixture was added allyl iodide (0.57 ml) and warmed at 0°C • After 2 hours, the reaction was quenched by aqueous ammonium chloride and the resulting mixture extracted with ether. The organic layers were washed with water and brine, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel (hexane : methylene chloride = 1 : 1) to give l-(4-isobutylphenyl )-4-penten-l-one (86 mg). NMR (CDCI3, δ ) • 0.89 (6H, d, J=7Hz), 1.89 (1H, m), 2.4 - 2.6 (2H, m), 2.53 (2H, d, J=7Hz), 3.07 (2H, t, J=7Hz), 5.45 - 5.65 (2H, m), 5.9 (1H, m), 7.22 (2H, d, J=8Hz), 7.88 (2H, d, J=8Hz). Preparation 3

To a stirred suspension of magnesium (783 mg) and iodine (5 mg) in tetrahydrofuran (50 ml) was added a solution of 2- butenyl chloride (2.64 ml) in tetrahydrofuran (15 ml) dropwise at 50°C. After stirring for 30 minutes, aluminum chloride (4.7 g) in ether (17 ml) was added at -78°C, and then stirred for additional 10 minutes, 4-isobutylbenzene (3.9 g) in tetrahydrofuran (2 ml) was added and the reaction mixture was warmed to 0°C. After 1.5 hours, a solution of ammonium chloride in water was added and the mixture was extracted with ether. The organic layers were washed with water and brine, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel (hexane : ether = 5 : 1) to give

(E)-l-(4-isobutylρhenyl)-3-penten-l-ol (2.07 g). NMR (CDClβ, δ ) ' 0.89 (12H, d, J=7Hz), 1.59 (3H, d, J=7Hz),

1.84 (1H, m), 2.46 (4H, d, J=7Hz), 2.35 - 2.7 (2H, m), 4.68 (1H, dd, J=7.5Hz), 5.3 - 5.75 (2H, m), 7.12 (2H, d, J=8Hz), 7.26 (2H, d, J=8Hz). Preparation 4

To a solution of chlorotrimethylsilane (16.3 g) and triethylamine (30.3 g) in N,N-dimethylformamide (50 ml) was added 4' -isobutylacetophenone (22.0 g). The yellow solid was immediately filtered off, and the filtrate was refluxed for 20 hours. The mixture was cooled, diluted with hexane, and washed with cooled aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 4-isobutyl-a-- trimethylsi lyloxystyrene (9.0 g) as an oil.

NMR (CDCla, δ ) : 0.16 (9H, s), 1.65 - 1.85 (1H, m), 2.35 (2H, d, J=7Hz), 4.27 (1H, d, J=1.5Hz), 4.76 (1H, d, J=1.5Hz), 6.98 (2H, d, J=8.5Hz), 7.38 (2H, d, J=8.5Hz). Preparation 5

Iodosylbenzene (2.18 g) was dissolved in ethanol (45 ml), and boron trifluoride etherate (2.55 g) was added. The mixture was stirred at -70°C, and then 4-isobutyl-a-trimethylsilyl- oxylstyrene (2.24 g) was added. The mixture was stirred at -70°c for 30 minutes, and then the temperature was slowly raised to room temperature. The ethanol was evaporated and water was added. The mixture was neutralized with aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, and concentrate. The residue was chromatographed on silica gel column eluting with hexane-ethyl acetate (94 : 6) to give 4' -isobutyl-2-ethoxyacetophenone (1.90 g) as an oil. NMR (CDCh, δ ) : 0.91 (6H, d, J=7Hz), 1.30 (3H, t, J=7Hz), 1.8 - 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.65 (2H, q, J=7Hz), 4.74 (2H, s), 7.24 (2H, d, J=8Hz), 7.87 (2H, d, J=8Hz). Preparation 6

4' -Isobutyl-2-ethoxyacetophenone (1.02 g) was added to a solution of (+)-B-chlorodi isopinocampheylborane (1.78 g) in tetrahydrofuran (5 ml) at -20°C- After 4 hours, the solvent was removed and the residue was dissolved in diethyl ether (40 ml), diethanola ine (1.1 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off and washed with diethyl ether, the combined filtrates were concentrated and the residue was chromatographed on silica gel column (hexane : ethyl acetate = 6 : 1 as eluent) to give (S)- l-(4-isobutylphenyl )-2-ethoxyethanol (960 mg) as an oil. NMR (CDCla, δ ) : 0.89 (6H, d, J=7Hz), 1.25 (3H, t, J=7Hz), 1.75 - 1.95 (1H, m), 2.47 (2H, d, J=7Hz), 2.79 (1H, s), 3.35 - 3.7 (4H, m), 4.87 (1H, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz). Preparation 7

The following compound was obtained by treating 4'- isobutyl-2-ethoxyacetophenone with (-)-B-chlorodiiso¬ pinocampheylborane according to a similar manner to that of Preparation 6.

(R)-l-(4-Isobutylphenyl)-2-ethoxyethanol

NMR (CDCla, δ ) • 0.89 (6H, d, J=7Hz), 1.25 (3H, t, J=7Hz), 1.75 - 1.95 (1H, m), 2.47 (2H, d, J=7Hz), 2.79 (1H, s ) , 3.35 - 3.7 (4H, ), 4.87 (1H, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz). Preparation 8

To a solution of benzylmagnesium chloride (1.51 g) in diethyl ether (100 ml) was added 4-heptanone (1.14 g). The mixture was stirred at 0°C for 30 minutes, and then aqueous ammonium chloride was added. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (9 : 1) to give l-phenyl-2-propyl-2-pentanol (0.41 g) as an oil. NMR (CDC1₃, δ ) : 0.8 - 1.0 (6H, m), 1.3 - 1.7 (9H, m), 2.38 (1H, t, J=7.5Hz), 2.74 (1H, s), 7.15 - 7.4 (5H, m). Preparation 9

To a solution of l-phenyl-2-propyl-2-pentanol (1.60 g) in pyridine (20 ml) was added thionyl chloride (5 ml) at 0°C . The mixture was stirred at 0°C_. for 1 hour, and poured into ice water and extracted with diethyl ether. The organic layer was washed with 0.5 N hydrochloric acid and water, dried over magnesium sulfate and concentrated. The residue was dissolved in a mixture of methanol (10 ml) and 1,4-dioxane (15 ml), and 10% palladium on carbon (0.2 g) was added. The mixture was stirred under hydrogen atmosphere (3 atm) at room temperature for 2 hours. Removal of catalyst and evaporation of solvent gave l-phenyl-2-propylpentane (374 mg) as an oil. NMR (CDCls, δ ) ■ 0.86 (6H, t, J=7Hz), 1.1 - 1.45 (8H, m), 1.55

- 1.75 (1H, m), 2.52 (2H, d, J=7Hz), 7.1 - 7.35 (5H, ). Preparation 10

Sodium (cut to small pieces) was slowly added to methanol (25 ml), and then 4' -isobutyl-2-chloroacetophenone in methanol (10 ml) was added. The mixture was stirred at 50°C for 1 hour, and then neutralized with aqueous citric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (9 : 1) to give 4'-isobutyl- 2-methoxyacetophenone (142 mg) as an oil. NMR (CDCla, δ ) : 0-91 (6H, d, J=7Hz), 1.75 - 2.05 (1H, m), 2.53

(2H, d, J=7Hz), 3.51 (3H, s), 4.70 (2H, s), 7.24 (2H, d,

J=8.5Hz), 7.86 (2H, d, J=8.5Hz). Preparation 11

The following compound was obtained according to a similar manner to that of Preparation 10. 4' -Isobutyl-2-ethoxyacetophenone NMR (CDCla, δ ) ■ 0.91 (6H, d, J=7Hz), 1.30 (3H, t, J=7Hz), 1.8

- 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.66 (2H, q, J=7Hz),

4.73 (2H, s), 7.24 (2H, d, J=8.5Hz), 7.87 (2H, d, J=8.5Hz). Preparation 12

The mixture of 4' -isobutyl-3-chloropropionophenone (1.12 g) and potassium carbonate (2.07 g) in methanol (10 ml) was stirred at room temperature for 5 hours. The insoluble materials were filtered off and the filtrate was poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and concentrated to give 4' -isobutyl-3- methoxypropionophenone (1.10 g) as an oil. NMR (CDCla, δ ) - 0.90 (6H, d, J=7Hz), 1.8 - 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.23 (2H, t, J=7Hz), 3.38 (3H, s), 3.82 (2H, t, J=7Hz), 7.23 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz).

Preparation 13

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

4' -Isobutyl-3-ethoxypropionophenone

NMR (CDCla, δ ) • 0.91 (6H, d, J=7Hz), 1.20 (3H, t, J=7Hz), 1.80 - 2.0 (1H, m), 2.53 (2H, d, J=7Hz), 3.26 (2H, t, J=7Hz), 3.55 (2H, q, J=7Hz), 3.87 (2H, t, J=7Hz), 7.23 (2H, d, J=8.5Hz), 7.89 (2H, d, J=8.5Hz).

Preparation 14

To a stirred solution of 2-butynoyl chloride (556 mg) in methylene chloride (10 ml) was added aluminum chloride (721 mg). After 10 minutes, isobutylbenzene (0.85 ml) was added to the reaction mixture. After 30 minutes, water was added to the reaction mixture and extracted with methylene chloride. The organic layers were washed with sodium hydrogencarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (hexane : methylene chloride = 1 : 1) to give l-(4-isobutylphenyl )-2- butyn-1-one (496 mg).

NMR (CDCla, δ ) • 0.91 (6H, d, J=7Hz), 1.91 (1H, m), 2.16 (3H, s), 2.55 (2H, d, J=7Hz), 7.25 (2H, d, J=8Hz), 8.06 (2H, d, J=8Hz).

Preparation 15 The following compounds were obtained according to a similar manner to that of Preparation 14.

(1) (E)-l-(4-Isobutylphenyl)-2-penten-l-one

NMR (CDCla, δ ) ^•• 0.91 (6H, d, J=7Hz), 1.14 (3H, t, J=7Hz), 1.90 (1H, m), 2.34 (2H, m), 2.54 (2H, d, J=7Hz), 6.88 (1H, dt, J=ll.lHz), 7.12 (1H, dt, J=11.6Hz), 7.23 (2H, d, J=9Hz),

7.87 (2H, d, J=9Hz).

(2) 4' -Isobutyl-3-chloropropionophenone

NMR (CDCla, δ ) ■ 0.91 (6H, d, J=7Hz), 1.7 - 2.05 (1H, ), 2.55 (2H, d, J=7Hz), 3.45 (2H, t, J=7Hz), 3.93 (2H, t, J=7Hz), 7.26 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz).

(3) 4' -Isobutyl-2-chloroacetophenone

NMR (CDCla, δ ) 0.91 (6H, d, J=7Hz), 1.75 - 2.05 (1H, ), 2.55(211, d, J=7Hz), 4.70 (2H, s), 7.27 (2H, d, J=8.5Hz),

7.88 (2H, d, J=8.5Hz).

(4) 4-(2-Propylpentyl)benzoyl chloride

NMR (CDCla, δ ) • 0.87 (6H, t, J=7Hz), 1.1 - 1.45 (8H, m), 1.6 - 1.8 (1H, m), 2.61 (2H, d, J=7Hz), 7.28 (2H, d, J=8.5Hz), 8.03 (2H, d, J=8.5Hz).

(5) 3-(4-Fluorobenzoyl) indole

NMR (DMSO-de, δ ) : 7.2 - 7.55 (5H, m), 7.55 - 7.6 (2H, m), 7.8

- 8.0 (3H, m), 8.22 (1H, m). Preparation 16

To a solution of indole (936 mg) in tetrahydrofuran (15 ml) was added 3 M solution of methylmagnesium bromide (2 ml). The mixture was stirred at room temperature for 30 minutes, and then 4-(2-propylpentyl )benzoyl chloride (445 mg) in tetrahydrofuran (10 ml) was added. After stirred for 1 hour, the mixture was poured into ice - 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (4 : 1) to give 3-[4-(2-propylpentyl Jbenzoyl ] indole (114 mg) as solid. NMR (DMSO-dβ, δ ) • 0.86 (6H, t, J=7Hz), 1.15 - 1.45 (8H, m),

1.6 - 1.8 (1H, m), 2.60 (2H, d, J=7Hz), 7.2 - 7.35 (4H, ),

7.5 - 7.6 (1H, m), 7.72 (2H, d, J=8.5Hz), 7.95 (1H, s),

8.2 - 8.3 (1H, m). Preparation 17

To a stirred solution of l-(4-isobutylphenyl )-2-butyn-l-one (467 mg) in ethanol (8 ml) was added sodium borohydride (101 mg) at ambient temperature. After 1 hour, aqueous potassium biphosphate solution was added and concentrated in vacuo. The residue was extracted with ether. The organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane : ethyl acetate = 4 : 1) to give l-(4- isobutylphenyl)-2-butyn-l-ol (338 mg). NMR (CDCls, δ ) : 0.89 (6H, d, J=7Hz), 1.85 (1H, m), 1.91 (3H, d, J=2Hz), 2.47 (2H, d, J=7Hz), 5.41 (1H, m), 7.04 (2H, d,

J=8Hz), 7.43 (2H, d, J=8Hz). Preparation 18

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

(1 ) l-(4-Isobutylphenyl )-4-penten-l-ol

NMR (CDCla, δ ) ■ 0.89 (6H, d, J=7Hz), 1.7 - 2.3 (5H, m), 2.45 (2H, d, J=7Hz), 4.67 (IH, t, J=7Hz), 4.9 - 5.1 (2H, ), 5.84 (IH, ), 7.11 (2H, d, J=8Hz), 7.24 (2H, d, J=8Hz).

(2) l-(4-Isobutylphenyl)-3-methoxy-l-propanol

NMR (CDCla, δ ) • 0.89 (6H, t, J=7Hz), 1.75 - 2.15 (3H, m), 2.47 (2H, d, J=7Hz), 3.38 (3H, s), 3.5 - 3.7 (2H, m), 4.85 - 4.95 (IH, m), 7.12 (2H, d, J=8.5Hz), 7.27 (2H, d, J=8.5Hz).

(3) l-(4-Isobutylphenyl)-3-ethoxy-l-propanol

NMR (CDCla, δ ) • 0.90 (6H, d, J=7Hz), 1.23 (3H, t, J=7Hz), 1.75 - 2.15 (3H, m), 2.47 (2H, d, J=7Hz), 3.45 - 3.7 (5H, m), 4.85 - 4.95 (IH, m), 7.11 (2H, d, J=8.5Hz), 7.28 (2H, d, J=8.5Hz).

(4) l-(4-Isobutylphenyl)-2-methoxyethanol

NMR (CDCla, δ ) : 0.89 (6H, d, J=7Hz), 1.7 - 1.95 (IH, m), 2.47 (2H, d, J=7Hz), 3.35 - 3.6 (5H, ), 4.87 (IH, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz).

(5) l-(4-Isobutylphenyl)-2-ethoxyethanol

NMR (CDC1₃, δ ) : 0.89 (6H, d, J=7Hz), 1.25 (3H, t, J=7Hz), 1.75 - 1.95 (IH, m), 2.47 (2H, d, J=7Hz), 2.79 (IH, s), 3.35 - 3.7 (4H, m), 4.87 (IH, dd, J=5.5Hz, 6.5Hz), 7.12 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5Hz).

Preparation 19 To a solution of 6-undecanol (10.0 g) and carbon tetrabromide (38.5 g) in tetrahydrofuran (400 ml) was added triphenylphosphine (30.4 g). The mixture was stirred at room temperature for 5 hours. After the white solid was filtered off, the filtrate was concentrated. n-Hexane (400 ml) was added to the residue and the pricipitate was filtered off. The filtrate was concentrated and the residual oil was distilled under reduced pressure to give 6-bromoundecane (9.38 g) as a colorless oil. NMR (CDCls, δ ) : 0.90 (6H, t, J=7Hz), 1.15 - 1.65 (12H, m), 1.7

- 1.95 (4H, m), 3.95 - 4.1 (IH, m). Preparation 20

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

(1) 4-Bromoheptane

NMR (CDCI3, δ ) '■ 0.93 (6H, t, J=7Hz), 1.35 - 1.65 (4H, m), 1.7 - 1.9 (4H, m), 4.0 - 4.15 (IH, m).

(2) 7-Bromotridecane

NMR (CDC , δ ) ■ 0.89 (6H, t, J=7Hz), 1.2 - 1.7 (16H, ), 1.75

- 1.9 (4H, m), 3.95 - 4.1 (IH, m).

(3) 8-Bromopentadecane

NMR (CDCh, δ ) • 0.88 (6H, t, J=7Hz), 1.2 - 1.6 (20H, m), 1.7 - 1.9 (4H, m), 3.95 - 4.1 (IH, m).

(4) 9-Bromoheρtadecane

NMR (CDCla, δ ) • 0.88 (6H, t, J=7Hz), 1.2 - 1.65 (24H, m), 1.75

- 1.9 (4H, m), 3.95 - 4.1 (IH, m). (5) 4-Bromoundecane

NMR (CDCla, δ ) : 0.8 - 1.0 (6H, m), 1.2 - 1.65 (12H, m), 1.7 -

1.9 (4H, m), 3.95 - 4.1 (IH, m). Preparation 21

The following compound was obtained according to a similar manner to that of Example 5.

Ethyl 4-[3-(4-fluorobenzoyl ) indol-l-yl]butyrate NMR (CDCla, δ ) : 1.22 (3H, t, J=7Hz), 2.1 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.27 (2H, t, J=7Hz), 7.18 (2H, t, J=9Hz), 7.3 - 7.5 (3H, m), 7.54 (IH, s), 7.86 (2H, m), 8.38 (IH, m). Example 1

To a mixture of ethyl 4-[3-(4-hydroxybenzoyl) indol-1- yl]butyrate (188 mg), l-(4-isobutylphenyl)-2-butyn-l-ol (108 mg) and triphenylphosphine (140 mg) in tetrahydrofuran (5 ml) was added diethyl azodicarboxylate (0.084 ml) at 0°C. After 1 hour, the mixture was evaporated in vacuo and chromatographed on silica gel (hexane : ethyl acetate = 3 : 1) to give ethyl 4- [3-[4-[l-(4-isobutylphenyl )-2-butynyloxy]benzoyl ]indol-1- yljbutyrate (28 mg). NMR (CDCla, δ ) • 0.90 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz),

1.8 - 2.0 (IH, m), 1.92 (3H, d, J=2Hz), 2.15 - 2.4 (4H, m), 2.50 (2H, d, J=7Hz), 4.11 (2H, q, J=7Hz), 4.27 (2H, t, J=7Hz), 5.87 (IH, d, J=2Hz), 7.1 - 7.5 (7H, m), 7.52 (2H, d, J=8Hz), 7.60 (IH, s), 7.84 (2H, d, J=9Hz), 8.39 (IH, 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-isobutylphenyl )-4-pentenyloxy]benzoyl ]- indol-1-yl ]butyrate

NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.7

- 2.4 (9H, m), 2.45 (2H, d, J=7Hz), 4.09 (2H, q, J=7Hz), 4.23 (2H, t, J = 7Hz), 4.95 - 5.25 (2H, m), 5.87 (IH, m), 6.92 (2H, d, J=9Hz), 7.12 (2H, d, J=8Hz), 7,2 - 7.45 (5H, m), 7.53 (IH, s), 7.73 (2H, d, J=9Hz), 8.37 (IH, m).

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

NMR (CDCla, δ ) : 0.88 (6H, d, J=7Hz), 1.19 (3H, t, J=7Hz), 1.55 (3H, d, J=7Hz), 1.84 (IH, m), 2.1 - 2.35 (4H, m), 2.44 (2H, d, J=7Hz), 2.55 - 2.9 (2H, m), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.18 (IH, t, J=7Hz), 5.4 - 5.7 (2H, m), 6.92 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2 - 7.45 (5H, m), 7.52 (IH, s), 7.72 (2H, d, J=9Hz), 8.35 (IH, m),

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

NMR (CDCla, δ ) ■ 0.89 (6H, d, J=7Hz), 1.20 (3H, t, J=7Hz), 1.75

- 1.95 (IH, m), 2.0 - 2.4 (6H, m), 2.46 (2H, d, J=7Hz), 3.3

- 3.5 (4H, m), 3.55 - 3.7 (IH, m), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.40 (IH, dd, J=2.5 Hz, 7Hz), 6.95 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, S), 7.74 (2H, d, J=8.5Hz), 8.3 - 8.4 (IH, m),

(4) Ethyl 4-[3-[4-[l-(4-isobutylphenyl )-3-ethoxypropoxy]benzoyl ] indol-1-yl ]butyrate NMR (CDCla, δ ) : 0.88 (6H, d, J=7Hz), 1.20 (6H, t, J=7Hz),

1.75 - 1.95 (IH, m), 2.0 - 2.4 (6H, m), 3.4 - 3.7 (4H, m), 4.10 (2H, q, J=7Hz), 4.23 (2H, t, J=7Hz), 5.40 (IH, dd, J=2.5Hz, 7Hz), 6.96 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m),

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

NMR (CDCla, δ ) ^■• 0.89 (6H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.7

- 1.95 (IH, m), 2.1 - 2.35 (4H, m), 2.46 (2H, d, J=7Hz), 3.48 (3H, s), 3.6 - 3.72 (IH, m), 3.78 - 3.9 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.42 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.52 (IH, s), 7.74 (2H, d, J=8.5Hz), 8.3 - 8.4 (IH, m),

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

NMR (CDCla, δ ) • 0.89 (6H, d, J=7Hz), 1.15 - 1.3 (6H, m), 1.75

- 1.95 (IH, ), 2.1 - 2.35 (4H, m), 2.46 (2H, d, J=7Hz), 3.5 - 3.75 (3H, ), 3.8 - 3.95 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).

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

NMR (CDCla, δ ) '■ 0.88 (6H, d, J=7Hz), 1.15 - 1.3 (6H, m), 1.7 - 2.0 (IH, ), 2.1 - 2.4 (4H, m), 2.47 (2H, d, J=7Hz), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.42 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=8.5Hz), 8.3 - 8.4 (IH, m). (8) Ethyl 4-[3-[4-[(S)-l-(4-isobutylphenyl)-2-ethoxyethoxy]- benzoyl ] indol-1-yl ]butyrate

NMR (CDCla, δ ) : 0.89 (6H, d, J=7Hz), 1.15 - 1.35 (6H, m), 1.7 - 2.0 (IH, m), 2.1 - 2.4 (4H, ), 2.46 (2H, d, J=7Hz), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.10 (2H, q, J=7Hz), 4.24 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.13 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, m), 7.53 (IH, s), 7.74 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m). Example 3

A mixture of ethyl 4-[3-[4-hydroxybenzoyl )indol-l- yl]butyrate (176 mg), 6-bromoundecane (176 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (4 ml) was stirred at room temperature for 15 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and water. 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-(l-pentylhexyloxy)benzoyl ] indol-1-yl ]butyrate (118 mg) as an oi 1. NMR (CDCh, δ ) ■ 0.89 (6H, m), 1.15 - 1.8 (19H, m), 2.1 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2 - 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

Example 4

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

(1) Ethyl 4-[3-[4-(l-propylbutoxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) : 0.94 (6H, t, J=7Hz), 1.22 (3H, t, J=7Hz), 1.3

- 1.8 (8H, m), 2.1 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.3 - 4.45 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.82 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

(2) Ethyl 4-[3-[4-(l-hexylheplyloxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) 0.89 (6H, t, J=7Hz), 1.15 - 1.5 (19H, m), 1.55

- 1.8 (4H, m), 2.15 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2

- 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, ), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

(3) Ethyl 4-[3-[4-(l-heptyloctyloxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) : 0.88 (6H, t, J=7Hz), 1.2 - 1.5 (23H, m), 1.55

- 1.8 (4H, m), 2.15 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2

- 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

(4) Ethyl 4-[3-[4-(l-octylnonyloxy)benzoyl ]indol-l-yl]butyrate NMR (CDCh, δ ) ^•■ 0.88 (6H, t, J=7Hz), 1.2 - 1.5 (27H, m), 1.55

- 1.8 (4H, m), 2.15 - 2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2

- 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.82 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m). (5) Ethyl 4-[3-[4-(l-ρropyloctyloxy)benzoyl]indol-l-yl]butyrate NMR (CDCh, δ ) : 0.8 - 1.0 (6H, m), 1.2 - 1.8 (19H, m), 2.15 -

2.4 (4H, m), 4.12 (2H, q, J=7Hz), 4.2 - 4.4 (3H, ), 6.97 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.60 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

(6) Ethyl 4-[3-(4-hexyloxybenzoyl ) indol-1-yl ]butyrate

NMR (CDCh, δ ) : 0.91 (3H, t, J=7Hz), 1.22 (3H, t, J=7Hz), 1.3

- 1.6 (6H, m), 1.75 - 1.9 (2H, m), 2.15 - 2.4 (4H, ), 4.0 - 4.2 (4H, m), 4.27 (2H, t, J=7Hz), 6.98 (2H, d, J=9Hz), 7.25

- 7.5 (3H, ), 7.58 (IH, s), 7.84 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

Example 5

A mixture of 3-[4-(2-propylpentyl )benzoyl Jindole (109 mg), ethyl 4-bromobutyrate (77 mg) and potassium carbonate (136 mg) in dimethylformamide (3 ml) was stirred at room temperature for 16 hours. The insoluble materials were filtered off, and the filtrate was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (4 : 1) to give ethyl 4-[3-[4-(2- propylpentyl )benzoyl ]indol-l-yl]butyrate (142 mg) as an oil. NMR (CDCh, δ ) ■ 0.89 (6H, t, J=7Hz), 1.15 - 1.5 (IH, m), 1.6 - 1.8 (IH, m), 2.1 - 2.4 (4H, m), 2.61 (2H, d, J=7Hz), 4.11 (2H, q, J=7Hz), 4.27 (2H, t, J=7Hz), 7.2 - 7.5 (5H, m), 7.59 (IH, s), 7.75 (2H, d, J=8.5Hz), 8.35 - 8.45 (IH, m). Example 6

To a solution of ethyl 4-[3-[4-(l-pentylhexyIoxy)benzoyl]- indol-l-yl]butyrate (112 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml) was added 1 N aqueous solution of sodium hydroxide (1 ml). The mixture was stirred at room temperature for 2 hours, and then poured into a mixture of ethyl acetate and 0.5 N hydro¬ chloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[3-[4-(l-pentylhexyloxy)benzoyl]indol-l-yl]butyric acid

(86 mg) as an oil. NMR (CDCh, δ ) : 0.89 (6H, t, J=7Hz), 1.2 - 1.8 (16H, m), 2.1 - 2.3 (2H, m), 2.40 (2H, t, J=7Hz), 4.2 - 4.4 (3H, ), 6.95 (2H, d, J=9Hz), 7.25 - 7.45 (3H, m), 7.61 (IH, s), 7.82 (2H, d, J=9Hz), 8.3 - 8.4 (IH, ). Example 7

The following compounds were obtained according to a similar manner to that of Example 6.

(1) 4-[3-[4-[l-(4-Isobutylphenyl)-2-butynyloxy]benzoyl]indoI-l- yl]butyric acid

NMR (CDCh, δ ) : 0.90 (6H, d, J=7Hz), 1.75 - 2.0 (IH, m), 1.90 (3H, d, J=2Hz), 2.1 - 2.3 (2H, m), 2.3 - 2.45 (2H, m), 2.49 (2H, d, J=7Hz), 4.27 (2H, t, J=7Hz), 5.84 (IH, d, J=2Hz), 7.1 - 7.45 (7H, m), 7.51 (2H, d, J=8Hz), 7.60 (2H, d, J=9Hz), 8.37 (IH, m).

(2) (E)~4-[3-[4-[l-(4-Isobutylphenyl)-2-pentenyloxy]benzoyl]- indol-l-yl]butyric acid NMR (CDCh, δ ) • 0.88 (6H, d, J=7Hz), 0.93 (3H, t, J=7Hz),

1.47(2H, m), 1.82 (IH, m), 2.1 - 2.5 (6H, m), 4.25 (2H, t, J=7Hz), 5.88 (IH, t, J=7Hz), 7.0 - 7.1 (4H, m), 7.2 - 7.45 (7H, m), 7.57 (IH, s), 7.77 (2H, d, J=8Hz), 8.35 (IH, m).

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

NMR (CDCh, δ ) • 0.88 (6H, d, J=7Hz), 1.7 - 2.3 (7H, ), 2.38 (2H, t, J=7Hz), 2.43 (2H, d, J=7Hz), 4.23 (2H, t, J=7Hz), 4.9 - 5.25 (2H, m), 5.86 (IH, m), 6.91 (2H, d, J=9Hz), 7.11 (2H, d, J=8Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.72 (2H,d, J=9Hz), 8.33 (IH, ).

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

NMR (CDCh, δ ) • 0.87 (6H, d, J=7Hz), 1.54 (3H, d, J=7Hz),

1.83(1H, m), 2.18 (2H, m), 2.37 (2H, t, J=7Hz), 2.43 (2H, d, J=7Hz), 2.5 - 2.9 (2H, m), 4.23 (2H, t, J=7Hz), 5.17 (IH, t, J=7Hz), 5.35 - 5.6 (2H, m), 6.92 (2H, d, J=9Hz), 7.10 (2H, d, J=8Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.72 (2H, d, J=8Hz), 8.33 (IH, ).

(5) 4-[3-[4-(l-Propylbutoxy)benzoyl ]indol-1-yl ]butyric acid

NMR (CDCh, δ ) ^•• 0.94 (6H, t, J=7Hz), 1.3 - 1.8 (8H, m), 2.15 - 2.35 (2H, m), 2.40 (2H, t, J=7Hz), 4.2 - 4.45 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.45 (3H, m), 7.61 (IH, s), 7.82 (2H, d, J=9Hz), 8.35 - 8.4 (IH, m).

(6) 4-[3-[4-(l-Hexylheptyloxy)benzoyl ] indol-1-yl ]butyric acid NMR (CDCh, δ ) : 0.89 (6H, t, J=7Hz), 1.2 - 1.5 (16H, m), 1.55 - 1.8 (4H, ), 2.15 - 2.3 (2H, m), 2.41 (2H, t, J=7Hz), 4.2

- 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

(7) 4-[3-[4-(l-Heptyloctyloxy)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) ■ 0.88 (6H, t, J=7Hz), 1.15 - 1.5 (20H, m),

1.55- 1.8 (4H, m), 2.15 - 2.3 (2H, m), 2.40 (2H, t, J=7Hz),

4.2 - 4.4 (3H, m), 6.95 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.3 - 8.45 (IH, m).

(8) 4-[3-[4-(l-0ctylnonyloxy)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) • 0.88 (6H, t, J=7Hz), 1.2 - 1.5 (24H, m), 1.55

- 1.8 (4H, m), 2.15 - 2.3 (2H, m), 2.41 (2H, t, J=7Hz), 4.2

- 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.35 - 8.45 (IH, m).

(9) 4-[3-[4-(l-Propyloctyloxy)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) ■ 0.8 - 1.0 (6H, m), 1.2 - 1.8 (16H, m), 2.15 -

2.3 (2H, m), 2.40 (2H, t, J=7Hz), 4.2 - 4.4 (3H, m), 6.96 (2H, d, J=9Hz), 7.25 - 7.5 (3H, m), 7.61 (IH, s), 7.83 (2H, d, J=9Hz), 8.3 - 8.45 (IH, m).

(10) 4-[3-(4-Hexyloxybenzoyl)indol-l-yl]butyric acid

NMR (DMSO-de, δ ) • 0.89 (3H, t, J=7Hz), 1.2 - 1.55 (6H, m), 1.65 - 1.85 (2H, m), 1.95 - 2.15 (2H, m), 2.24 (2H, t, J=7Hz), 4.07 (2H, t, J=7Hz), 4.30 (2H, t, J=7Hz), 7.07 (2H, d, J=9Hz), 7.2 - 7.4 (2H, m), 7.65 (IH, d, J=7Hz), 7.80 (2H,d, J=9Hz), 8.02 (IH, s), 8.2 - 8.3 (IH, m).

(11) 4-[3-[4-[l-(4-Isobutylphenyl)-3-methoxypropoxy]benzoyl]- indol-l-yl]butyric acid NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 1.7 - 1.95 (IH, m),

2.0 - 2.5 (8H, m), 3.3 - 3.5 (4H, m), 3.55 - 3.7 (IH, m), 4.23 (2H, t, J=7Hz), 5.39 (IH, dd, J=3Hz, 7Hz), 6.94 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).

(12) 4-[3-[4-[l-(4-Isobutylphenyl )-3-ethoxypropoxy] indol-1- yl]butyric acid

NMR (CDCh, δ ) : 0.88 (6H, d, J=7Hz), 1.20 (3H, t, J=7Hz), 1.7 - 1.95 (IH, m), 2.0 - 2.5 (8H, m), 3.4 - 3.7 (4H, m), 4.23 (2H, t, J=7Hz), 5.41 (IH, dd, J=2.5Hz, 7Hz), 6.95 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, ), 7.53 (IH, s), 7.73 (2H, d, _.J=9Hz), 8.3 - 8.4 (IH, m).

(13) 4-[3-[4-[l-(4-Isobutylphenyl )-2-methoxyethoxy]benzoyl ]- indol-1-yl ]butyric acid

NMR (CDCh, δ ) : 0.89 (6H, d, J=7Hz), 1.7 - 1.95 (IH, m), ^*2.1 - 2.5 (6H, m), 3.47 (3H, s), 3.6 - 3.7 (IH, m), 3.75 - 3.9 (IH, m), 4.23 (2H, t, J=7Hz), 5.42 (IH, dd, J=4.5Hz, 6Hz), 6.97 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.52 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, ).

(14) 4-[3-[4-[l-(4-Isobutylphenyl )-2-ethoxyethoxy]benzoyl]indol- l-yl]butyric acid

NMR (CDCh, δ ) '• 0.88 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz), 1.7 - 1.95 (IH, m), 2.1- 2.25 (2H, m), 2.3 - 2.5 (4H, m), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.22 (2H, t, J=7Hz), 5.40 (IH, dd, J=4.5Hz, 6Hz), 6.97 (2H, d, J=9Hz), 7.11 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.52 (IH, s), 7.72 (2H, d, J=9Hz ) , 8. 3 - 8. 4 ( IH, m ) .

(15) 4-[3-[4-[(R)-l-(4-Isobutylphenyl)-2-ethoxyethoxy]benzoyl]- ϊndol-l-yl]butyric acid

NMR (CDCh, δ ) : 0.88 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz), 1.7

- 2.0 (IH, m), 2.1- 2.5 (6H, m), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, m), 4.23 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.97 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.2 - 7.45 (5H, m), 7.53 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).

(16) 4-[3-[4-[(S)-l-(4-Isobutylphenyl)-2-ethoxyethoxy]benzoyl]- indol-l-yl]butyric acid

NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 1.22 (3H, t, J=7Hz), 1.7

- 1.95 (IH, m), 2.1- 2.5 (6H, m), 3.5 - 3.75 (3H, m), 3.8 - 3.95 (IH, ), 4.24 (2H, t, J=7Hz), 5.41 (IH, dd, J=4.5Hz, 6Hz), 6.98 (2H, d, J=9Hz), 7.12 (2H, d, J=8.5Hz), 7.25 - 7.45 (5H, ), 7.52 (IH, s), 7.73 (2H, d, J=9Hz), 8.3 - 8.4 (IH, m).

(17) 4-[3-[4-(2-Propylpentyl)benzoyl]indol-l-yl]butyric acid NMR (CDCh, δ ) 0.88 (6H, t, J=7Hz), 1.15 - 1.55 (8H, ), 1.6

- 1.8 (IH, m), 2.1 - 2.5 (4H, m), 2.60 (2H, d, J=7Hz), 4.27 (2H, t, J=7Hz, ), 7.2 - 7.5 (5H, m), 7.60 (IH, s), 7.76 (2H, d, J=8.5Hz), 8.35 - 8.45 (IH, m).

Example 8

To a solution of (E)-l-(4-isobutylphenyl)-2-penten-l-ol (202 mg) in dimethylformamide (3 ml) was added sodium hydride (41 mg) and heated at 40°C for 30 minutes. To the solution was then added ethyl 4-[3-(4-fluorobenzoyl ) indol-1-yl ]butyrate (327 mg) and the mixture was heated at 50 °c for 30 minutes. After cooling and dilution with toluene, the mixture was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane : ethyl acetate = 3 : 1) to give ethyl (E)-4-[3-[4-[l- (4-isobutylphenyl)-2-pentenyloxy]benzoyl]indol-l-yl ]butyrate (93 mg).

NMR (CDCh, δ ) ■ 0.88 (6H, d, J=7Hz), 0.94 (3H, t, J=7Hz), 1.20 (3H, t, J=7Hz), 1.4 - 1.6 (2H, m), 1.83 (IH, m), 1.9 - 2.4 (4H, m), 2.44 (2H, d, J=7Hz), 4.10 (2H, q, J=7Hz, ), 4.24 (2H, t, J=7Hz), 5.89 (IH, t, J=7Hz), 7.0 - 7.4 (11H, ), 7.54 (IH, s), 7.78 (2H, d, J=9Hz), 8.38 (IH, m).

Claims

CLAIMS 1. A compound of the formula :

wherein R¹ is carboxy or protected carboxy,

R² is hydrogen, lower alkyl or halogen,

R³ is aryl which may have suitable substituent(s),

A is lower alkylene,

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

Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R³ is alkyl, and a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein

R¹ is carboxy or esterified carboxy, and

R³ is aryl which may be substituted by lower alkyl.

3. A compound of claim 2, wherein

R¹ is carboxy or lower alkoxycarbonyl, and R³ is phenyl substituted by lower alkyl.

4. A process for preparing a compound of the formula :

wherein R¹ is carboxy or protected carboxy,

R² is hydrogen, lower alkyl or halogen,

R³ is aryl which may have suitable substituent(s),

A is lower alkylene,

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

Y is lower alkylene substituted by lower alkoxy, lower alkenylene or lower alkynylene; or Y-R³ is alkyl, or a salt thereof, which comprises, (1) reacting a compound of the formula :

wherein R¹ , R^z and A are each as defined above, and

X¹ is -0- or -NH- or a salt thereof, with a compound of the formula :

wherein R³ and Y are each as defined above, and

W¹ is leaving group, or a salt thereof, to give a compound of the formula

wherein R¹, R², R³, A, X¹ and Y are each as defined above, or a salt thereof, or (2) reacting a compound of the formula :

wherein R², R³, X and Y are each as defined above, or a salt thereof, with a compound of the formula :

W²-A-R¹ wherein R¹ and A are each as defined above, and

W² is acid residue, or a salt thereof, to give a compound of the formula:

A-R¹

wherein R¹, R², R³, A, X and Y are each as defined above, or a salt thereof, or ( 3 ) sub ject i ng a compound of the formu l a

wherein R² , R³, A, X and Y are each as defined above, and

R¹, is protected carboxy, or a salt thereof, to elimination reaction of the carboxy protective group, to give a compound of the formula :

wherein R², R³ , A, X and Y are each as defined above, or a salt thereof, or (4) reacting a compound of the formula :

wherein R¹ , R² and A are each as defined above, and

W³ is acid residue, or a salt thereof, with a compound of the formula : H-X^Y-R³ wherein R³ , X¹ and Y are each as def ined above, or a sal t thereof , to give a compound of the formula :

wherein R¹ , R² , R³ , A, X¹ and Y are each as defined above, or a salt thereof.

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

6. A method for treating or preventing testosteron 5a- 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 testosteron δa-reductase inhibitor. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.