WO1993013099A1

WO1993013099A1 - ARYL KETONES AS TESTOSTERONE 5α-REDUCTASE INHIBITORS

Info

Publication number: WO1993013099A1
Application number: PCT/JP1992/001674
Authority: WO
Inventors: Satoshi Okada; Kozo Sawada; Akio Kuroda; Shinya Watanabe; Hirokazu Tanaka
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1991-12-31
Filing date: 1992-12-21
Publication date: 1993-07-08
Also published as: GB9127531D0; JPH08500082A; EP0620818A1

Abstract

Heterocyclic compound of the formula: R1-A-CO-X-Y-R2, in which R1 is carboxy(lower)alkyl or protected carboxy(lower)alkyl, R2 is optionally substituted aralkyl, X is optionally substituted arylene, Y is -O- or (a), wherein R6 is hydrogen, lower alkyl, optionally substituted aralkyl or amino-protective group, and A is a bivalent radical derived from imidazopyridine, azulene, thiophene, pyrrolo[2,3-b]pyridine, quinolone, indazole or dihydrobenzimidazole, each of which may be substituted by one or more suitable substituent(s), which are useful as a testosterone 5α-reductase inhibitor.

Description

DESCRIPTION

Aryl Ketones as testosterone 5* - reductase Inhibitors

Technical Field

The present invention relates to novel heterocyclic compound. More particularly, it relates to novel heterocyclic compound or a pharmaceutically acceptable salt thereof which has pharmacological activities such as inhibitory activity on testosteron 5α-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 heterocyclic compound or a pharmaceutically acceptable salt thereof, which is of use as a testosteron 5α-reductase inhibitor.

Another object of the present invention is to provide a process for preparation of said heterocyclic compound or a salt thereof. A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said heterocyclic compound or a pharmaceutically acceptable salt thereof. Still further object of the present invention is to provide a use of said heterocyclic compound or a pharmaceutically acceptable salt thereof as a medicament such as testosteron 5α-reductase inhibitor useful for treating or preventing testosteron 5α-reductase-mediated diseases such as prostatomegaly, prostatism, alopecia, acnes, and the like in human being or animals.

The heterocyclic compound of the present invention is novel and can be represented by the formula (I) :

R-^A-CO-X-Y-R² (I)

in which R is carboxy(lower)alkyl or protected carboxy(lower)alkyl,

2 R is optionally substituted aralkyl,

X is optionally substituted arylene,

wherein R6 is hydrogen, lower alkyl, optionally substituted aralkyl or amino-protective group, and

A is a bivalent radical derived from imidazopyridine, azulene, thiophene, pyrrolo[2,3-bjpyridine, quinolone, indazole or dihydrobenzimidazole, each of which may be substituted by one or more suitable substituent(s) .

According to the present invention, the object compound (I) and a salt thereof can be prepared by the following processes. Process 1

R -A-CO-X-Y-H HO-R

(ID (III) or a salt thereof or its reactive derivative at the hydroxy group, or a salt thereof

R¹-A-CO-X-Y-R²

(I) or a salt thereof

Process 2

Removal or the carboxy-protective group

(I-a) or a salt thereof

(l-b) or a salt thereof

wherein R 1, R2, A, X and Y are each as defined above,

R_. is protected carboxy(lower)alkyl, and R, 1 is carboxy(lower)alkyl.

Suitable salts of the compound (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'-dibenzγlethylenediamine 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. The compound (I) possesses stereoisomers such as optical isomers due to the presence of asymmetric carbon atom(s), and such isomers are also included within a scope of the present invention.

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" may include straight or branched one having 1 to 6 carbon ato (s) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atoms.

"Carboxy(lower)alkyl" means lower alkyl as explained above, which is substituted by a carboxy group at its optional positions, and suitable example thereof may be carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and the like, in which preferable one is carboxy(C..-C.)alkyl and the most preferable one is 3-carboxypropyl.

"Protected carboxy(lower)alkyl" means carboxy(lower)alkyl as explained above, in which the carboxy group is protected by a conventional carboxy-protective group, and suitable "protected carboxy" moiety of "protected carboxy(lower)alkyl" may include an esterified carboxy group. Suitable examples of the ester moiety of an

"esterified carboxy" may be a conventional one 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, etc.) which may have at least one suitable substituent(s) , for example, lower cycloalkyKlower)alkyl ester (e.g. 1-cyclopropylethyl, etc.), lower alkanσyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)- acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl este , l(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-ethylbutγryloxymethyl ester,

3,3-dimethylbutyryloxymethyl ester, 1(or 2)-pentanoyloxy- ethyl ester, etc.) lower alkanesulfonyKlower) lkyl 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-propγl-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-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzγl 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.

Preferable example of "protected carboxy(lower)alkyl" thus defined may be esterified carboxy(lower)alkyl such as lower alkoxycarbonyKlower)alkyl, more preferably 3-lower alkoxycarbonylpropyl (e.g. 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 3-propoxycarbonylpropyl,

3-isopropoxycarbonylpropyl, 3-butoxycarbonylpropyl, 3-isobutoxycarbonylpropy1, 3-tert-butoxycarbonyIpropyl, 3-pentyloxycarbonyIpropyl, 3-tert-pentyloxycarbonyIpropyl, 3-hexyloxycarbonyIpropyl, etc. ) . "Aralkyl" in "optionally substituted aralkyl" means straight or branched C--C-_Q, preferably C--Cg alkyl substituted by aryl, and suitable "optionally substituted aralkyl" thus defined may include aralkyl (e.g. trityl, benzhydryl, benzyl, phenethyl, naphthylmethyl , 1-phenylethγl, 1-phenylpropyl, 1-phenylbutyl, 1-phenylpenty1, 1-phen Ihexy1, 1-phenylheptyl, 1-phenyloctyl, 1-phenyldecyl, 2 , 2-dimethyl-1-phenylpropyl, etc. ) , substituted ar(lower)alkyl, for example, aralkyl substituted by one or more, preferably one to four substituents such as lower alkyl as mentioned above, halogen (e.g. fluoro, chloro, bromo, iodo, etc.), cyano, carboxy, protected carboxy as mentioned above, aryl (e.g. phenyl, tolyl, xylyl , naphthyl, etc. ) , a idated carboxy such as carbamoyl, mono or di(lower)alkylcarbamoyl (e.g. methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl . diethylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, etc. ) , lower alkylarylcarbamoyl (e.g. isobutylphenylcarbamoyl, etc. ) , and the like.

Preferable example of thus defined "optionally substituted aralkyl" may be benzyl, benzhydryl, trityl, phenethyl, 1-phenylethy1, methylbenzyl , isobutylbenzyl, methylphenylethyl, isobutylphenylethyl, methylphenylpropyl, isobutylphenyIpropyl, methylphenylpentyl, isobutylphenylpent 1, bis(methylphenyl)methyl, bis(propylphenyl)methyl, bis(butylphenyl)methyl, bis(isobutylphenyl)methyl, bis(chlorophenyl)methyl, (cyano) (isobutylphenyl)methyl, (carboxy) (isobutylphenyl)methyl, (benzyloxycarbony1) (isobutylphenyl)methyl, (N,N-diethylcarbamoyl) (isobutylphenyl) ethyl, (t-butylcarbamoyl) (isobutylphenyl)methyl, (phenylcarbamoyl) (isobutylphenyl)methyl, (isobutylphenylcarbamoyl) (isobutylphenyl)methyl, etc. ] , and the like, more preferably bis[ (lower)alkylphenyl]methyl, and the most preferably bis[isobutylphenyl]methyl.

Suitable "amino-protective group" may be a conventional protective group which is used in the field of peptide chemistry, that is, may include acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), ar(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.), and the like.

"Optionally substituted arylene" means a bivalent radical derived from arene, preferably ^cg~^c*ιg ^arene' ^such as benzene, toluene, xylene, mesitylene, naphthalene, and the like, which may be substituted by one or more, preferably one or two suitable substituents such as halogen as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isobutoxy, butoxy, etc. ) , and the like. Suitable example thereof may be 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 5-methyl-1,3-phenylene, 2,3-dimethyl-l,4-phenylene, 1,2-naphthylene,

3-fluoro-l,4-phenylene, and the like, and more preferably 1,4-phenylene or 1,3-phenylene.

Suitable "a bivalent radical derived from imidazopyridine" may be imidazo[l,5-a]pyridin-diyl such as imidazo[l,5-a]pyridin-l,3-diγl, and the like.

Suitable "a bivalent radical derived from azulene" may be azulen-diyl such as azulen-l,3-diyl, and the like. Suitable "a bivalent radical derived from thiophene" may be thien-diyl such as thien-2,5-diyl, and the like. Suitable "a bivalent radical derived from pyrrolo[2,3-b]pyridine" may be lH-pyrrolo[2,3-b]pγridin-diyl such as lH-pyrrolo[2,3-b]pyridin-l,3-diγl, and the like.

Suitable "a bivalent radical derived from guinolone" may be 4-(lH)-quinolon-diyl such as 4- ( lH) -guinolon-l , 3-diyl, and the like.

Suitable "a bivalent radical derived from indazole" may be lH-imidazol-diyl such as lH-indazol-l,3-diyl, and the like. Suitable "a bivalent radical derived from dihydrobenzimidazole" may be 2,3-dihydro-lH-benzimidazol-diyl such as 2,3-dihγdro-lH-benzimidazol-l,3-diyl, and the like.

The bivalent radicals mentioned above may be substituted by one or more, preferably one to three suitable substituent(s) such as aryl (e.g. phenyl, tolyl, xylyl, naphthyl, etc. ) , lower alkyl as mentioned above, halogen as mentioned above, hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), and the like. Suitable "halogen" may be the same as those given in the above.

Suitable "protected hydroxy" may be lower alkyl, ar(lower)alkyl and acyloxy explained above, and the like.

The processes 1 and 2 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 its reactive derivative at the hydroxy group, or a salt thereof.

Suitable salt of the compounds (II) and (III) or its reactive derivative at the hydroxy group may be the same that exemplified for the compound (I) .

Suitable "reactive derivative at the hydroxy group" of the compound (III) may include an acid residue such as halo (e.g. bromo, chloro, iodo, etc.), acyloxy (e.g. acetoxy, mesyloxy, tosyloxy, etc.), and the like. This reaction is usually carried out in a solvent such as chloroform, dichloromethane, benzene,

N,N-dimethylformamide, dimethyl sulfoxide, 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 carboante, potassium carbonate, etc.], 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.

Also, this reaction can be carried out in the presence of a conventional condensing agent which is capable of condensing alcohols and amines.

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 (l-b) or a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to removal reaction of the carboxy-protective ι group in R cL.

Suitable salt of the compounds (I-a) and (l-b) may be the same as that exemplified for the compound (I) .

In the present removal reaction, and conventional methods used in the removal of the carboxy-protective group, for example, hydrolysis, reduction, removal using Lewis acid, etc. are applicable. When the carboxy-protective group is an ester, it can be removed by hydrolysis or removal 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 carboante (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.), and 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, benzoic 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 such as alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, N,N-dimethylformamide, water or a mixed solvent thereof.

The reaction temperature is not critical, and its may suitably be selected in accordance with the kind of the carboxy-protective group and the removing method. The removal using Lewis acid is preferably to remove substituted or unsubstituted ar(lower)alkyl ester and carried out by reacting the compound (I-a) 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 removal 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 can be applied preferably for removing the protective-group such as halo(lower)alkyl (e.g. 2-iodoethγl, 2,2,2-trichloroethyl, etc.) ester, ar(lower)alkyl (e.g. benzyl, etc.) ester or the like. The reduction method applicable for the removal 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 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. The object compound (I) thus prepared can be iolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.

The object compound (I) of the present invention can be converted to its salt by a conventional method.

The optically active compound can be prepared by a conventional optical resolution method or by selecting the optical active starting compound.

The starting compound (II) can be prepared by the following methods, the details of which are shown in Preparations mentioned below, or a conventional manner.

Method A

Z -CO-X-Ya (V)

R¹-A-H R -A-CO-X-Ya

Lewis Acid

(IV) (VI) or a salt thereof or a salt thereof

Method B

Method C

H-X-Ya

(IX) (VI) or a salt thereof or a salt thereof

Method D

Removal of the carboxy-protective group

ITcL-A-CO-X-Ya Rj-A-CO-X-Ya

(VI-a) (Vl-b) or a salt thereof or a salt thereof

Method E

Reduction

R -A-CO-X-NO, R -A-CO-X-ΝH,

(VI-c) (III-a) or a salt thereof or a salt thereof

Method F

Removal of the hydroxy-protective group in Yb

R -A-CO-X-Yb R -A-CO-X-OH

(VI-d) (Ill-b) or a salt thereof or a salt thereof wherein R1, Rg1, R,1, A and X are each as defined above, Z 1, Z? and Z3 are each hydrogen,

Ya is nitro or protected hydroxy, and

Yb is protected hydroxy.

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

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 prostatomegaly, prostatism, 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 :

4-[3-[4-[Bis(4-isobutylphenyl)methylamino]benzoyl]- imidazo[1,5-a]pyridin-l-yl]butyric acid

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

Test Methods i) Materials

₃ 1,2,6,7- H-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 3 includes 85-105 Ci of 1,2,6,7- H-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 inut :-, the reaction was extracted with 1 ml of ethyl acetate. Fifty μl of ethyl acetate phase was chromatographed 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-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) or a pharmaceutically acceptable salt of the present invention is 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, external and topical administration. The pharmaceutical preparation may be in solid or semi-solid from such as tablet, granule, powder, capsule, suppository, cream, ointment, 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 very from and also depend upon the age, conditions of the patient, a kind of diseases, 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.

to be continued on the next page

Preparation 1

(1) To a solution of 2-(aminomethyl)pyridine (1.74 g) in pyridine (5 ml) was added glutaric anhydride (1.84 g) at ambient temperature. After stirring for 2 hours, the resulting solid was collected and washed with dichloromethane to give 4-[N-(2-pyridylmethyl)carbamoyl]- butyric acid (3.38 g) .

¹H-NMR (DMSO-dg, δ) : 1.55 (2H, m), 2.15-2.3 (4H, ), 4.32 (2H, d, J=6Hz), 7.15-7.3 (2H, m) , 7.75 (1H, dt, J=2, 8Hz), 8.35-8.55 (2H, m)

(2) To a suspension of 4-[N-(2-pyridylmethyl)carbamoyl]- butyric acid (3.38 g) in ethanol (100 ml) was added camphorsulfonic acid (3.8 g) . After 10 minutes, the mixture was heated under reflux using a reflux condenser o containing 3A molecular sieves. After 3 hours, the mixture was evaporated, diluted with saturated aqueous sodium hydrogencarbonate and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to give ethyl 4-[N-(2-pyridylmethyl)carbamoyl]butyrate (3.22 g) .

^■"^•H-NMR (CDC1₃, δ) : 1.25 (3H t, J=7Hz) , 2.01 (2H, m), 2.3-2.5 (4H, m) , 4.13 (2H, q, J=7Hz), 4.59 (2H, d, J=2Hz), 6.95 (1H, m) , 7.2-7.4 (2H, m) , 7.75 (1H, dt, J=l, 7Hz), 8.57 (1H, m)

(3) A solution of ethyl 4-[N-(2-pyridylmethyl)carbamoyl]- butyrate (692 mg) and phosphorus oxychloride (1.4 ml) in benzene (5 ml) were heated under reflux for 5 hours. Water was then added to the cooled mixture, and the resulting solution was made basic and extracted with ether. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (eluent : ethyl acetate to give ethyl 4-(imidazo[l,5-a]pyridin-3-yl)- butyrate (638 mg) .

¹H-NMR (CDC1₃, δ) : 1.25 (3H, t, J=7Hz), 2.26 (2H, m), 2.48 (2H, t, J=7Hz), 3.11 (2H, t, J=7Hz), 4.14 (2H, q, J=7Hz), 6.55-6.8 (2H, m) , 7.48 (1H, s), 7.43 (1H, dt, J=9, 1Hz) , 7.88 (1H, dd,

J=7Hz)

Preparation 2

(1) To a solution of (2-carboxyethyl)triphenylphosphonium chloride (6.87 g) in dimethylformamide (20 ml) was added sodium hydride (1.48 g, 60% in mineral oil) at ambient temperature. After 20 minutes, l-formylimidazo[l,5-a]- pyridine (2.46 g) was added thereto and the mixture was stirred at 30°C for 1 hour. Ice was added to the mixture, followed by acidifying it to pH 5 with IN hydrochloric acid, and then extraction with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The residue was chromatographed on silica gel (eluent : a mixture of chloroform and methanol, 9:1) to give 4-(imidazo[l,5-a]pyridin-l-yl)-trans-3-butenoic acid (613 mg) .

^•^J-N R (DMSO-dg, δ) : 3.20 (2H, dd, J=l, 7Hz) , 6.32 (1H, dt, J=16, 7Hz), 6.63 (1H, dt, J=l, 7Hz), 6.74 (1H, d, J=16Hz), 6.78 (1H, m) , 7.65 (1H, d, J=9Hz), 8.27 (1H, d, J=7Hz), 8.33 (1H, s)

(2) To a solution of 4-(imidazo[l,5-a]pyridin-l-yl)- trans-3-butenoic acid (1.91 g) in ethanol (100 ml) was added camphorsulfonic acid (2.4 g) , and the mixture was o heated under reflux using reflux condenser containing 3A molecular sieves. After 2 hours, the mixture was evaporated, diluted with saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and, evaporated in vacuo. The residue was chromatographed on silica gel (eluent : ethyl acetate) to give ethyl 4-(imidazo[l,5-a]pyridin-l-yl)-trans-3- butenoate (1.2 g) .

^■"-H-NMR (CDC1₃, δ) : 1.28 (3H, t, J=7Hz) , 3.30 (2H, dd, J=l, 7Hz), 4.18 (2H, q, J=7Hz), 6.4-6.6 (2H, m), 6.65-6.8 (2H, m) , 7.49 (1H, d, J=9Hz), 7.85 (1H, d, J=7Hz), 8.04 (1H, s)

(3) To a solution of ethyl 4-(imidazo[l,5-a]pyridin-l- yl)-trans-3-butenoate (1.2 g) in ethanol (5 ml) was added 10% palladium on carbon (200 mg) , and the mixture was stirred for 2 hours under hydrogen atmosphere (4 atm) . The reaction mixture was filtered through a celite pad, and removal of the solvent from the filtrate in vacuo gave ethyl 4-(imidazo[1,5-a]pyridin-l-yl)butyrate (1.05 g) .

¹H-NMR (CDC1₃, δ) : 1.24 (3H, t, J=7Hz) , 2.10 (2H, m), 2.36 (2H, t, J=7Hz), 2.94 (2H, t, J=7Hz), 4.12 (2H, q, J=7Hz), 6.50 (1H, dt, J=l,7Hz), 6.63 (1H, m), 7.38 (1H, d, J=9Hz), 7.87 (1H, d, J=7Hz), 8.12 (1H, s)

Preparation 3

(1) To a stirred solution of ethyl succinyl chloride (836 mg) in dichloromethane (30 ml) was added aluminum chloride (831 mg) at ambient temperature. After 10 minutes, a solution of azulene (503 mg) in dichloromethane was added. After one hour, ice was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with water, aqueous sodium hydrogencarbonate and brine, dried over sodium sulfate and then evaporated in vacuo. The residue was chromatographed on silica gel to give ethyl 4-(azulen-l-yl)-4-oxobutyrate (422 mg) .

¹H-NMR (CDC1₃, δ) : 1.28 (3H, t, J=7Hz) , 2.81 (2H, t, J=7Hz), 3.48 (2H, t, J=7Hz) , 4.18 (2H, q, J=7Hz), 7.29 (1H, d, J=4Hz), 7.49 (1H, t. J=9Hz ) , 7 . 60 ( 1H, t , J=9Hz ) , 7. 83 ( 1H, t, J=9Hz ) , 8. 37 ( 1H, d, J=4Hz ) , 8.50 ( 1H, d, J=9Hz ) , 9. 88 ( 1H, d, J=9Hz )

(2) To a stirred solution of ethyl 4-(azulen-l-yl)-4- oxobutyrate (206 mg) in tetrahydrofuran (3 ml) was added 1M tetrahydrofuran solution of diborane (1.37 ml) at 0°C. After stirring at ambient temperature for 20 minutes and 50°C for additional 20 minutes, the reaction was quenched by aqueous potassium dihydrogen phosphate at 0°C. The reaction mixture was extracted with ether. The separated organic layer was washed with aqueous sodium hydrogencarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 2:1) to give ethyl 4- azulen-1-yl)butyrate (96 mg) .

¹H-NMR (CDC1₃, δ) : 1.25 (3H, t, J=7Hz) , 2.08 (2H, m) , 2.36 (2H, t, J=7Hz), 3.12 (2H, t, J=7Hz) , 4.11 (2H, q, J=7Hz), 7.08 (2H, m) , 7.34 (1H, br s), 7.54 (1H, t, J=9Hz), 7.79 (1H, br s), 8.27 (2H, m)

Preparation 4 To a solution of 3-nitrobenzoyl chloride (713 mg) in 1,2-dichloroethane (5 ml) was added aluminum chloride (650 mg) . After 10 minutes, ethyl 4-(imidazo[l,5-a]pyridin- 3-yl)butyrate (405 mg) in 1,2-dichloroethane (5 ml) was added thereto. The resultant mixture was heated under reflux for 6 hours. The mixture was diluted with ethyl acetate and then washed with water, saturated aqueous sodium hydrogencarbonate, and brine. The solution was dried over sodium sulfate, and the solvent was removed by evaporation in vacuo. The residue was chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 1:2) to give ethyl 4-[l-(3-nitrobenzoyl)imidazo- [l,5-a]pyridin-3-yl]butyrate (240 mg) .

¹H-NMR (CDC1₃, δ) : 1.27 (3H, t, J=7Hz) , 2.24 (2H, m), 2.59 (2H, t, J=7Hz), 3.14 (2H, t, J=7Hz) , 4.16 (2H, t, J=7Hz), 6.99 (1H, dt, J=l, 7Hz),

7.32 (1H, m), 7.68 (1H, t, J=8Hz), 8.16 (1H, ) , 8.38 (1H, m), 8.55 (1H, dt, J=l, 8Hz), 8.72 (1H, ) , 9.43 (1H, m)

The compounds described in the following Preparations 5 to 11 could be obtained in accordance with a similar manner to that of Preparation 4.

Preparation 5 Ethyl 4-[l-(4-nitrobenzoyl)imidazo[l,5-a]pyridin-3- yl] utyrate

^■^i-NMR (CDC1₃, δ) : 1.27 (3H, t, J=7Hz), 2.20 (2H, m), 2.55 (2H, t, J=7Hz), 3.13 (2H, t , J=7Hz), 4.15 (2H, q, J=7Hz) , 7.00 (1H, dt, J=l, 7Hz), 7.34 (1H, ddd, J=l, 7, 9Hz), 8.18 (1H, dt, J=7,

1Hz), 8.33 (2H, m) , 8.5-8.6 (3H, m)

Preparation 6

Ethyl 4-[3-(3-nitrobenzoyl)imidazo[1,5-a]pyridin-l- yl]butyrate

^" -I-NMR (CDC1₃, δ) : 1.25 (3H, t, J=7Hz), 2.19 (2H, m), 2.48 (2H, t, J=7Hz), 3.04 (2H, t, J=7Hz), 4.14 (2H, q, J=7Hz) , 7.11 (1H, dt, J=7.lHz), 7.28 (1H, m), 7.70 (1H, t, J=8Hz), 7.76 (1H, m) , 8.51 (1H, m), 8.79 (1H, dt, J=8Hz), 9.41 (1H, m), 9.86 (1H, dt, J=7, 1Hz)

Preparation 7

Ethyl 4-[3-(4-nitrobenzoyl)imidazo[1,5-a]pyridin- 1-yl]butyrate ^■"^•H-NMR (CDC1₃, δ) : 1.25 (3H, t, J=7Hz), 2.17 (2H, m), 2.47 (2H, t, J=7Hz), 3.04 (2H, t, J=7Hz) , 4.14 (2H, q, J=7Hz), 7.11 (IH, dt, J=7_flHz), 7.29 (IH, m), 7.77 (IH, dt, J=9_;lHz), 8.36 (2H, • d, J=9Hz), 8.60 (2H, d, J=9Hz), 9.87 (IH, dt,

J=7 _j 1Hz )

Preparation 8

Ethyl 4-[3-(3-nitrobenzoyl)azulen-1-yl]butyrate ¹H-NMR (CDC1₃, δ) : 1.22 (3H, t, J=7Hz), 2.05 (2H, m), 2.38 (2H, t, J=7Hz), 3.09 (2H, t, J=7Hz), 4.11 (2H, q, J=7Hz), 7.58 (IH, t, J=9Hz), 7.68 (IH, d, J=9Hz), 7.72 (IH, t, J=9Hz) , 7.85 (IH, s), 7.90 (IH, t, J=9Hz), 8.17 (IH, m) , 8.42 (IH, m), 8.53 (IH, d, J=9Hz), 8.57 (IH, m) , 9.71 (IH, d, J=9Hz)

Preparation 9

Ethyl 4-[3-(4-nitrobenzoyl)azulen-1-yl]butyrate -"Ή-N R (CDC1₃, δ) : 1.22 (3H, t, J=7Hz) , 2.05 (2H, m), 2.37 (2H, t, J=7Hz), 3.08 (2H, t, J=7Hz), 4.11 (2H, q, J=7Hz), 7.58 (IH, t, J=9Hz), 7.68 (IH, t, J=9Hz), 7.81 (IH, s), 7.90 (IH, m) , 7.96 (2H, d, J=8Hz), 8.38 (2H, d, J=8Hz) , 8.53 (IH, d, J=9Hz), 9.77 (IH, d, J=9Hz)

Preparation 10

Ethyl 4-[1-(4-methoxybenzoyl)imidazo[1,5-a]pyridin-3- yl]butyrate ¹H-NMR (CDC1₃, δ) : 1.27 (3H, t, J=7Hz), 2.21 (2H, m) , 2.55 (2H, t, J=7Hz), 3.13 (2H, t, J=7Hz), 3.90 (3H, s), 4.15 (2H, q, J=7Hz), 6.88 (IH, dt, J=l, 7Hz), 7.00 (2H, d, J=9Hz) , 7.19 (IH, m) , 8.07 (IH, dt, J=7, 1Hz), 8.49 (2H, d, J=9Hz) , 8.45-8.55 (IH, m) Preparation 11

Ethyl 4-[1-(3-methoxybenzoyl)imidazo[1,5-a]pyridin-3- yl]butyrate

^■"^■H-NMR (CDC1₃, δ) : 1.26 (3H, t, J=7Hz) , 2.21 (2H, ), 2.55 (2H, t, J=7Hz), 3.12 (2H, t, J=7Hz), 3.90 (3H, s), 4.15 (2H, q, J=7Hz), 6.92 (IH, dt, J=7, 1Hz), 7.10 (IH, ), 7.23 (IH, m) , 7.41 (IH, t, J=8Hz), 7.95 (IH, m), 8.03 (IH, m) , 8.10 (IH, ), 8.51 (IH, m)

Preparation 12

To a solution of ethyl 4-[l-(3-nitrobenzoyl)imidazo- [l,5-a]pyridin-3-yl]butyrate in ethanol (10 ml) was added 4N sodium hydroxide (1.9 ml) , and the mixture was heated under reflux for 40 minutes. After removal of the organic solvent in vacuo, the resulting aqueous solution was made acidic with saturated aqueous potassium dihydrogen phosphate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give

4-[1-(3-nitrobenzoyl)imidazo[1,5-a]pyridin-3-yl]butyric acid (638 mg) .

^■"^"H-NMR (DMSO-dg, δ) : 2.05 (2H, m) , 2.48 (2H, t,

J=7Hz), 3.13 (2H, t, J=7Hz), 7.17 (IH, dt, J=l, 7Hz), 7.52 (IH, dd, J=7, 9Hz), 7.84 (IH, t,

J=8Hz), 8.3-8.5 (2H, m) , 8.59 (IH, d, J=7Hz), 8.78 (IH, m) , 9.28 (IH, m)

Preparation 13 To a solution of 4-[l-(3-nitrobenzoyl)imidazo[l,5-a]- pyridin-3-yl]butyric acid (93 mg) in dioxane and ethanol (5 ml; 1:1) was added 10% palladi n on carbon (15 mg) , and the mixture was stirred for 3 hours under hydrogen atmosphere (4 atms) . The reaction mixture was then filtered through a celite pad. Removal of the solvent in vacuo gave 4-[l-(3-aminobenzoγl)imidazo[l,5-a]pyridin-3- yl]butyric acid (94 mg) .

¹H-NMR (CDC1₃-CD₃0D, δ) : 2.23 (2H, m) , 2.56 (2H, t, J=7Hz), 3.13 (2H, t, J=7Hz) , 6.96 (IH, m) , 7.05-7.5 (3H, m) , 7.8 (IH, m) , 7.92 (IH, m) ,

8.13 (IH, m), 8.42 (IH, d, J=9Hz)

The compounds described in the following Preparations 14 to 16 could be obtained in accordance with a similar manner to that of Preparation 13.

Preparation 14

Ethyl 4-[l-(4-aminobenzoyl)imidazo[1,5-a]pyridin-3- yl]butyrate ¹H-NMR (CDC1₃, δ) : 1.27 (3H, t, J=7Hz) , 2.20 (2H, m), 2.53 (2H, t, J=7Hz), 3.14 (2H, t, J=7Hz) , 4.15 (2H, q, J=7Hz) , 6.75 (2H, d, J=9Hz), 6.87 (IH, dt, J=l, 7Hz), 7.17 (IH, m) , 8.06 (IH, d, J=7Hz)_Λ 8.37 (2H, d, J=9Hz), 8.48 (IH, dt, J=9, 1Hz)

Preparation 15

Ethyl 4-[3-(3-aminobenzoyl)imidazo[1,5-a]pyridin-l- yl]butyrate - l- (CDC1₃, δ) : 1.25 (3H, t, J=7Hz), 2.17 (2H, m), 2.47 (2H, t, J=7Hz), 3.03 (2H, t, J=7Hz), 4.15 (2H, q, J=7Hz), 6.89 (IH, m) , 7.01 (IH, dt, J=l, 7Hz), 7.16 (IH, m), 7.29 (IH, t, J=8Hz), 7.6-7.9 (3H, m), 9.92 (IH, dt, J=7Hz)

Preparation 16

Ethyl 4-[3-(4-aminobenzoyl)imidazo[1,5-a]pyridin-l- yl]butyrate

^■ l-NMR (CDC1₃, δ) : 1.25 (3H, t, J=7Hz), 2.17 (2H, m), 2.44 (2H, t, J=7Hz), 3.03 (2H, t, J=7Hz), 4.13 (2H, q, J=7Hz), 6.72 (2H, d, J=9Hz), 6.92 (IH, dt, J=l, 7Hz), 7.09 (IH, m) , 7.64 (IH, dt, J=8, 1Hz), 8.42 (2H, d, J=9Hz), 9.76 (IH, dt, 3=1, 1Hz)

Preparation 17

To a stirred suspension of ethyl 4-[3-(3- nitrobenzoyl)azulen-l-yl]butyrate (200 mg) in ethanol (2.5 ml) and water (2 ml) was added iron powder (166 mg) and ferrous sulfate 7 hydrate (16 mg) , and the mixture was heated under reflux for an hour. The reaction mixture was cooled and extracted with chloroform. The organic layer was washed with water, aqueous sodium hydrogencarbonate and brine, and then evaporated in vacuo to give ethyl 4-[3-(3-aminobenzoyl)azulen-l-yl]butyrate (179 mg) .

¹H-NMR (CDC1₃, δ) : 1.22 (3H, t, J=7Hz), 2.07 (2H, m), 2.36 (2H, t, J=7Hz), 3.08 (2H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 6.88 (IH, m) , 7.1-7.35 (3H, m), 7.47 (IH, t, J=9Hz), 7.55 (IH, t, J=9Hz) , 7.81 (IH, t, J=9Hz), 7.99 (IH, s), 8.45 (IH, d,

J=9Hz), 9.62 (IH, d, J=9Hz)

Preparation 18

Ethyl 4-[3-(4-aminobenzoyl)azulen-l-γl]butyrate could be obtained in accordance with a similar manner to that of Preparation 17.

^■"^■H-NMR (CDC1₃, δ) : 1.23 (3H, t, J=7Hz), 2.08 (2H, m), 2.37 (2H, t, J=7Hz), 3.09 (2H, t, J=7Hz) , 4.12 (2H, q, J=7Hz), 6.73 (2H, d, J=8Hz) , 7.40 (IH, t, J=9Hz), 7.47 (IH, t, J=9Hz), 7.7-7.85

(IH, m), 7.76 (2H, t, J=8Hz), 7.99 (IH, s), 8.43 (IH, d, J=9Hz), 9.45 (IH, d, J=9Hz)

Preparation 19 To a solution of ethyl 4-[l-(4-methoxybenzoyl)- imidazo[1,5-a]pyridin-3-yl]butyrate in dichloromethane (10 ml) and ethanethiol (1.0 ml) was added aluminum chloride (1.5 g) at 0°C. After stirring for 40 minutes, the solvent was removed by evaporation and the residue was poured into ice. The resulting solid was collected,washed successively with water, ethanol and dichloromethane, and then dried in vacuum desicator to give ethyl 4-[1-( -hγdroxybenzoyl)imidazo[1,5-a]pyridin-3-yl]butyrate (618 mg) . ^" l-NMR (DMSO-dg, δ) : 1.16 (3H, t, J=7Hz), 2.07 (2H, m), 2.50 (2H, t, J=7Hz), 3.11 (2H, t, J=7Hz), 4.02 (2H, q, J=7Hz) , 6.87 (2H, d, J=9Hz), 7.04 (IH, dt, J=l, 7Hz), 7.33 (IH, m) , 8.35 (IH, d, J=9Hz), 8.38 (2H, d, J=9Hz), 8.48 (IH, d, J=7Hz)

Preparation 20

Ethyl 4-[1-(3-hydroxybenzoyl)imidazo[1,5-a]pyridin- 3-yl]butyrate could be obtained in accordance with a similar manner to that of Preparation 19. "hl-NMR (CDC1₃, δ) : 1.24 (3H, t, J=7Hz) , 2.18 (2H, m), 2.51 (2H, t, J=7Hz), 3.09 (2H, t, J=7Hz), 4.16 (2H, q, J=7Hz), 6.92 (IH, dt, J=l, 7Hz), 7.01 (IH, m), 7.24 (IH, m) , 7.36 (IH, t, J=8Hz), 7.77 (IH, d, J=7Hz), 8.05-8.15 (2H, m) , 8.52 (IH, d, J=9Hz)

Preparation 21

(1) A mixture of ethyl 3-(3-nitrophenyl)-3-oxopropionate (4.0 g), triethyl orthoformate (4.21 ml) and acetic anhydride (4.77 ml) was heated at 120°C for 4 hours. After evaporation of the solvent, the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (4:1) to give ethyl 2-(ethoxymethylene)-3-(3-nitrophenγl)-3-oxopropionate (3.73 g) as an oil. ¹H-NMR (CDC1₃, δ) : 1.18 (3H, t, J=8Hz) , 1.28 (3H, t, J=8Hz), 4.15 (2H, q, J=8Hz) , 4.18 (2H, q, J=8Hz), 7.67 (IH, t, J=8Hz), 7.82 (IH, s) , 8.22 (IH, dt, J=8, 1Hz), 8.44 (IH, dt, J=8, 1Hz), 8.67 (IH, t, J=lHz)

(2) A mixture of ethyl 2-(ethoxymethylene)-3- (3-nitrophenyl)-3-oxopropionate (3.65 g) and aniline (1.13 ml) in chloroform (20 ml) was stirred at 25°C for 1 hour. The precipitated crystals were collected by filtration to give ethyl 3-(3-nitrophenyl)-3-oxo-2-

(phenylaminomethylene)propionate (3.4 g) .

¹H-NMR (CDC1₃, δ) : 0.90 (2/3H, t, J=8Hz) , 1.06

(4/3H, t, J=8Hz), 4.00-4.14 (2H, ) , 7.20-7.64 (6H, m), 7.82 (2/3H, dt, J=8, 1Hz), 7.95 (3/1H, dt, J=8, 1Hz), 8.25-8.40 (2H, m) , 8.48 (1/3H, d,

J=14Hz), 8.66 (2/3H, d, J=14Hz)

(3) A solution of ethyl 3-(3-nitrophenyl)-3-oxo-2-

(phenylaminomethylene)propionate (1.0 g) in diphenyl ether (10 ml) was heated at 180°C for 4 hours, and the reaction mixture was allowed to cool to 25°C. The precipitates were collected by filtration to give

3- ( 3-nitrobenzoyl ) -4-quinolone ( 315 mg) .

^■ -I-NMR ( DMSO-dg , δ ) : 7 . 47 ( IH, dt , J=2 , 8Hz ) , 7 . 68-7. 84 ( 3H, m) , 8 . 12 ( 2H , d , J=8Hz ) , 8.38-8.46 (2H, m) , 8.51 (IH, s)

Preparation 22

(1) Ethyl 2-(ethoxymethylene)-3-(4-nitrophenyl)- 3-oxopropionate could be obtained in accordance with a similar manner to that of Preparation 21-(1).

¹H-NMR (CDC1₃, δ) : 1.15 (3H, t, J=8Hz), 1.28 (3H, t, J=8Hz), 4.04-4.22 (4H, m) , 8.02 (2H, d, J=10Hz), 8.30 (2H, d, J=10Hz)

(2) Ethyl 3-(4-nitrophenyl)-3-oxo-2-

(phenylaminomethylene)propionate could be obtained in accordance with a similar manner to that of Preparation 21-(2). ^■'Ή-NMR (CDC1₃, δ) : 0.88 (3/3H, t, J=8Hz), 1.02

(6/3H, t, J=8Hz), 4.04 (2/3H, q, J=8Hz) , 4.06 (4/3H, q, J=8Hz), 7.20-7.34 (3H, m) , 7.45 (2H, q, J=8Hz), 7.60 (4/3H, d, J=10Hz), 7.75 (2/3H, d, J=10Hz), 8.26 (2H, d, J=10Hz), 8.50 (1/3H, d, J=16Hz), 8.66 (1/3H, d, J=16Hz)

(3) 3-(4-Nitrobenzoyl)-4-quinolone could be obtained in accordance with a similar manner to that of Preparation 21-(3). -"-H- (DMSO-dg, δ) : 7.47 (IH, dt, J=2, 8Hz), 7.19

(IH, dd, J=2, 8Hz), 7.76 (2H, dq, J=2, 8Hz), 7.88 (2H, d, J=10Hz), 8.12 (IH, d, J=8Hz), 8.30 (2H, d, J=10Hz), 8.52 (IH, s)

Preparation 23

A mixture of 3-(3-nitrobenzoyl)-4-quinolone (300 mg) , ethyl 4-bromobutyrate (0.29 ml) and potassium carbonate (423 mg) in N,N-dimethylformamide (10 ml) was stirred at 50°C for 4 hours. 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, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-(3-nitrobenzoyl)-4-quinolon-l-yl]butyrate (358 mg) as yellow crystals.

¹H-NMR (CDC1₃, δ) : 1.32 (3H, t, J=8Hz), 2.23-2.48 (2H, ), 2.53 (2H, t, J=8Hz), 4.22 (2H, q, J=8Hz), 4.38 (2H, t, J=8Hz), 7.50 (IH, dt, J=2, 8Hz), 7.64 (2H, t, J=8Hz), 7.70-7.85 (2H, m) ,

8.12 (2H, dd, J=2, 8Hz), 8.36-8.50 (3H, m) , 8.62 (IH, t, J=2Hz)

The compounds of the following Preparations 24 to 27 could be obtained by reacting the corresponding starting compounds with ethyl 4-bromobutyrate in accordance with a similar manner to that of Preparation 23.

Preparation 24 Ethyl 4-[3-(4-nitrobenzoyl)-4-quinolon-l-yl]butyrate ^■"^■H-NMR (CDC1₃, δ) : 1.30 (3H, t, J=8Hz), 2.20-2.35 (2H, m), 2.52 (2H, t, J=8Hz), 4.23 (2H, q, J=8Hz), 4.38 (2H, t, J=8Hz), 7.51 (IH, dt, J=2, 8Hz), 7.73-7.82 (2H, m) , 7.90 (2H, d, J=10Hz), 8.30 (2H, d, J=10Hz), 8.42 (IH, t, J=2Hz), 8.46

(IH, dd, J=2, 8Hz)

Preparation 25

Ethyl 4-[3-(3-nitrobenzoyl)-lH-pyrrolo[2,3-b]pyridin- 1-yl]butyrate

^■"^•H-NMR (CDC1₃, δ) : 1.20 (3H, t, J=8Hz), 2.20-2.44 (2H, ), 2.38 (2H, t, J=8Hz), 4.08 (2H, q, J=8Hz), 4.48 (2H, t, J=8Hz) , 7.35 (IH, dd, J=5, 8Hz), 7.73 (IH, s), 7.74 (IH, t, J=7Hz), 8.18 (IH, dd, J=l, 7Hz), 8.40-8.52 (2H, m) , 8.65-8.72

(2H, m) Preparation 26

Ethyl 4- ( 3 -carboxy-lH-indazol-1-yl ) butyrate ¹H-NMR (DMSO-dg, δ) : 1.12 (3H, t, J=8Hz), 2.00-2.20 (2H, m), 2.32 (2H, t, J=8Hz), 3.97 (2H, q, J=8Hz), 4.56 (2H, t, J=8Hz), 7.23 (IH, t,

J=8Hz), 7.44 (IH, t, J=8Hz ) , 7.60 (IH, d, J=8Hz), 8.20 (IH, d, J=8Hz)

Preparation 27 Benzyl 4-[3-(l-methγlvinyl)-2,3-dihydro-2-oxo-lH- benzimidazol-1-yl]butyrate

^■'Ή-NMR (CDC1₃, δ) : 2.05-2.21 (2H, m) , 2.24 (3H, d, J=lHz), 2.48 (2H, t, J=8Hz), 3.94 (2H, t, J=8Hz), 3.94 (2H, t, J=8Hz), 5.13 (2H, s), 5.19 (IH, s), 5.25 (IH, q, J=lHz), 6.96-7.14 (4H, m) ,

7.36 (5H, s)

Preparation 28

To a solution of benzyl 4-[3-(l-methylvinyl)-2,3- dihydro-2-oxo-lH-benzimidazol-l-yl)butyrate (980 mg) in tetrahydrofuran (10 ml) were added water (10 ml) and sulfuric acid (2 ml), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was partitioned between ether and water. 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 eluting with 20% ethyl acetate in hexane to give benzyl 4-(2,3-dihydro-2-oxo-lH- benzimidazol-1-yl)butyrate (342 mg) as an oil. ^-N R (CDC1₃, δ) : 2.13 (2H, quintet, J=8Hz) , 2.49

(2H, t, J=8Hz), 3.96 (2H, t, J=8Hz), 5.12 (2H, s), 6.96-7.10 (4H, m) , 7.36 (5H, s)

Preparation 29 A solution of 3-nitrobenzyl chloride (230 mg) in dichloromethane (5 ml) was added to a mixture of benzyl 4-(2,3-dihγdro-2-oxo-lH-benzimidazol-l-yl)butyrate (320 mg), diisopropylethylamine (0.36 ml) and 4-(dimethylamino)pyridine (25 mg) in dichloromethane (10 ml) at 25°C. After 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 the solvent, the residue was chromatogrpahed on silica gel eluting with 20% ethyl acetate in hexane to give benzyl

4-[3-(3-nitrobenzyl)-2,3-dihydro-2-oxo-lH-benzimidazol-l- yl]butyrate (331 mg) as an oil.

¹H-NMR (CDC1₃, δ) : 2.10 (2H, quin, J=8Hz), 2.47 (2H, t, J=8Hz), 3.89 (2H, t, J=8Hz) , 5.08 (2H, s), 7.04 (IH, dd, J=l, 8Hz), 7.20-7.30 (2H, m) , 7.35 (5H, s), 7.67 (IH, t, J=8Hz), 8.02-8.08 (2H, m), 8.40-8.46 (IH, m) , 8.58 (IH, t, J=lHz)

Preparation 30

(1) To a solution of ethyl 4-(3-carboxy-lH-indazol-l-yl)- butyrate (990 mg) in dichloromethane (20 ml) were added oxalyl chloride (0.33 ml) and N,N-dimethylformamide (1 drop), and the mixture was stirred at 25°C for 2 hours. Evaporation of the solvent gave ethyl 4-[3-(chloroformyl)- lH-indazol-l-yl]butyrate (1.02 g) as yellow solid, which was used for the next step without further purification.

(2) To a solution of ethyl 4-[3-(chloroformyl)-lH- indazol-1-yl]butyrate (350 rag) in anisol (10 ml) was added aluminum chloride (475 mg) at 25°C, and the mixture was stirred at the same temperature for 30 minutes. 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 the solvent, the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-(4-methoxybenzoyl)-lH-indazol-l-yl]butyrate (224 mg) as an oil.

" ϊ-NMR (CDC1₃, δ) : 1.22 (3H, t, J=8Hz), 2.26-2.42

(4H, m), 3.91 (3H, s) , 4.13 (2H, q, J=8Hz), 4.58 (2H, t, J=8Hz), 7.03 (2H, d, J=9Hz), 7.30-7.56 (3H, m), 8.42 (2H, d, J=9Hz), 8.44 (IH, dd, J=l, 8Hz)

Preparation 31

3-(3-Nitrobenzoyl)-lH-pγrrolo[2,3-b]pyridine could be obtained by reacting lH-pyrrolo[2,3-b]pyridine with 3-nitrobenzoyl chloride in accordance with a similar manner to that of Preparation 4.

"h-I-NMR (DMSO-dg, δ) : 7.36 (IH, dd, J=5, 8Hz), 7.87 (IH, t, J=7Hz), 8.26 (IH, d, J=7Hz), 8.35-8.66 (5H, m)

The compounds of the following Preparations 32 to 35 could be obtained from the corresponding ethyl esters in accordance with a similar manner to that of Preparation 12.

Preparation 32

4-[3-(3-Nitrobenzoyl)-4-quinolon-l-yl]butyric acid ¹H-NMR (DMSO-dg, δ) : 1.92-2.15 (2H, m) , 2.46 (2H, t, J=8Hz), 4.46 (2H, t, J=8Hz), 7.53 (IH, t, J=8Hz), 7.74 (IH, t, J=8Hz), 7.86 (2H, dt, J=l,

8Hz), 7.98 (IH, d, J=8Hz) , 8.15 (1H_Λ dd, J=2, 8Hz), 8.23 (IH, dd, J=2, 8Hz), 8.38-8.46 (2H, m), 8.63 (IH, s) Preparation 33

4-[3-(4-Nitrobenzoyl)-4-quinolon-l-yl]butyric acid ¹H- MR (CDC1₃:CD₃0D = 1:1, δ) : 2.12-2.38 (2H, m) , 2.45 (2H, t, J=8Hz), 4.38 (2H, t, J=8Hz), 7.45 (IH, dt, J=2, 8Hz), 7.70-7.85 (2H, m) , 7.85 (2H, d, J=10Hz), 8.22 (2H, d, J=10Hz), 8.35 (2H, dd, J=2, 8Hz), 8.45 (IH, s)

Preparation 34 4-[3-(4-Hydroxybenzoyl)-lH-indazol-l-yl]butyric acid ^•"^■H-NMR (CDC1₃:CD₃0D = 1:1, δ) : 2.28-2.46 (4H, m) , 4.60 (2H, t, J=8Hz), 6.93 (2H, d, J=9Hz), 7.30-7.60 (3H, m) , 8.30 (2H, d, J=9Hz), 8.40 (IH, dd, J=l, 8Hz)

Preparation 35

4-[3-(3-Nitrobenzoyl)-lH-pyrrolo[2,3-b]pyridin-1-yl]- butyric acid

^•"Ή-NMR (DMSO-dg, δ) : 2.0-2.40 (2H, m) , 2.26 (2H, t, J=8Hz), 4.38 (2H, t, J=8Hz), 7.38 (IH, dd, J=5,

8Hz), 7.88 (IH, t, J=8Hz), 8.28 (IH, dd, J=2, 8Hz), 8.42 (IH, s), 8.44-8.56 (3H, m) , 8.58 (IH, dd, J=2, 8Hz)

The compounds of the following Preparations 36 to 38 could be obtained by reducing the corresponding nitro compounds with palladium on carbon in accordance with a similar manner to that of Preparation 13.

Preparation 36

4-[3-(3-Aminobenzoyl)-4-quinolon-l-yl]butyric acid ¹H-NMR (DMSO-dg, δ) : 1.92-2.10 (2H, m) , 2.38 (2H, t, J=8Hz), 4.40 (2H, t, J=8Hz), 6.78 (IH, dd, J=2, 8Hz), 6.92 (IH, d, J=8Hz), 6.98 (IH, t, J=2Hz), 7.10 (IH, t, J=8Hz) , 7.50 (2H, t, _ -ifi -

J=8Hz), 7.78-8.02 (2H, m) , 8.23 (2H, dd, J=2, 8Hz), 8.35 (IH, s)

Preparation 37

4-[3-(4-Aminobenzoyl)-4-quinolon-l-yl]butyric acid ^" l-NMR (DMSO-dg, δ) : 1.92-2.10 (2H, m) , 2.38 (2H, t, J=8Hz), 4.36 (2H, t, J=8Hz), 6.54 (2H, d, J=8Hz), 7.30-7.50 (IH, m) , 7.54 (2H, d, J=14Hz), 7.70-7.95 (3H, m) , 8.22 (IH, s)

Preparation 38

4-[3-(3-Aminobenzoyl)-lH-pyrrolo[2,3-b]pyridin-1-yl]^■ butyric acid

¹H-NMR (CDC1₃:CD₃0D = 1:1, δ) : 2.20-2.32 (2H, m) , 2.38 (2H, t, J=8Hz), 4.42 (2H, t, J=8Hz),

6.90-7.40 (5H, m) , 7.86 (IH, s), 8.40 (IH, dd, J=l, 5Hz), 8.65 (IH, dd, J=l, 8Hz)

Preparation 39 4-[3-(3-Aminobenzoyl)-2,3-dihydro-2-oxo-lH- benzimidazol-1-yl]butyric acid could be obtained by reducing benzyl 4-[3-(3-nitrobenzoyl)-2,3-dihydro-2-oxo- IH-benzimidazol-l-yl]butyrate with palladium on carbon in accordance with a similar manner to that of Preparation 13.

¹H-NMR (DMSO-dg, δ) : 1.80-2.00 (2H, m) , 2.33 (2H, t, J=8Hz), 3.86 (2H, t, J=8Hz), 6.75-7.40 (7H, m), 7.68 (IH, dd, J=l, 8Hz)

Preparation 40

Ethyl 4-[3-(4-hydroxybenzoyl)-IH-indazol-l-ylJ- butyrate could be obtained in accordance with a similar manner to that of Preparation 19.

^•'Ή-NMR (CDC1₃, δ) : 1.24 (3H, t, J=8Hz), 2.26-2.42 (4H, m), 4.15 (2H, q, J=8Hz) , 4.58 (2H, t, J=8Hz ) , 6 . 18 ( IH, s ) , 6 . 96 ( 2H , d, J=9Hz ) , 7 . 30-7. 56 ( 3H, m) , 8 . 35 ( 2H, d , J=9Hz ) , 8 . 45 ( 2H, dd, J=l , 8Hz )

Preparation 41

Ethyl 4-(thien-2-yl)butyrate could be obtained by reacting 4-(thien-2-yl)butyric acid with ethanol in accordance with a similar manner to that of Preparation 2-(2). ¹H-NMR (CDC1₃, δ) : 1.26 (3H, t, J=7Hz), 2.01 (2H, m), 2.35 (2H, t, J=7Hz), 2.89 (2H, t, J=7Hz), 4.13 (2H, q, J=7Hz) , 6.79 (IH, m) , 6.92 (IH, dd, J=3, 5Hz), 7.12 (IH, dd, J=l, 5Hz)

Preparation 42

Ethyl 4-oxo-4-(3-phenylthien-2-yl)butyrate could be obtained by reacting 3-phenylthiophene with ethyl succinyl chloride in accordance with a similar manner to that of Preparation 3-(1) . ^•'Ή-NMR (CDC1₃, δ) : 1.21 (3H, t, J=7Hz), 2.58 (2H, m), 2.79 (2H, t, J=7Hz), 4.09 (2H, q, J=7Hz), 7.05 (IH, d, J=5Hz), 7.35-7.5 (5H, m) , 7.54 (IH, d, J=5Hz)

Preparation 43

To a stirred solution of HgCl₂ (0.41 g) in cone. HC1 (0.2 ml) and water (5 ml) was added zinc dust (4.1 g) . After 10 minutes, the aqueous layer was decanted off. To the residue was added water (3 ml), cone. HC1 (5 ml), acetic acid (1 ml) and ethyl 4-oxo-4-(3-phenylthien-2-yl)- butyrate (514 mg) in toluene (5 ml), and the mixture was refluxed for 1.5 hours. After cooling, the reaction mixture was extracted with toluene. The combined organic layer were washed with water, aqueous sodium hydrogencarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (hexane:dichloromethane = 1:1) to give ethyl 4-(3-phenylthien-2-yl)butyrate (249 mg) .

^■"^■H-NMR (CDC1₃, δ) : 1.22 (3H, t, J=7Hz), 1.85-2.1 (2H, m), 2.32 (2H, t, J=7Hz), 2.92 (2H, t,

J=7Hz), 4.08 (2H, q, J=7Hz), 7.00 (IH, d, J=5Hz), 7.18 (IH, d, J=5Hz), 7.2-7.5 (5H, m)

The compounds of the following Preparations 44 and 45 could be obtained by reacting the corresponding starting compounds with 3-nitrobenzoyl chloride in accordance with a similar manner to that of Preparation 4.

Preparation 44 Ethyl 4-[5-(3-nitrobenzoyl)thien-2-yl]butyrate

¹H-NMR (CDC1₃, δ) : 1.28 (3H, t, J=7Hz), 2.08 (2H, m), 2.42 (2H, t, J=7Hz), 2.98 (2H, t, J=7Hz), 4.16 (2H, q, J=7Hz), 6.93 (IH, d, J=4Hz), 7.49 (IH, d, J=4Hz), 7.72 (IH, t, J=8Hz), 8.17 (IH, m), 8.43 (IH, m) , 8.68 (IH, m)

Preparation 45

Ethyl 4-[5-(3-nitrobenzoyl)-3-phenylthien-2-yl]- butyrate

¹H-NMR (CDC1₃, δ) : 1.23 (3H, t, J=7Hz), 1.95-2.15 (2H, m), 2.36 (2H, , t, J=7Hz), 3.00 (2H, t, J=7Hz), 4.08 (2H, q, J=7Hz) , 7.3-7.5 (5H, m) , 7.53 (IH, s), 7.71 (IH, t, J=8Hz), 8.2 (IH, m) , 8.43 (IH, m) , 8.72 (IH, m)

The compounds of the following Preparations 46 and 47 could be obtained by reducing the corresponding nitro compound in accordance with a similar manner to that of Preparation 17. Preparation 46

Ethyl 4-[5-(3-aminobenzoyl)thien-2-yl]butyrate ¹H-NMR (CDC1₃, δ) : 1.28 (3H, t, J=7Hz) , 2.05 (2H, m), 2.40 (2H, t, J=7Hz), 2.95 (2H, t, J=7Hz) , 4.15 (2H, q, J=7Hz) , 6.83-6.94 (2H, m) , 7.11 (IH, m), 7.15-7.3 (2H, m) , 7.51 (IH, d, J=4Hz)

Preparation 47

Ethyl 4-[5-(3-aminobenzoyl)-3-phenylthien-2-yl]- butyrate 1. H-NMR (CDC1₃, δ) : 1.21 (3H, t, J=7Hz) , 1.9-2.15 (2H, m), 2.34 (2H, t, J=7Hz), 2.98 (2H, t, J=7Hz), 4.08 (2H, q, J=7Hz) , 6.8-7.5 (9H, m) , 7.58 (IH, s)

to be continued on the next page

Example 1

To a solution of 4-[l-(3-aminobenzoyl)imidazo[l,5-a]- pyridin-3-yl]butyric acid (93 mg) in dichloromethane (6 ml) were added diisopropylethyl amine (0.12 ml) and bis(4-isobutylphenyl)chloromethane (109 mg) in dichloromethane (2 ml). After stirring overnight at ambient temperature, the reaction was quenched by saturated aqueous potassium dihydrogen phosphate and IN hydrochloric acid (0.29 ml). The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Thin layer chromatography of the concentrate with ethyl acetate furnished 4-[l-[3-[bis(4-isobutylphenyl)- methylamino]benzoyl]imidazo[1,5-a]pyridin-3-yl]butyric acid (77 mg) .

^■4-I-NMR (CDC1₃, δ) : 0.84 (12H, d, J=7Hz), 1.81 (2H, m), 2.18 (2H, m) , 2.52 (4H, d, J=7Hz), 2.54 (2H, t, J=7Hz), 3.10 (2H, t, J=7Hz), 5.52 (IH, s), 6.7-6.9 (2H, m), 7.0-7.85 (10H, m) , 7.6-7.7 (2H, m), 7.98 (IH, d, J=7Hz), 8.40 (IH, d, J=8Hz)

The compounds described in the following Examples 2 to 8 could be obtained by reacting the corresponding starting compounds with bis(4-isobutγlphenyl)chloromethane in accordance with a similar manner to that of Example 1.

Example 2

Ethyl 4-[1-[4-[bis(4-isobutylphenyl)methylamino]- benzoyl]imidazo[1,5-a]pyridin-3-yl]butyrate ^-N R (CDC1₃, δ) : 0.88 (12H, d, J=7Hz), 1.25 (3H, t, J=7Hz), 1.85 (2H, m) , 2.18 (2H, m) , 2.45 (4H, d, J=7Hz), 2.51 (2H, t, J=7Hz), 3.09 (2H, t, J=7Hz), 4.13 (2H, q, J=7Hz) , 4.64 (IH, br d, J=4Hz), 5.59 (IH, br d, J=4Hz), 6.58 (2H, d, J=9Hz), 6.83 (IH, dt, J=l, 7Hz), 7.05-7.17 (5H, m) , 7.34 ( 4H, d, J=8Hz ) , 8. 02 ( IH, d, J=7Hz ) , 8 . 36 ( 2H, d , J=9Hz ) , 8 . 49 ( IH , d, J=9Hz )

Example 3 Ethyl 4-[3-[3-[bis(4-isobutylphenγl)methylamino]- benzoyl]imidazo[1,5-a]pyridin-l-γl]butyrate

^-NM (CDC1₃, δ) : 0.88 (12H, d, J=7Hz) , 1.24 (3H, t, J=7Hz), 1.83 (2H, m), 2.13 (2H, m) , 2.41 (2H, t, J=7Hz), 2.43 (4H, d, J=7Hz), 3.01 (2H, t, J=7Hz), 4.10 (2H, q, J=7Hz) , 5.57 (IH, s), 6.70

(IH, m), 6.96 (IH, dt, J=l, 7Hz), 7.09 (4H, d, J=8Hz), 7.0-7.3 (2H, m) , 7.27 (4H, d, J=8Hz), 7.55-7.75 (3H, m) , 9.76 (IH, d, J=7Hz)

Example 4

Ethyl 4-[3-[4-[bis(4-isobutylphenyl)methylamino]- benzoyl]imidazo[1,5-a]pyridin-1-yl]butyrate

^•'^"H-NMR (CDC1₃, δ) : 0.89 (12H, d, J=7Hz), 1.24 (3H, t, J=7Hz), 1.85 (2H, m) , 2.13 (2H, m) , 2.40 (2H, t, J=7Hz), 2.46 (4H,, d, J=7Hz), 3.0 (2H, t,

J=7Hz), 4.12 (2H, q, J=7Hz) , 4.70 (IH, br d, J=4Hz), 5.50 (IH, br d, J=4Hz), 6.60 (2H, d, J=9Hz), 6.89 (IH, dt, J=l, 7Hz), 7.06 (IH, m) , 7.10 (4H, d, J=8Hz), 7.23 (4H, d, J=8Hz), 7.62 (IH, dt, J=9, 1Hz), 8.38 (2H, d, J=9Hz), 9.72

(IH, d, J=7Hz)

Example 5

Ethyl 4-[3-[3-[bis(4-isobutylphenyl)methylamino]- benzoyl]azulen-l-yl]butyrate

^■^- MR (CDC1₃, δ) : 0.85 (12H, d, J=7Hz), 1.20 (3H, t, J=7Hz), 1.81 (2H, m), 2.03 (2H, m) , 2.32 (2H, t, J=7Hz), 2.41 (4H, d, J=7Hz), 3.04 (2H, t, J=7Hz), 4.08 (2H, q, J=7Hz) , 5.51 (IH, s), 6.8-7.2 (4H, m) , 7.06 (4H, d, J=8Hz), 7.28 (4H, d, J=8Hz), 7.43 (IH, t, J=9Hz), 7.52 (IH, t, J=9Hz), 7.79 (IH, t, J=9Hz), 7.92 (IH, s), 8.43 (IH, d, J=9Hz), 9.60 (IH, d, J=9Hz)

Example 6

Ethyl 4-[3-[4-[bis(4-isobutylphenyl)methylamino]- benzoyl]azulen-1-yl]butyrate

^■"-H-NMR (CDC1₃, δ) : 0.89 (12H, d, J=7Hz), 1.23 (3H, t, J=7Hz), 1.84 (2H, m), 2.06 (2H, m), 2.35 (2H, t, J=7Hz), 2.45 (4H, d, J=7Hz), 3.08 (2H, t,

J=7Hz), 4.11 (2H, q, J=7Hz), 4.68 (IH, br d, J=4Hz), 5.59 (IH, br d, J=4Hz), 6.60 (2H, d, J=8Hz), 7.11 (4H, d, J=8Hz), 7.25 (4H, d, J=8Hz), 7.38 (IH, t, J=9Hz), 7.43 (IH, t, J=9Hz), 7.73 (2H, d, J=8Hz), 7.68-7.8 (IH, m) ,

7.98 (IH, s), 8.41 (IH, d, J=9Hz), 9.41 (IH, d, J=9Hz)

Example 7 Ethyl 4-[l-[4-[bis(4-isobutylphenγl)methoxy]benzoyl]- imidazo[1,5-a]pyridin-3-yl]butyrate

^■ i-N R (CDC1₃, δ) : 0.88 (12H, d, J=7Hz), 1.26 (3H, t, J=7Hz), 1.84 (2H, m), 2.17 (2H, m) , 2.44 (4H, d, J=7Hz), 2.51 (2H, t, J=7Hz), 3.09 (2H, t, J=7Hz), 4.13 (2H, q, J=7Hz), 6.28 (IH, s), 6.86

(IH, dt, J=l, 7Hz), 7.03 (2H, d, J=9Hz), 7.11 (4H, d, J=8Hz), 7.17 (IH, m) , 7.31 (4H, d, J=8Hz), 8.05 (IH, d, J=7Hz), 8.38 (2H, d, J=9Hz), 8.48 (IH, d, J=9Hz)

Example 8

Ethyl 4-[1-[3-[bis(4-isobutylphenyl)methoxy]benzoyl]- imidazo[1,5-a]pyridin-3-y1]butyrate

¹H-NMR (CDC1₃, δ) : 0.87 (12H, d, J=7Hz), 1.26 (3H, t, J=7Hz), 1.83 (2H, m) , 2.17 (2H, m) , 2.42 (4H, d, J=7Hz), 2.53 (2H, t, J=7Hz) , 3.10 (2H, t, J=7Hz), 4.14 (2H, q, J=7Hz), 6.32 (IH, s), 6.88 (IH, dt, J=l, 7Hz), 7.09 (4H, d, J=8Hz), 7.05-7.4 (3H, m), 7.33 (4H, d, J=8Hz), 7.9-8.0 (2H, m), 8.09 (IH, d, J=7Hz), 8.46 (IH, dt, J=8,

1Hz)

Example 9

To a solution of ethyl 4-[l-[4-[bis(4- isobutylphenyl)methylamino]benzoyl]imidazo[1,5-a]pyridin- 3-yl]butyrate (120 mg) in ethanol (5 ml) was added IN sodium hydroxide (0.8 ml). After stirring for 40 minutes, the reaction mixture was evaporated in vacuo. To the residual solution were then added a solution of aqueous potassium dihydrogen phosphate (1 ml) and IN hydrochloric acid (0.8 ml), and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After evaporation of the solvent the residue was chromatographed on silica gel (eluent : ethyl acetate) to give 4-[l-[4- [bis(4-isobutylphenyl)methylamino]benzoyl]imidazo- [1,5-a]pyridin-3-yl]butyric acid (78 mg) .

^• l-N R (CDC1₃, δ) : 0.88 (12H, d, J=7Hz), 1.83 (2H, m), 2.19 (2H, m) , 2.44 (4H, d, J=7Hz), 2.55 (2H, t, J=7Hz), 3.14 (2H, t, J=7Hz), 5.59 (IH, s), 6.59 (2H, d, J=9Hz), 6.83 (IH, t, J=7Hz),

7.05-7.18 (5H, m) , 7.22 (IH, d, J=7Hz), 7.98 (IH, d, J=7Hz), 8.26 (2H, d, J=9Hz), 8.44 (IH, d, J=9Hz)

The compounds described in the following Examples 10 to 15 could be obtained by hydrolyzing the corresponding ethyl ester with aqueous sodium hydroxide in accordance with a similar manner to that of Example 9. Example 10

4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]- imidazo[1,5-a]pyridin-1-yl]butyric acid

^■"^•H-NMR (CDC1₃, δ) : 0.87 (12H, d, J=7Hz), 1.82 (2H, m), 2.13 (2H, m) , 2.42 (4H, d, J=7Hz), 2.48 (2H, t, J=7Hz), 3.03 (2H, t, J=7Hz), 5.56 (IH, s), 6.69 (IH, m), 6.96 (IH, dt, J=l, 7Hz), 7.07 (4H, d, J=8Hz), 7.05-7.3 (2H, m) , 7.27 (4H, d, J=8Hz), 7.53 (IH, m), 7.6-7.7 (2H, m) , 9.75 (IH, d, J=7Hz)

Example 11

4-[3-[4-[Bis(4-isobutylphenyl)methylamino]benzoyl]- imidazo[1,5-a]pyridin-1-yl]butyric acid ^■'^■H-NMR (CDC1₃, δ) : 0.89 (12H, d, J=7Hz), 1.84 (2H, m) , 2.13 (2H, m) , 2.45 (4H, d, J=7Hz), 2.48 (2H, t, J=7Hz), 3.05 (2H, t, J=7Hz), 5.59 (IH, s), 6.59 (2H, d, J=9Hz), 6.90 (IH, dt, J=7, 1Hz), 7.07 (IH, m), 7.10 (4H, d, J=8Hz), 7.23 (4H, d, J=8Hz), 7.60 (IH, dt, J=9, 1Hz), 8.28 (2H, d,

J=9Hz), 9.71 (IH, dt, J=7, 1Hz)

Example 12

4-[3-[3-[Bis-(4-isobutylphenyl)methylamino]benzoyl]- azulen-1-γl]butyric acid

^■ l-NMR (CDC1₃, δ) : 0.85 (12H, d, J=7Hz) , 1.82 (2H, m), 2.05 (2H, m) , 2.40 (2H, t, J=7Hz), 2.42 (4H, d, J=7Hz), 3.06 (2H, t, J=7Hz), 5.51 (IH, s), 6.68 (IH, m), 7.08 (4H, d, J=8Hz), 7.0-7.3 (3H, m), 7.25 (4H, d, J=7Hz), 7.42 (IH, t, J=9Hz) ,

7.51 (IH, t, J=9Hz), 7.78 (IH, t, J=9Hz), 7.92 (IH, s), 8.41 (IH, d, J=9Hz), 9.59 (IH, d, J=9Hz) Example 13

4-[3-[4-[Bis(4-isobutylphenyl)methylamino] enzoyl]- azulen-1-yl]butyric acid

¹H-NMR (CDC1₃, δ) : 0.88 (12H, d, J=7Hz), 1.84 (2H, m), 2.07 (2H, m) , 2.51 (2H, t, J=7Hz), 2.45 (4H, d, J=7Hz), 3.09 (2H, t, J=7Hz), 5.58 (IH, s), 6.58 (2H, d, J=8Hz), 7.11 (4H, d, J=8Hz), 7.23 (4H, d, J=8Hz), 7.35 (IH, t, J=9Hz) , 7.42 (IH, t, J=9Hz), 7.72 (2H, d, J=8Hz), 7.65-7.8 (IH, m), 7.97 (IH, s), 8.39 (IH, d, J=9Hz), 9.40 (IH, d, J=9Hz)

Example 14

4-[1-[4-[Bis(4-isobutylphenyl)methoxy]benzoyl]- imidazo[l,5-a]pyridin-l-yl]butyric acid

¹H-NMR (CDC1₃, δ) : 0.88 (12H, d, J=7Hz), 1.83 (2H, m), 2.18 (2H, m) , 2.43 (4H, d, J=7Hz), 2.56 (2H, t, J=7Hz), 3.11 (2H, t, J=7Hz), 6.28 (IH, s), 6.84 (IH, dt, J=l, 7Hz), 7.04 (2H, d, J=9Hz) , 7.10 (4H, d, J=8Hz), 7.13 (IH, m) , 7.30 (4H, d,

J=8Hz), 7.98 (IH, d, J=7Hz), 8.33 (2H, d, J=9Hz), 8.46 (IH, d, J=9Hz)

Example 15 4-[1-[3-[Bis(4-isobutylphenyl)methoxy]benzoyl]- imidazo[1,5-a]pyridin-3-yl]butyric acid

^•"^■H-NMR (CDC1₃, δ) : 0.85 (12H, d, J=7Hz) , 1.81 (2H, m), 2.19 (2H, m) , 2.41 (4H, d, J=7Hz), 2.57 (2H, t, J=7Hz), 3.11 (2H, t, J=7Hz), 6.29 (IH, s), 6.86 (IH, dt, J=l, 7Hz) , 7.08 (4H, d, J=8Hz),

7.05-7.4 (3H, m), 7.31 (4H, d, J=8Hz), 7.88-7.95 (2H, m), 7.99 (IH, d, J=7Hz), 8.43 (IH, d, J=9Hz) The compounds of the following Examples 16 to ^'24 could be obtained by reacting the corresponding amino or hydroxy compounds with bis(4-isobutylphenyl)chloromethane in accordance with a similar manner to that of Example 1.

Example 16

4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]-4- quinolon-l-yl]butyric acid

¹H-NMR (CDC1₃, δ) : 0.85 (12H, d, J=8Hz), 1.70-1.90 (2H, m), 2.10-2.30 (2H, m) , 2.42 (4H, d, J=8Hz),

2.40-2.50 (2H, m) , 4.25-4.40 (2H, m) , 5.46 (IH, s), 6.80-7.80 (15H, m) , 8.14 (IH, s), 8.46 (IH, d, J=8Hz)

Example 17

4-[3-[4-Bis(4-isobutylphenyl)methylamino]benzoyl]- 4-quinolon-l-yl]butyric acid

^-N R (CDC1₃, δ) : 0.90 (12H, d, J=8Hz), 1.74-1.96 (2H, m), 2.14-2.32 (2H, m) , 2.46 (4H, d, J=8Hz), 2.50 (2H, t, J=8Hz), 4.35-4.50 (2H, m) , 5.63

(IH, s), 6.62 (2H, d, J=14Hz), 7.12 (4H, d, -J=12Hz), 7.22 (4H, d, J=12Hz), 7.5-7.6 (IH, m) , 7.70 (2H, d, J=14Hz), 7.80-7.96 (2H, m) , 8.25 (IH, s), 8.46 (IH, d, J=8Hz)

Example 18

4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]- 2,3-dihydro-2-oxo-lH-benzimidazol-l-yl]butyric acid

^■^- R (CDC1₃, δ) : 0.88 (12H, d, J=8Hz), 1.68-1.92 (2H, m), 2.0-2.18 (2H, m) , 2.02-2.15 (2H, m) ,

2.43 (4H, d, J=8Hz), 2.46 (2H, t, J=8Hz), 3.86 (2H, t, J=8Hz), 5.44 (IH, s), 6.70 (IH, dd, J=l, 8Hz), 7.00-7.30 (14H, m) , 7.82 (IH, dd, J=l, 8Hz) Example 19

4-[3-[4-[Bis(4-isobutylphenyl)metoxγ]benzoyl]-1H- indazo-1-yl]butyric acid

^" t-I-NMR (CDC1₃, δ) : 0.90 (12H, d, J=8Hz) , 1.75-1.96 (2H, m), 2.26-2.45 (4H, m) , 2.46 (4H, d, J=8Hz),

4.56 (2H, t, J=8Hz), 6.28 (IH, s), 7.06 (2H, d, J=9Hz), 7.12 (4H, d, J=8Hz), 7.20-7.50 (7H, m) , 8.30 (2H, d, J=9Hz), 8.42 (IH, d, J=8Hz)

Example 20

4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]- lH-pyrrolo[2,3-b]pyridin-l-yl]butγric acid

^-NMR (CDC1₃, δ) : 0.87 (8H, d, J=8Hz), 1.72-1.95

(2H, m), 2.14-2.28 (2H, m) , 2.38 (2H, t, J=8Hz), 2.42 (4H, d, J=8Hz), 4.36 (2H, t, J=8Hz), 5.51

(IH, s), 6.74 (IH, dd, J=2, 8Hz), 7.0-7.34 (12H, m), 7.60 (IH, s), 8.40 (IH, dd, J=l, 5Hz), 8.68 (IH, dd, J=l, 8Hz)

Example 21

Ethyl 4-[5-[3-[bis(4-isobutylphenyl)methylamino]- benzoyl]thien-2-yl] utyrate

^■"^"H-NMR (CDC1₃, δ) : 0.89 (12H, d, J=7Hz), 1.26 (3H, t, J=7Hz), 1.84 (2H, m) , 2.05 (2H, m) , 2.38 (2H, t, J=7Hz), 2.45 (4H, d, J=7Hz), 2.90 (2H, t,

J=7Hz), 4.15 (2H, q, J=7Hz), 5.48 (IH, s), 6.70 (IH, d, J=4Hz), 6.7-7.7 (13H, m)

Example 22 Ethyl 4-[5-[3-[bis(4-isobutylphenyl)methylamino]- benzoyl]-3-phenylthien-2-yl]butyrate

^XH-NMR (CDC1₃, δ) : 0.88 (12H, d, J=7Hz), 1.21 (3H, t, J=7Hz), 1.7-2.1 (4H, m) , 2.32 (2H, t, J=7Hz), 2.43 (2H, d, J=7Hz), 2.94 (2H, t, J=7Hz), 4.08 (2H, q, J=7Hz), 5.50 (IH, m) , 6.68 (IH, m) , 7. 0-7. 5 ( 16H, m) , 7.53 ( IH, s )

Example 23

4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]- azulen-1-yl]butyric acid

^•'^•H-NMR (CDC1₃, δ) : 0.85 (12H, d, J=7Hz), 1.82 (2H, m), 2.05 (2H, m) , 2.40 (2H, t, J=7Hz), 2.42 (4H, d, J=7Hz), 3.06 (2H, t, J=7Hz) , 5.51 (IH, s), 6.68 (IH, m), 7.08 (4H, d, J=8Hz), 7.0-7.3 (3H, m), 7.25 (4H, d, J=7Hz), 7.42 (IH, t, J=9Hz),

7.51 (IH, t, J=9Hz), 7.78 (IH, t, J=9Hz), 7.92 (IH, s), 8.41 (IH, d, J=9Hz), 9.59 (IH, d, J=9Hz)

Example 24

4-[1-[4-[Bis(4-isobutylphenyl)methoxy]benzoyl]- imidazo[1,5-a]pyridin-1-yl]butyric acid

^■ l-NMR (CDCK, δ) : 0.88 (12H, d, J=7Hz), 1.83 (2H, m) , 2.18 (2H, m) , 2.43 (4H, d, J=7Hz), 2.56 (2H, t, J=7Hz), 3.11 (2H, t, J=7Hz), 6.28 (IH, s) ,

6.84 (IH, dt, J=l, 7Hz), 7.04 (2H, d, J=9Hz), 7.10 (4H, d, J=8Hz), 7.13 (IH, m) , 7.30 (4H, d, J=8Hz), 7.98 (IH, d, J=7Hz), 8.33 (2H, d, J=9Hz), 8.46 (IH, d, J=9Hz)

The compounds of the following Examples 25 to 27 could be obtained by hydrolyzing the corresponding ethyl ester compound with an aqueous sodium hydroxide in accordance with a similar manner to that of Example 9.

Example 25

4-[5-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]- thien-2-yl]butyric acid

^"hl-NMR (CDC1₃, δ) : 0.88 (12H, d, J=7Hz) , 1.83 (2H, m), 2.03 (2H, m) , 2.43 (2H, t, J=7Hz), 2.45 (4H, - -

d, J=7Hz), 2.92 (2H, t, J=7Hz) , 5.50 (IH, s), 6.70 (IH, d, J=4Hz), 6.74 (IH, m) , 6.97 (IH, m) , 7.05-7.3 (11H, m)

Example 26

4-[5-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]-3- phenylthien-2-yl]butyric acid

^■'^'H-NMR (CDC1₃, δ) : 0.87 (12H, d, J=7Hz) , 1.7-2.15 (4H, m), 2.38 (2H, t, J=7Hz), 2.42 (2H., d, J=7Hz), 2.97 (2H, t, J=7Hz) , 5.49 (IH, s) , 6.68

(IH, m), 7.0-7.45 (16H, m) , 7.53 (IH, s)

Example 27

4-[1-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]- imidazo[l,5-a]pyridin-3-yl]butyric acid

¹H-NMR (CDC1₃, δ) : 0.84 (12H, d, J=7Hz), 1.81 (2H, m), 2.18 (2H, m) , 2.52 (4H, d, J=7Hz), 2.54 (2H, t, J=7Hz), 3.10 (2H, t, J=7Hz), 5.52 (IH, s), 6.7-6.9 (2H, m), 7.0-7.85 (10H, m) , 7.6-7.7 (2H, m), 7.98 (IH, d, J=7Hz), 8.40 (IH, d, J=8Hz)

Preparation 48

Methyl 4-[1-(4-hydroxγbenzoyl)imidazo[1,5-a]pyridin-3 yl]butyrate could be obtained in accordance with a similar manner to that of Preparation 19.

¹H-NMR (DMSO-dg, δ) : 2.08 (2H, m) , 2.53 (2H, t,

J=7Hz), 3.10 (2H, t, J=7Hz), 3.58 (3H, s), 6.88 (2H, d, J=9Hz), 7.05 (IH, t, J=7Hz), 7.33 (IH, m) 8.3-8.45 (3H, m) , 8.48 (IH, d, J=7Hz)

Preparation 49

To a solution of 4-acetoxybenzoyl chloride (75 mg) and aluminum chloride (51 mg) in dichloromethane (3 ml) was added a solution of ethyl 4-(azulen-1-yl)butyrate (92 mg) i dichloromethane (2 ml) . Af er stirring at room temperature for 1 hour, the mixture was washed with 7% hydrochloric aci and water, dried over magnesium sulfate and evaporated. Th residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1) to give ethyl 4-[3-(4-acetoxγbenzoyl)azulen-l-yl]butyrate (71 mg) as an oil.

¹H-NMR (CDC1₃, δ) : 9.65 (IH, d, J=9Hz), 8.49 (IH, d, J=9Hz), 7.93 (2H, d, J=10Hz), 7.75-7.9 (2H, m) , 7.4-7.6 (2H, m) , 7.25 (2H, d, J=10Hz), 7.2-7.3 (IH, m), 4.13 (2H, q, J=7Hz), 3.09 (2H, t, J=7Hz)

2.37 (2H, t, J=7Hz), 2.36 (3H, s), 2.0-2.2 (2H, m), 1.24 (3H, t, J=7Hz)

Preparation 50 To a solution of ethyl 4-[3-(4-acetoxybenzoyl)- azulen-1-γl]butyrate (40 mg) in ethanol (1 ml) was added sodium hydride 60% dispersion in mineral oil (5mg). After stirring at room temperature fro 10 minutes, the mixture wa poured into 7% hydrochloric acid and extracted with ethyl acetate (10 ml). The organic layer was washed with water, dried over magnesium sulfate and evaporated to give ethyl 4-[3-(4-hydroxybenzoyl)aculen-l-yl]butγrate (39 mg) as an oil. ¹H-NMR (CDC1₃, δ) : 9.55 (IH, d, J=9Hz) , 8.45 (IH, d

J=9Hz), 7.96 (IH, s), 7.80 (2H, d, J=9Hz), 7.7-7 (IH, m), 7.4-7.6 (2H, m) , 6.93 (2H, d, J=9Hz), 6.50 (IH, brs), 4.13 (2H, q, J=7Hz) , 4.13 (2H, q J=7Hz), 3.10 (2H, t, J=7Hz), 2.40 (2H, t, J=7Hz) 2.0-2.2 (2H, m) , 1.23 (3H, t, J=7Hz)

Example 28

To a mixture of methyl 4-[l-(4-hγdroxγbenzoyl)- imidazo[l,5-a]pyridin-3-yl]butγrate (267 mg) , (R)-l-(4-isobutγlphenγl)butanol (179 mg) and triphenylphosphine (228 mg) in a mixture of tetrahydrofura (1 ml) and toluene (4 ml) was added diethyl azodicarboxyla (0.137 ml) at -20°C. After the mixture was stirred at -20 for 3 hours, acetic acid (0.05 ml) was added and the mixtu was warm up to room temperature. The solvent was evaporat under reduced pressure and the residue was chromatographed on silica gel (n-hexane/ethyl acetate, 3:2) to give methyl (S)-4-[1-[4-[1-(4-isobutylphenyl)butoxy]benzoyl]imidazo- [1,5-a]pyridin-3-yl]butyrate (119 mg) as an oil. ¹H-NMR (CDC1₃, δ) : 0.88 (6H, d, J=6.5Hz) , 0.96 (3H, t, J=7.5Hz), 1.3-2.3 (7H, m) , 2.44 (2H, d, J=6.5Hz), 2.53 (2H, t, J=7Hz) , 3.09 (2H, t, J=7.5Hz), 3.69 (3H, s), 5.19 (IH, dd, J=5Hz, 8Hz 6.8-7.0 (3H, m) , 7.05-7.3 (5H, m) , 8.03 (IH, d, J=7Hz), 8.35 (2H, d, J=9Hz), 8.48 (IH, d, J=9Hz) Example 29

Ethyl (S)-4-[3-[4-[l-(4-isobutylphenγl)butoxy]benzoyl] azulen-1-yl]butyrate could be obtained by reacting the corresponding starting compound with (R)-l-(4-isobutylphenyl)butanol in accordance with a simila manner to that of Example 28.

¹H-NMR (CDC1₃, δ) : 9.49 (IH, d, 9Hz), 8.43 (IH, d, 9Hz), 7.92 (IH, s), 7.75 (2H, d, 9Hz) , 7.7-7.8 (IH, m), 7.3-7.6 (2H, m) , 7.26 (2H, d, 9Hz) , 7.11 (2H, d, 9Hz), 6.92 (2H, d, 9Hz), 5.19 (IH, m) ,

4.11 (2H, q, 7Hz), 3.07 (2H, t, 7Hz) , 2.44 (2H, d 7Hz), 2.38 (2H, t, 7Hz) , 2.0-2.1 (3H, m) , 1.7-2.0 (2H, m), 1.3-1.7 (2H, m) , 1.23 (3H, t, 7Hz), 0.98 (3H, t, 7Hz), 0.89 (6H, d, 7Hz) The compounds described in the following Examples 30 and 31 could be obtained by hydrolyzing the corresponding ethyl ester with aqueous sodium hydroxide in accordance wit a similar manner to that of Example 9.

Example 30

(S)-4-[l-[4-[l-(4-Isobutylphenyl)butoxy]benzoyl]- imidazo[1,5-a]pyridyn-3-yl]butyric acid

¹H-NMR (CDC1₃, δ) : 0.88 (6H, d, J=6.5Hz), 0.96 (3H, t, J=7.5Hz), 1.3-2.3 (7H, m) , 2.43 (2H, d, J=6.5Hz), 2.58 (2H, t, J=7Hz), 3.12 (2H, t,

J=7.5Hz), 5.18 (IH, dd, J=5Hz, 8Hz), 6.8-7.0 (3H, m) , 7.09 (2H, d, J=8.5Hz), 7.15-7.3 (3H, m) , 7.98 (IH, d, J=7Hz), 8.30 (2H, d, J=9Hz), 8.47 (IH, d, J=9Hz)

Example 31

(S)-4-[3-[4-[l-(4-Isobutγlphenyl)butoxy]benzoyl]- azulen-1-yl]butyric acid

^■"^•H-NMR (CDC1₃, δ) : 9.49 (IH, d, J=9Hz), 8.42 (IH, d, J=9Hz), 7.92 (IH, s), 7.75 (2H, d, J=9Hz), 7.7-7.8 (IH, m) , 7.3-7.6 (2H, m), 7.25 (2H, d, J=9Hz) , 7.10 (2H, d, J=9Hz), 6.93 (2H, d, J=9Hz), 5.19 (IH, m) , 3.10 (2H, t, J=7Hz), 2.4-2.5 (4H, m), 2.0-2.2 (3H, m) , 1.7-2.0 (2H, m) , 1.3-1. (2H, m), 0.97 (3H, t, J=7Hz), 0.89 (6H, d, J=7Hz)

Claims

1. A compound of the formula

R¹-A-CO-X-Y-R² (I)

in which R is carboxy(lower)alkyl or protected carboxy(lower)alkyl,

2 R is optionally substituted aralkyl,

X is optionally substituted arylene, „6

Y is -O- or -N- , wherein R is hydrogen, lower alkyl, optionally substituted aralkyl or amino-protective group, and A is a bivalent radical derived from imidazopyridine, azulene, thiophene, pyrrolo[2,

3-b]pyridine, quinolone, indazole or dihydrobenzimidazole, each of which may be substituted by one or more suitable substituent(s) , or a pharmaceutically acceptable salt thereof.

A compound of claim 1, in which

R -A- can be represented by the formula

R- R^~

R^J R^J

R R^J

wherein R is as defined above, and

X is phenylene.

A process for preparing a compound of the formula

R¹-A-CO-X-Y-R² (I)

m which R 1, R2, A, X and Y are each as defined above, or a salt which comprises

(1) reacting a compound of the formula

R -A-CO-X-Y-H (ID

in which R , A, X and Y are each as defined above, or a salt thereof with a compound of the formula :

HO-R" (III) 2 in which R is as defined above, or its reactive derivative at the hydroxy group, or a salt thereof to give the compound (I) , or

(2) removing the carboxy-protective group from a compound of the formula :

R^-A-CO-X-Y-R² (I-a)

in which R is protected carboxy(lower)alkyl, and

R^a2, A, X and Y are each as defined above, or a salt thereof to give a compound of the formula :

e in which R, is carboxy(lower)alkyl, and

R , A, X and Y are each as defined above, or a salt thereof.

4. 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.

5. 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.

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

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

8. 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.