WO2006046683A1

WO2006046683A1 - Thiazolylbenzofuran derivatives as leukotriene and prostaglandin d2 receptor antagonists

Info

Publication number: WO2006046683A1
Application number: PCT/JP2005/019854
Authority: WO
Inventors: Shinji Shigenaga; Koichi Higuchi; Koichiro Mukoyoshi; Daisuke Tanabe; Takayuki Inoue; Kentaro Sato; Yoshiyuki Tenda; Susumu Tsujimoto
Original assignee: Astellas Pharma Inc
Current assignee: Astellas Pharma Inc
Priority date: 2004-10-25
Filing date: 2005-10-24
Publication date: 2006-05-04
Anticipated expiration: 2007-04-25

Abstract

There is provided a compound of the formula (I): wherein R1 is lower alkyl, R2 is lower alkyl substituted with a substituent selected from the group consisting of carboxy and esterified carboxy, and R3 is lower alkoxy substituted with lower alkylcarbamoyl, or a pharmaceutically acceptable salt thereof, which are useful as a medicament.

Description

D E S C R I P T I O N

THIAZOLYLBENZOFURAN DERIVATES AS LEUKOTRIENE AND PROSTAGLANDIN D2

RECEPTOR ANTAGONISTS

Technical Field

This invention relates to a thiazolylbenzofuran derivative anda salt thereof, which is useful as amedicament.

Background Art Some thiazolylbenzofuran derivatives having activities as leukotriene and Slow Reacting Substance of Anaphylaxis (hereinafter referred to as SRSA) antagonists or inhibitors have been known, for example, in International Publication No. WO 97/27190. Additionally, some pyridopyrrolizine and pyridoindolizine derivatives having activites as prostaglandin receptor antagonist, more particularly, prostaglandin D₂ receptor (hereinafter referred to as DP receptor) antagonists have been known, for example, in International Publication No. WO 2004/039807. However, none of the publications specifically disclose the thiazolylbenzofuran derivative and a salt of the present invention.

Disclosure of Invention This invention relates to thiazolylbenzofuran derivatives, whichhaveantagonisticorinhibitoryactivities for both of leukotriene and DP receptors, to a process for their production, to a pharmaceutical composition comprising the same and to a use thereof.

Accordingly, one object of this invention is to provide the thiazolylbenzofuranderivatives, whichhave antagonistic or inhibitory activities for both of leukotriene and DP receptors.

Another object of this invention is to provide a process for production of thiazolylbenzofuran derivatives of the invention.

Another object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, one or more thiazolylbenzofuran derivatives of the invention. Another object of this invention is to provide a use of the compound or the pharmaceutically acceptable salt thereof of this invention for the production of therapeutic agent for allergy and/or inflammation.

Another object of this invention is to provide a method oftreatmentand/orpreventionforallergyand/orinflammation including administering a therapeutically effective amount ofthecompoundorthepharmaceuticallyacceptablesaltthereof of this invention to a patient.

The thiazolylbenzofuran derivatives of this invention can be represented by the following general formula (I):

wherein

R¹ is lower alkyl,

R² is lower alkyl substitutedwith a substituent selected from the group consisting of carboxy and esterified carboxy, and

R³ is loweralkoxy substitutedwithloweralkylcarbamoyl, or pharmaceutically acceptable salts thereof.

Some of the compounds of formula (I) may contain one or more asymmetric centers andthus theycan exist as enantiomers or diastereoisomers. This invention includes both mixtures and separated individual isomers.

The compounds of the formula (I) may also exist in tautomeric forms and the invention includes bothmixtures and separated individual tautomers.

The compounds of the formula (I) and its salts can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate. Also includedinthe scopeof inventionareradiolabelled derivatives of compounds of formula (I) which are suitable for biological studies. In the above and subsequent description of the present specification, suitable examples, of the various definitions to be includedwithin the scope of the invention are explained in detail in the following. The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.

Suitable "lower alkyl" , and lower alkyl moiety in the term "lower alkylcarbamoyl" may be a linear or branched one, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like.

Suitable "lower alkoxy" may be a linear or branched one, such as methoxy, ethoxy, propoxy, isopropoxy (or 1-methylethoxy) ; butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, or the like. Suitable "esterified carboxy" may be lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), substituted or unsubstituted aryloxycarbonyl (e.g. phenoxycarbonyl, naphtyloxycarbonyl, tolyloxyσarbonyl, cumenyloxycarbonyl, xylyloxycarbonyl, etc.), substituted or unsubstituted aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxyσarbonyl, tolylmethoxycarbonyl, etc.) and the like, inwhichpreferable one is lower alkoxycarbonyl and more preferable one is methoxycarbonyl or ethoxycarbonyl.

Suitable "loweralkylcarbamoyl" maybemethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, and. the like, in which preferable one is methylcarbamoyl. Preferred "lower alkyl" for R¹ may be tert-butyl.

Preferred "lower alkyl substituted with a substituent selected from the group consisting of carboxy and esterified carboxy" for R² may be methyl and isopropyl, each of which is substituted with carboxy or methoxycarbonyl. Preferred "lower alkoxy subustituted with lower alkylcarbamoyl" for R³ may be methoxy and isopropoxy, each of which is substituted with methylcarbamoyl.

In addition, the compound of the present invention may form a salt, which is included in the present invention as long as pharmaceutically acceptable. Examples of the salt includeadditionsaltswithamineralacidsuchashydrochloric acid, hydrobromicacid, hydroiodicacid, sulfuricacid, nitric acid , phosphoric acid, and the like, or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonicacid, succinic acid, fumaricacid, maleicacid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like; salts with an inorganic base such as sodium, potassium, magnesium, calcium, and the like; or an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like; and ammonium salts, and the like.

The compounds (I) or its salts are able to be produced in a similarmanner to the processes described in the Examples shown below. In order to illustrate the usefulness of the compounds

(I) of the invention, the pharmacological test data of the representative compound of the compound (I) are shown in the following.

³H-Prostaglandin D₂ receptor binding assay (i) Test Method:

(a) Membrane preparation

Transformedhuman embryonickidney (HEK) 293 cells which stably expressed human DP receptor were homogenized in the sucrose buffer by using ultrasonic homogenizer. The homogenate was centrifuged (300 g, 10 min) to remove tissue clumps andthe supernatantwas centrifuged (100,000g, 30min) .

The pellet was resuspended in the binding buffer and centrifuged again. The obtained pellet was stored at -80⁰C until use. (b) ³H-Prostaglandin D₂ binding to membrane

The pellet of membrane fraction was resuspended in the binding buffer. ³H-Prostaglandin D₂ (1 nM) and various concentrations of the test compound was incubated with 25 μg of the membrane preparation in binding at 4°C for two hours. The test compound was dissolved in dimethyl sulfoxide.

Separation of receptor-bound from free ³H-Prostaglandin D₂ wasachievedbyimmediatefiltrationthroughGF/Bglassfilters using a harvester and washed with ice-cold wash buffer. The radioactivity was determined by a liquid-scintillation counter (PerkinElmerTopCountNXT) . Non-specificbindingwas defined as binding in the presence of 1 pM prostaglandin D₂. (ii) Test Result:

³H-Leukotriene D₄ receptor binding assay (i) Test Method:

(a) Membrane preparation Humanhistiocytic lymphomacells, U973, werehomogenized in sucrose buffer by using ultrasonic homogenizer. The homogenate was centrifuged (300 g, l0 min) to remove tissue clumps andthe supernatantwas centrifuged (100,000 g, 30min) . The pellet was resuspended in binding buffer and centrifuged again. The obtained pellet was stored at -80⁰C until use.

(b) ³H-Leukotriene D₄ binding to membrane

Thepelletofmembranefractionwasresuspendedinbinding buffer. ³H-Leukotriene D₄ (0.4 nM) and test compound was incubated with 25 μg of the membrane preparation in binding at ambient temperature for one hour. The test compound was dissolved in dimethyl sulfoxide. Separation of receptor-bound from free ³H-Leukotriene D₄ is achieved by immediatefiltrationtroughGF/Bglassfiltersusingharvester and washed with ice-cold wash buffer. The radioactivity was determined by a liquid-scintillation counter (PerkinElmer TopCount NXT) . Non-specific binding was defined as binding in the presence of 1 μM leukotriene D₄. (ii) Test Result:

Effects on infiltration of eosinophils in BALF at mouse eosinophilia model (i) Test Method:

Specific pathogen-free male BALB/σ mice were used. Mice were actively sensitized by intraperitoneal injection of 8 μg ovalbumin (OA) with 2 mg aluminum hydroxide hydrate gel suspension on day 0 and day 5. OA-immunized mice were challenged by an intranasal administration of 40 μL of saline containing 12.8 μg OA under pentobarbital sodium anesthesia. Sham-challenged mice were administered saline under the same condition. The compound was dissolved in saline and subcutaneously administrated twice a day on day 12 and day 13. On day 14, bronchoalveolar lavage fluid (BALF) was collected by lavaging whole-lung three times with 0.5 mL aliquots of Ca²⁺ and Mg²⁺ free phosphate buffered saline (PBS) via the tracheal cannula. The BALF was centrifuged, and separated cells were resuspended in PBS. The cells were counted with a hemacytometer and cells were cytocentrifuged ontoaglass slide. CellswerestainedwithHemacolor® (Merck) , andthreehundredcellsweredifferentiatedbylightmicroscopy based on conventional morphological criteria, (ii) Test Result:

Effects on endogenous LT-mediated bronchoconstriction induced by antigen challenge in guinea pigs (i) Test Method:

Male Hartley guinea pigs were passively sensitized by intravenous injection of serum containing homologous anti-ovalbumin IgG. On the following day, the antigen(ovalbumin) was intravenous administered to the animals under treatment with pyrilamine (histamine antagonist), indomethacin (cyclooygenase inhibitor), and propranolol (beta-blocker) , and immediate bronchoconstriction was induced. The compounds were dissolved in saline and administrated subcutaneously at one hour before antigen challenge. The immediate response was measured using a modification of the method of Konzett and Rδssler. (ii) Test Result:

It appeared, fromthe above-mentioned Test Results, that the compound (I) orapharmaceuticallyacceptable salt thereof of the present invention have antagonistic and inhibitory activities for both of leukotriene and DP receptors, and are useful for the treatment and/or prevention of allergy or inflammation inhumanbeings oranimals, andmoreparticularly for prevention and/or treatment of asthma, psoriasis, hepatitis, bronchitis, gastritis, esophagitis, pancreatic, arthritis, nephritis, inflammatoryboweldisease, shock (e.g. septic shock, anaphylactic shock, etc.), arteriosclerosis, myocardial infarction, cerebral vasospasm, rhinitis (e.g. allergic rhinitis, etc.), conjunctivitis, eczema, ischemic cerebral disease, chronic obstructive pulmonary disease, cerebraledema, adult respiratorydistress syndrome, neonatal pulmonary hypertension, Chrohri's disease, dermatitis (e.g. atopic dermatitis, etc.), rheumatism, gastric ulcer, peptic ulcer, gout, sinusitis, food allergy, systemic mastocytosis, urticaria, ulcerative colitis and the like.

For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration. The pharmaceutical preparations may be capsules, tablets including chewable tablets, dragees, granules, suppositories, solution, lotion, inhalant, ophthalmic preparations, collunarium, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of therapeutically effective amount of thecompound (I) willvarydependingupon the age andcondition of each individual patient, an average single dose of about 0.01 rag, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/bpdy and about 1,000 mg/body may be administered per a day.

(Production Methods)

The compound (I) and a salt thereof of the present invention can be prepared by the following processes.

The compound and its pharmaceutically acceptable salt can be prepared by various known synthesis methods, using characteristics based on its basic skeleton or the kinds of functional groups. The representative preparation methods will be explained in detail as below. According to the kinds of functional groups, it is advantageous in some cases in terms of preparation technique to substitute afunctional groupwith a suitable protection group, i.e. , a group that can be easily converted into the functional group, in the step of a preparation of starting material or intermediate. Then, if necessary, the protection group is removed to obtain a desired compound. Examples of the functional group include hydroxy, carboxy, and amino, and examples of the protection group include those described in "Protective Groups in Organic Synthesis ", third edition, edited by Greene and Wuts. It is preferable to suitably use them depending on reaction conditions.

(wherein

R¹ is as defined in the foregoing,

R²¹ is as loweralkyl substitutedwithesterifiedcarboxy, R²² is lower alkyl substituted with carboxy,

R³is loweralkoxysubstitutedwithloweralkylcarbamoyl,

R⁴ is lower alkyl, and

X is lower alkoxy substituted with esterified carboxy)

This is a method for producing the compounds of the invention (I-a) wherein R² in the formula (I) is lower alkyl substituted with carboxy. Starting material (Ia) of this method and related compounds are described in WO 97/27190. In thefirst step, acompound (Ib) canbe obtainedbyhydrolysis of a compound (Ia) . In the second step, the compound of the invention (I-a) canbepreparedby the aminolysis of acompound (Ib) with (Ic).

As hydrolysis reagent for the first step, NaOH aq, KOH aq, and the like can be used. The reaction is carried out in an inert organic solvent such as an alcohol including MeOH, EtOH, andthelike; oraetherincludingtetrahydrofuran (THF) , dioxane, diglyme and the like, under cooling, cooling to ambient temperature, or ambient temperature to heating.

Aminolysis of the second step can be carried out in an inert organic solvent such as an alcohol; an ether; and the like, undercooling, coolingtoambienttemperature, orambient temperaturetoheating. Inthestep, methylester, ethylester, or the like is preferably used as esterified carboxy in "X" of the formula (I) . <Second production method>

(wherein

R¹, R³, R⁴, R²¹, R²²andXareeachasdefinedintheforegoing. Y is lower alkoxy substituted with carboxy. This is a method for producing the compounds of the invention (I-a) wherein R² in the formula (I) is lower alkyl substituted with carboxy, and the compounds of the invention (I-b) wherein R² in the formula (I) is lower alkyl substituted with esterified carboxy. In the first step, the esterified carboxy for X of (Ia) can be deprotected with a common method to produce (Ie). In the second step, the compound (I-b) is obtained in amidation of a compound (Ic) with (Ie). In the third step, the compound of the invention (I-a) is obtained inasimilarmannerto thefirst stepinFirstproductionmethod from the compound of the invention (I-b).

The deprotection of the first step can be carried out in an inert organic solvent such as a halogenated hydrocarbon including dichloromethane, dichloroethane, chloroform and the like,- an aromatic hydrocarbon including benzene, toluene, xylene and the like; an ether including diethylether, THF, dioxane, diglyme and the like; an ester including ethyl acetate; N,N-dimethylformamide (DMF); dimethylsulfoxide (DMSO); and the like, under cooling, cooling to ambient temperature, or ambient temperature to heating. As a common method of the deprotection in the step, hydrogenolysis catalysedbyPalladiumoncarbon, hydrolysiswith strong acid, and the like can be exemplified as well as the method described in the first step in the First product method.

In the second step, it is preferable to carry out the reaction using a condensing agent such as dicylcohexylcarbodiimide, carbonyldiimidazole, diphenylphosphorylazide, diethylphosphorylcyanide, or 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) , andphosphorous oxychlorideinpyridine solvent, orthelike. Inthestep, althoughitvariesdepending on the reactive derivatives or condensing agent, similar condition (solvent and temperature) can be applicable to the steps of the First production method. In order to progress the reaction smoothly, it is advantageous in some cases to employ an excess amount of the compound (Ic) or carry out the reaction in the presence of a base such as N-methylmorpholine, trimethylamine, triethylamine, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine, and the like. And, a salt consisting of a strong acid and weak base suchas pyridinehydrochloride, pyridine p-toluenesulfonate, N,N-dimethylaniline hydrochloride and the like can be used. Pyridine can also be used as a solvent. The hydrolysis of the third step can be carried out in accordance with the steps of the first production method. In the above and subsequent description of the present specification, the following abbreviations and acronyms mean ones as shown in the following table.

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

Methyl (5- (benzyloxy)-l-{ [2-(4-tert-butyl~l,3~ thiazol-2-yl) -1-benzofuran-5-yl]methyl}-IH-indol-3-yl) acetate (0.5g) was dissolved in TFA (4.78 ml) at 0 ⁰C under nitrogen atmosphere. Then thioanisole (0.364 ml) was added to the solution at 0 ⁰C. The reaction mixture was stirred at ambient temperature for 4 hr, and concentrated in vacuo. The residue was neutralized with NaHCO₃ aq, and the whole was extracted with EtOAc. The extract was dried over MgSO₄ and evaporated in vacuo. The resulting precipitates were purifiedby column chromatography on silica gel with amixture of tolueneandEtOAc (10:1-4:1). Theobjectivefractionswere collected and evaporated to give a solid of methyl(l-{ [2- (4-tert-butyl-1,3-thiazol-2-yl) -1-benzofuran-5-yl] methyl}-5-hydroxy-lH-indol-3-yl)acetate (415 mg) . NMR(CDCl₃,d):1.40(9H,s),3.69(3H,s),3.71(2H,s),4.95(lH,s), 5.30(2H,s) ,6.74(IH,dd,J=2.4,9.OHz),6.97(lH,s),7.02(lH,d,J =2.4Hz) ,7.10-7-25(4H,m) ,7.33(IH,d,J=I.OHz) ,7.44(IH,d,J=8. 4Hz), MASS(API-ES) ;473(M-H)^" The following compound was obtained in a similar manner to that of Preparation 1. Preparation 2

Ethyl 2-(l-{[2-(4-tert-butyl-l,3-thiazol-2-yl)-l- benzofuran-5-yl]methyl}-5-hydroxy-IH-indol-3-yl)-2- methylpropanoate

NMR(CDCl₃,d) :1.16(3H,t,J=7.2Hz) ,1.40(9H,s) , 1.64(6H,s) ,4.1 2(2H,q,J=7.2Hz),5.06(lH,s),5.31(2H,s) ,6.73(lH,dd,J=2.3,8. 7Hz) ,6.99(IH,s) ,6.98(IH,d,J=2.3Hz) ,7.11(IH,s) ,7.09(IH,dd, J=1.0,8.6Hz) ,7.12(IH,d,J=I.OHz),7.26(lH,s),7.31(lH,d,J=l. OHz) ,7.45(lH,d,J=8.5Hz) . MASS(API-ES) :515(M-H)^~. Preparation 3

Amixtureofmethyl (1~{ [2-(4-tert-butyl-l,3-thiazol-2- yl)-l-benzofuran-5-yl.methyl}-5-hydroxy-lH-indol-3-yl) acetate (1.2 g) , K₂CO₃ (1.4 g) , 2-bromo-2-methypropionic acid allyl ester (1.01 ml) , andKI (84 mg) in DMF (20 ml) was stirred at 60 °C for 5 hr. After cooling to ambient temperature the reaction mixture was poured into ice water and the whole was stirred at ambient temperature for 1 hr and extracted with EtOAc by three times. The combined extract was washed with brine and dried over Na₂SO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and EtOAc (10:1). The objective fractions were collected and evaporated to give a syrup of allyl 2-{[l-{[2-(4-tert-butyl-l,3-thiazol-2-yl)-l~ benzofuran-5-yl]methyl}-3-(2-methoxy-2-oxoethyl)-lH- indol-5-yl]oxy}- 2-methylpropanoate (650 mg) . NMR(CDCl₃,d);1.40(9H,s) ,1.58(6H,s) ,3.70(3H,s) ,3.71(2H,s) , 4.65-4.70(2H,m) ,5.23(IH,dd,J=I.2,10.3Hz) ,5.35(IH,dd,J=I.4 ,16.8Hz) ,5.30(2H,s) ,5.80-6.05(lH,m) ,6.83(IH,dd,J=2.2,8.9H z) ,6.97(lH,s) ,7.11-7.22(4H,m) ,7.26(lH,s) ,7.38(lH,d,J=O.9H z) , 7.48(lH,d,J=8.5Hz) . MASS(API+ES) ;623(M+Na)⁺

The following compound was obtained in a similar manner to that of Preparation 3. Preparation 4

Ethyl 2-(5- [2-(benzyloxy)-2-oxoethoxy]-l-{[2-(4-tert- butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl]methyl}-IH- indol-3-yl) -2-methylpropanoate

NMR(CDCl₃,d):1.15(3H,t,J=7.2Hz),1.40(9H,s),1.64(6H,s),4.1

0(2H,q,J=7.2Hz),4.68(2H,s),5.25(2H,s),5.33(2H,s),6.87(lH, dd,J=2.1,8.8Hz) ,6.98(IH,s) ,7.00(IH,S) ,7.12-7.27(1OH,m) ,7.

46(lH,d,J=8.5Hz) .

Mass(APCI+ES) ;687(M+Na)⁺

Preparation 5

Amixture of allyl 2- { [ l- { [ 2- ( 4-tert-butyl- l , 3-thiazol- 2-yl ) - l-benzofuran- 5-yl ] methyl} -3- ( 2 -methoxy-2-oxoethyl ) - lH-indol-5-yl]oxy}-2-methylpropanoate (620 mg) , tetrakis

(triphenyl-phosphine)palladium (119 mg) andmorpholine (0.54 ml) in THF (30 ml) was stirred at ambient temperature for 0.5 hr. After removal of solvent by evaporation the residue was partitioned between diluted HCl aq and EtOAc. The organic layerwas separated, dried over MgSO₄ and evaporated in vacuo.

The residue was purified by column chromatography on silica gel with a mixture of dichloromethane and MeOH (40:1-4:1).

The objective fractions were collected and evaporated to give 2-{ [l-{ [2-(4-tert-butyl-l,3-thiazol-2-yl) -1-benzofuran-5- yl]methyl}-3-(2-methoxy-2-oxoethyl)-IH-indol-5-yl]oxy}-2- methylpropanoic acid (550 mg) .

Preparation 6

To a solution of ethyl 2-(5- [2-(benzyloxy)-2- oxoethoxy]-l-{ [2-(4-tert-butyl-l,3-thiazol-2-yl) -1- benzofuran-5-yl]methyl}-IH-indol-3-yl)-2-methylpropanoate (120 mg) in MeOH (5 ml) was added 10% Pd/C (18 mg) , and the mixturewashydrogenatedwith3atmospherichydrogenatambient temperaturefor3hr. Themixturewas filteredandthefiltrate was evaporated in vacuo to give { [l-{ [2-(4-tert-butyl-l,3- thiazol-2-yl) -1-benzofuran-5-yl]methyl}-3-(2-ethoxy-1,1- dimethyl-2- oxoethyl) -lH-indol-5-yl]oxy}aceticacid (45mg) . Mass(APCI-ES) ;586(M-H)^~ Preparation 7

To an ice-cooling suspension of methyl 2-[ (l-{ [2-(4- tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl]methyl}-3- formyl- lH-indol-5-yl)oxy] -2-methylpropanoate (0.3 g) and4- (diethoxyphosphoryl) - but-2-enoicacidethylester (0.188ml) in THF (6 ml) was added NaH (60% in mineral oil, 56.5 mg) by small portions over 10 min. The whole was stirred at ambient temperatureovernight andthe reactionmixturewas pouredinto ice-cooled diluted HCl aq and the whole was extracted with EtOAc. The extract was dried over MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and EtOAc (20:1). The objective fractions were collected and evaporated to give a mixture mainly containing ethyl (2E,4E)-5-[l-{ [2-(4-tert- butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl]methyl}-5- (2- methoxy-1,1-dimethyl-2-oxoethoxy) -IH-indol-3-yl]-2,4- pentadienoate. The compound was used to next step without further purification.

MASS(APCI+ES) ;649(M+Na)⁺ Preparation 8

Amixture of methyl 2- [ (3-formyl-lH-indol-5-yl)oxy] -2- methylpropanoate (1.68 g) , 4-tert-butyl-2- (5-chloromethyl- benzofuran-2-yl)thiazole (1.97 g) andK₂CO₃ (2.67 g) inDMF(50 ml) was stirred at ambient temperature for 15 hr. The mixture was poured into water and the resulting precipitates were collected by filtration. The precipitates were purified by column chromatography on silica gel with a mixture of toluene and EtOAc (4:1) . The objective fractions were collected and evaporatedto give a solidofmethyl 2-[ (l-{ [2- (4-tert-butyl- l,3-thiazol-2-yl)-l-benzofuran-5-yl]methyl}-3-formyl-lH- indol-5-yl)oxy]-2-methylpropanoate (3.2 g) . NMR(CDCl₃,d) :1.40(9H,s) , 1.60(6H,S) ,3.84(3H,S) ,5.37(2H,s) , 6.92(lH,dd,J=2.1,8.8Hz),6.99(lH,s),7.12-7.27(3H,m),7.41 (IH,d,J=I.4Hz) ,7.52(lH,d,J=8.5Hz) ,7.66(IH,s) ,7.83(IH,d,J=

2.2Hz) ,9.93(lH;s) . , Mass(APCI+ES);553(M+Na)⁺ Preparation 9

To an ice cooling DMF(IO ml) was added dropwise POCl₃ (1.44 ml) at 5-8⁰C over 30 min. The mixture was stirred at same temperature for 30 min and thereto was added dropwise asolutionofmethyl2-(lH-indol-5-yloxy)-2-methylpropanoate (2.4g) in DMF (10 ml) over 10 min. After addition the whole was warmed to 35-40⁰C and stirred for 1 hr. The mixture was poured into ice water and thereto NaHCO₃ aq was added. The whole was stirred at ambient temperature overnight and extractedwithEtOAc. Theextractwas^'washedwithbrine, dried over MgSO₄ and evaporated in vacuo. The residue was purified bycolumnchromatographyonsilicagelwithamixtureoftoluene and EtOAc (5:1) . The objective fractions were collected and evaporated to give a solid of methyl 2-[ (3-formyl-lH-indol- 5-yl)oxy]-2-methylpropanoate (1.88 g) .

NMR(CDCl₃,d) :1.60(6H,s) ,3.85(3H,s) ,6.92(IH,dd,J=2.4,8.8Hz ) ,7.27(lH,d,J=8.8Hz) ,7.78(IH,d,J=3.OHz) ,7.80(IH,d,J=2.4Hz ) ,9.35(1H,S) ,9.98(lH,s) . Preparation 10

To an ice-cooling suspension of methyl 2-[(l-{[2- (4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl] methyl}-3-formyl-IH-indol-5-yl)oxy]-2-methylpropanoate (0.61 g) and (diethoxyphosphoryl)acetic acid ethyl ester (0.276 ml) in THF (6 ml) was added NaH (60% in mineral oil, 84.3 mg) by small portions over 10 min. The whole was stirred at ambient temperature overnight and the reaction mixture was poured into ice-cooled diluted HCl aq and the whole was extracted with EtOAc. The extract was dried over MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and EtOAc (20:1) to give a syrup of ethyl (2E)-3-[l-{ [2-(4-tert- butyl-1,3-thiazol-2-yl) -1-benzofuran-5-yl]methyl}-5-(2- methoxy-1,1-dimethyl-2-oxoethoxy) -lH-indol-3-yl]acrylate (0.464 g).

NMR( CDCl₃ , d) : 1 . 34 ( 3H , t , J=7 . 2Hz ) , 1 . 40 ( 9H , S ) , 1 . 60 ( 6H, s ) , 3 . 8 4(3H,s) ,4.25(2H,q,J=7.2Hz) ,5.35,(2H,s) ,6.35(IH,d,J=16.OHz) ,6.87(lH,dd,J=2.1,8.8Hz) ,6.98(IH,s) ,7.12-7.27(3H,m) ,7.39 (2H,s) ,7.44(IH,d,J=I.3Hz) ,7.49(IH,d,J=8.5Hz) ,7.84(IH,d,J= 16.0Hz). Mass(APCI+ES);623(M+Na)⁺ Preparation 11

Ethyl (2E)-3-[l-{[2-(4-tert-butyl-l,3-thiazol-2~ yl) -1-benzofuran-5-yl]methyl}-5-(2-methoxy-1,1-dimethyl- 2-oxoethoxy)-lH-indol-3-yl]acrylate (0.32 g) was dissolved into 40%methylamine inMeOH (12ml) , andthemixturewas sealed and stood at ambient temperature overnight. After removal of solvent byevaporation, theresiduewas partitionedbetween diluted HCl aq and dichloromethane. The organic layer was separated, dried over MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and EtOAc (4:1-1:1) to give a syrup of ethyl (2E)-3-{l-{ [2-(4-tert-butyl-l,3-thiazol-2-yl)-1- benzofuran-5-yl]methyl}-5- [1,1-dimethyl-2-(methylamino)- 2-oxoethoxy] -lH-indol-3-yl}acrylate (0.25 g) . NMR(CDCl₃,d):1.34(3H,t.J=7.2Hz),1.40(9H,s),1.50(6H,s) ,2.9 2(3H,d,J=5.0Hz) ,4.26(2H,q,J=7.2Hz) ,5.38(2H,s) ,6.32(IH,d,J =16.OHz) ,6.91(lH,dd,J=2.1,8.8Hz) ,6.99(IH,s) ,7.12-7.27(4H, m) ,7.40(IH,d,J=I.3Hz) ,7.46(IH,d,J=9..OHz) ,7.52(IH,d,J=8.5. Hz) ,7.85(lH,d,J=16.0Hz) . Mass(APCI+ES);;622(M+Na)⁺ Preparation 12 To an ice coolingmixture of 5-benzyloxy-lH-indole(2 g) , acetone(8.96 ml) and powdered NaOH (1.97 g) was added chloroform (0.939 ml) dropwise over 30 min at 2-5 ⁰C. The whole was stirred under reflux for 3 hr. After cooling to ambient temperature the mixture was poured into ice water. The whole was made acidic with diluted HCl aq and ex-tracted with EtOAc. The extract was dried over MgSO₄ and evaporated in vacuo. The resulting residue was dissolved into a mixture of EtOH (20 ml) and H₂SO₄ (0.2 ml) , and the mixture was stirred under reflux overnight. After removal of solvent by- evaporation, theresiduewaspurifiedbycolumnchromatography on silica gel with a mixture of toluene and EtOAc (1:1) . The objective fractions were collected and evaporated to give a syrup of ethyl 2- [5~(benzyloxy) -lH-indol-3-yl]-2- methylpropanoate (0.5g) . Mass(API+ES) ;360(M+Na)⁺ Preparation 13

To an ice cooling solution of ethyl 2-[5-(benzyloxy)-IH- indol-3-yl]-2-methylpropanoate (0.32g) inTHF (3ml) wasadded NaH (70mg, 60% inmineral oil) undernitrogen flow. Thewhole was stirred for 15 min at same temperature and thereto 4-tert- butyl-2-(5-chloromethyl-benzofuran-2-yl)thiazole (353 mg) was added and the whole was stirred at 65⁰C for 5 hr. After cooling to ambient temperature the mixture was poured into water 50 ml, and extractedwith EtOAc. The extract was washed with brine, dried over MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel withamixtureofn-hexaneandEtOAc (20:1-4:1) . Theobjective fractions were collected and evaporated to give a syrup of ethyl 2-[5-(benzyloxy)-l-{[2-(4-tert-butyl-l,3-thiazol-2- yl)-l-benzofuran-5-yl]methyl}-lH-indol-3-yl] -2- methylpropanoate (250 mg) .

NMR(CDCl₃,d) :1.16(3H,t,J=7.2Hz) , 1.40(9H,s)_. ,1.65(6H,s) ,4.0 8(2H,q,J=7.2 Hz) ,5.09(2H,s) ,5.32(2H,s) ,6.88(IH,dd,J=2.3, 8.8Hz) , 6.97(IH,s) ,7.00(lH,s) ,7.06-7.25(HH,m) . MASS(API+ES);629(M+Na)⁺ Preparation 14

To an ice cooling suspension of {5-benzyloxy-l- [2- 4-tert-butyl-thiazol-2-yl)benzofuran-5-ylmethyl]-IH- indol-3-yl}- acetic acid (5.6 g) and K₂CO₃ (2.81 g) in DMF(30 ml) was added methyl iodide (0.95 ml) . The whole was stirred for 2 hr at ambient temperature and poured into water, and the resulting precipitates were collected by filtration and washedwithwater. Thecrudeprecipitatesweredissolvedinto dichloromethane, and the solution was dried over MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and EtOAc (9:1). The objective fractions were collected and evaporated to give crystals of methyl (5-(benzyloxy)-l-{ [2- (4-tert-butyl-l,3-thiazol-2-yl) -1-benzofuran-5-yl] methyl}-lH-indol-3-yl)acetate (4.67 g) .

NMR(CDCl₃,d) :1.40(9H,s),3.68(3H,s) ,^'3.74(2H,s) ,5.11(2H,s) , 5.33(2H,s) , 6.92(lH,dd,J=2.2,8.9Hz) , 6.97 ( IH, s) , 7.11-7.48 (12H,m).

MASS(API+ES) ;587(M+Na)⁺. Preparation 15 Amixtureof5-benzyloxy-IH-indole (5.Ig) and10%Pd(OH)₂ on carbon 1.2 g in MeOH (50 ml) was hydrogenated with 3 atmospheric hydrogen at ambient temperature for 4 hr. After removal of catalyst by filtration the filtrate was evaporated in vacuo. The residue was dissolved in DMF (50 ml) , and thereto were added K₂CO₃ (6.32 g) , KI (758 mg) and methyl 2-bromo-2- methylpropionate(6.22 ml), and the whole was stirred at 55 ⁰C for 15 hr. Additional K₂CO₃ (1.44g) and methyl 2-bromo- 2-methylpropionate (1.3 ml) were added to the mixture, and the whole was further stirred at 67⁰C for 15 hr. The reaction mixture was poured into water and extracted with EtOAc. The extract was washedwith brine, dried over MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and EtOAc (5:1) . The objective fractions were collected and evaporated to give a syrup of methyl 2-(lH-indol-5-yloxy)-2-methylpropanoate (4.25 g).

NMR(CDCl₃,d) :1.57(6H,s),3.81(3H,s) ,6.45(IH,d,J=2.8Hz) ,6.8 4 (lH,dd,J=2.8,8.8Hz) ,7.12-7.27(3H,m) ,8.11(lH,brs) . Example 1 To a solution of {1-[2-(4-tert-butyl-l,3-thiazol-2-yl) -1-benzofuran-5-ylmethyl] -3-methoxycarbonylmethyl-IH- indol-5- yloxy}aceticacid (30mg) , methylaminehydrochloride (4.18 mg) , EDCI (11.8 mg) andHOBt (8.37 mg) in dichloromethane (1 ml) was added diisopropylethylamine (0.01 ml). After stirring for 3 hr at ambient temperature. The mixture was washed with diluted HCl aq and dried over MgSO₄ and evaporated in vacuo. The residue was purified by preparative silica TLC with developing with a mixture of toluene and EtOAc to give a syrup of methyl {1- [2-(4-tert-butyl-l,3-thiazol~2-yl) -1- benzofuran-5-ylmethyl] -5-methylcarbamoylmethoxy-IH-indol- 3-yl}acetate (23 mg) .

Mass(API+ES);568(M+Na)⁺.

The ester obtained by above procedure was dissolved into MeOH (0.6 ml) and thereto IM NaOH aq (0.066 ml) and the whole was stirred for 2 days and evaporated. The residue was partitioned between diluted HCl aq and EtOAc. The organic layer was separated, died over MgSO₄ and evaporated in vacuo. The residue was purified by preparative silica TLC with developing with a mixture of dichloromethane and MeOH (10:1) to give a solid of {l-{ [2-(4-tert-butyl-l,3-thiazol-2-yl) - l-benzofuran-5~yl]methyl}-5- [2- (methylamino) -2- oxoethoxy] -lH-indol-3-yl}acetic acid (3 mg) . NMR(CDCl₃,d):1.41(9H,s),2.91(3H,d,J=4.9Hz),3.77(2H,s),4.5 4(2H,s),5.33(2H,s) ,6.75(lH,m) ,6.83(IH,dd,J=2.4,8.8Hz) ,6.9 8(lH,s),7.08-7.20(4H,m) ,7.43(2H,brs) ,7.45(IH,d,J=8.4Hz.) MASS(API-ES) ,-530(M-H)^"

The following compound was obtained in a similar manner to that of Example 1. Example 2

2-{l-{[2-(4-tert-Butyl-1,3-thiazol-2-yl)-1-benzofuran-5- yl]methyl}-5-[2-(methylamino) -2-oxoethoxy]-IH-indol-3- yl}-2-methylpropanoic acid Mass(API-ES); 558(M-H)^' Example 3

To an ice cooling solution of 2-{ [l-{ [2-(4-tert-butyl- 1,3-thiazol-2-yl) -1-benzofuran-5-yl]methyl}-3-(2-methoxy- 2-oxoethyl)-lH-indol-5-yl]oxy}-2-methylpropanoic acid (550 mg) , methyl amine hydrochloride (234 mg) and O-(7- azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (451 mg) in dichloromethane (2 ml) was added diisopropylethylamine (1.72 ml) at 0 °C. The mixture was stirred at same temperature for 30 min and followed by ambient temperature for 1 hr. The mixture was washed with diluted HCl aq by 2 times, dried over MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and EtOAc (4:1-1:1) . The objective fractions were collected and evaporated to give a syrup of methyl {l-{ [2-(4-tert-butyl-l,3-thiazol-2-yl) -1- benzofuran-5-yl]methyl}-5- [1, l-dimethyl-2- (methylamino) - 2-oxoethoxy]-lH-indol-3-yl}acetate (477 mg) . NMR(CDCl₃,d):1.40(9H,s),1.48(6H,s),2.90(3H,d,J=5.0Hz),3.7 l(3H,s) ,3.73(2H,s) ,5.34(2H,s) ,6.82(IH,dd,J=2.2,8.9Hz) ,6.9 8(IH,s),7.00-7.10(IH,m),7.11-7.22(4H,m),7.26(IH,s),7.38 (IH,d,J=1.OHz) ,7.48(IH,d,J=8.5Hz) MASS(API+ES) ;596(M+Na)⁺ Example 4

To a solution of methyl (l-{ [2-(4-tert-butyl-l,3- thiazol-2-yl)-l-benzofuran-5-yl]methyl}-5-[l,l-dimethyl- 2-(methylamino)-2-oxoethoxy] -IH-indol-3-yl)acetate (470 mg) inMeOH (5ml) wasaddedIMNaOHaq (1.64ml) . Afterstirring at ambient temperature for 5 hr the mixture was evaporated. The residue was dissolved into water and filtered. The filtrate was made acidic with diluted HCl aq. The resulting precipitates were collected, washed with water and dried in vacuo (50 ⁰C, 2 hr) to give a solid of {l-{ [2-(4-tert- butyl-1,3-thiazol-2-yl)-l-benzofuran-5-yl]methyl}-5-[l,l- dimethyl-2-(methylamino)-2-oxoethoxy] -lH-indol-3-yl} acetic acid (425 mg) .

NMR(DMSO-d₆,d) :1.46(15H,s) ,2.65(3H,d,J=4.6Hz) ,3.60(2H,s) ,

,5.44(2H,s) ,6.77(lH,dd,J=2.2,8.9Hz) ,7.06(IH,d,J=2.2Hz) ,7.3

1(IH,dd,J=1.6and8.6Hz) ,7.40(IH,d,J=8.9Hz),7.42(lH,s),7.47

(IH,s) ,7.50(IH,s) ,7.63(IH,s) ,7.65(IH,d,J=8.5Hz) ,8.01-8.04 (lH,m).

MASS(API-ES); 558(M-H)^" Example 5

Ethyl (2E,4E)-5-[l-{[2-(4-tert-butyl-l,3-thiazol-2- yl) -1-benzofuran-5-yl]methyl}-5- (2-methoxy-1,1-dimethyl- 2-oxoethoxy)-lH-indol-3-yl]-2,4-pentadienoate (260 mg) was dissolvedinto 40%methylamine inMeOH (10ml) , andthemixture was sealed and stood at ambient temperature overnight. After removal of solvent byevaporation, theresiduewas partitioned betweendilutedHClaqanddichloromethane. Theorganiclayer was separated, dried over MgSO₄ and evaporated in vacuo. The residue was dissolved into MeOH (5 ml) and thereto was added 10% Pd/C (10 mg) . Thewholewas hydrogenatedwithatmospheric hydrogen at ambient temperature for 4 h. After removal of catalyst by filtration the filtrate was evaporated. The residue was purified by column chromatography on silica gel with a mixture of toluene and EtOAc (4:1-1:1) . The objective fractions were collected and evaporated to give a syrup of ethyl 5-{l-{[2-(4-tert~butyl-l,3-thiazol-2-yl)-l- benzofuran-5-yl] methyl}-5- [1,1-dimethyl-2-(methylamino)- 2-oxoethoxy] -lH-indol-3-yl} pentanoate (75 mg) . The ester was dissolved into a mixture of THF(I ml) and MeOH(I ml) and thereto was added IMNaOH aq (0.6 ml) and the whole was stirred for 5 hr and evaporated in vacuo. The residue was dissolved into water (5 ml) and the solutionwas made acidic with diluted HCl aq. The resulting precipitates were collected, washed with water and dried in vacuo to give a solid of

5-{l-{[2-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran- 5-yl]methyl}-5- [1,1- dimethyl-2- (methylamino) -2- oxoethoxy] -lH-indol-3-yl} pentanoic acid (50 mg) . NMR(CDCl₃,d) :1.41(9H,s),1.49(6H,s),1.70-1.80(4H,m) ,2.35-2 .40(2H,m) ,2.70-2.76(2H,m) ,2.90(3H,d,J=5.OHz) ,5.31(2H,s) ,6 .79(lH,dd,J=2.3,8.8Hz),6.98(lH,s),7.06-7.25(5H,m),7.32 ( lH , s ) , 7 . 46 ( lH , d , J=8 . 5Hz ) . MASS (APCI -ES ) ; 600 (M-H) ^~ Example 6

Ethyl (2E)-3-{l-{[2-(4-tert-butyl-l,3-thiazol-2-yl)- 1-benzofuran-5-yl]methyl}-5-[1,1-dimethyl-2-(methylamino) -2-oxoethoxy] -lH-indol-3-yl}acrylate (0.24 g) was dissolved into MeOH (5 ml) and thereto was added 10% Pd/C (100 mg) . The whole was hydrogenated with atmospheric hydrogen at ambient temperature for 5 hr. After removal of catalyst byfiltration thefiltratewas evaporatedinvacuo. Theresiduewaspurified bycolumnchromatographyonsilicagelwithamixtureoftoluene and EtOAc(4: 1-1: 1) . The objective fractions were collected and evaporated to give a syrup of ethyl 3-{l-{ [2-(4-tert- butyl-1,3-thiazol-2-yl) -1-benzofuran-5-yl]methyl}-5- [1, 1- dimethyl-2-(methylamino) -2-oxoethoxy] -lH-indol-3-yl} propanoate (0.25 g) .

NMR(CDCl₃,d) :1.20(3H,t,J=7.2Hz),1.40(9H,s),1.62(6H,s) ,2.6 8(2H,tlike) ,2.91(3H,d,J=5.OHz) ,3.05(2H,tlike) ,4.11(2H,q,J =7.2Hz) ,5.32(2H,s) ,6.82(IH,dd,J=2.3,8.8Hz) ,6.97(IH,s) ,6.9 8(IH,s) ,7.04(lH,brs) ,7.13(IH,dd,J=I.1,8.5Hz)7.15-7.25(3H, m) ,7.34(IH,d,J=I.IHz) ,7.47(IH,d,J=8.5Hz) . MASS(APCI+ES);624(M+Na)⁺ Example 7

Ethyl 3-{l-{[2-(4-tert-butyl-l,3-thiazol-2-yl)-l- benzofuran-5-yl]methyl}-5-[1,l-dimethyl-2-(methylamino)- 2-oxoethoxy] -lH-indol-3-yl}propanoate (0.24g) wasdissolved into EtOH (3 ml), and thereto was added IM NaOH aq (3 ml), the whole was stirred at 55⁰C for 2.5 hr. After removal of solvent by evaporation the residue was dissolved into water (5 ml) and the solution was made acidic with diluted HCl aq. The resulting precipitates were collected, washed with water and dried in vacuo to give a solid of 3-{l-{ [2-(4-tert-butyl- l,3~thiazol-2-yl)-l-benzofuran-5-yl]methyl}-5-[l,l- dimethyl-2-(methylamino)-2-oxoethoxy] -lH-indol-3-yl} propanoic acid (0.17 g) . NMR(DMSO-d₆,d) :1.34(15H,s) ,2.56(2H,t,J=7.9Hz) ,2.66(2H,d,J =5.2Hz) ,2.88(2H,t,J=7.9Hz) ,5.41(2H,s) ,6.75(IH,dd,J=2.2, 8.9Hz) ,7.06(lH,d,J=2.2Hz) ,7.28(IH,dd,J=I.6,8.6Hz) ,7.31(IH ,s) ,7.36(lH,d,J=8.9Hz) ,7.46(lH,s) ,7.49(IH,d,J=O.6Hz) ,7.57 (IH,d,J=I.6Hz) ,7.63(lH,d,J=8.5Hz) ,8.03-8.06(IH,m) ,12.00- 13.00(lH,br) .

MASS(APCI-ESI) ,-572(M-H)^" Example 8

(1-{ [2-(4-tert-Butyl-1,3-thiazol-2-yl) -1-benzofuran- 5-yl]methyl}-5-[1,l-dimethyl-2-(methylamino)-2-oxoethoxy] -lH-indol-3-yl)acetic acid (20 g) was dissolved into IM NaOH aq (35.73 ml). After dissolved complelety the solution was evaporated in vacuo and the residue was powdered dried in air overnight to give powders of sodium (l-{ [2-(4-tert-butyl -1,3-thiazol-2-yl)-1-benzofuran-5-yl]methyl}-5-[1,1- dimethyl-2-(methylamino)-2-oxoethoxy]-lH-indol-3-yl) acetate (22.2 g) . NMR(DMSO-d₆,d) : 1.33(6H,s) , 1.35(9H,s) ,2.66(3H,d,J=4.6Hz) ,3 .20(2H,s) ,5.38(2H,s) ,6.70(IH,dd,J=2.2,8.8Hz) ,7.12(IH,d,J= 2.2Hz) ,7.28-7.32(2H,m) ,7.47(IH,s) ,7.49(IH,s) ,7.61(IH,s) ,7 .63(lH,d,J=8.8Hz),8.00-8.03(lH,m) MASS(API-ES);560(M-H)^" (as free foam)

Claims

C L A I M S

1. Athiazolylbenzofurancompoundrepresentedbythe formula

wherein

R¹ is lower alkyl,

R² is lower alkyl substituted with a substituent selected from the group consisting of carboxy and esterified carboxy, and

R³ is lower alkoxy substituted with lower alkylcarbamoyl, or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1, wherein R¹ is tert-butyl,

R² is lower alkyl substituted with a substituent selected from the group consisting of carboxy and esterified carboxy, and R³ is lower alkoxy substituted with methylcarbamoyl, or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 2, which is (l-{ [2-(4-tert-butyl- 1,3-thiazol-2-yl)-1-benzofuran-5-yl]methyl}-5- [1,1- dimethyl-2-(methylamino)-2-oxoethoxy]-lH-indol-3-yl) acetic acid or its pharmaceutically acceptable salt.

4. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of Claim 1 as an active ingredient.

5. The pharmaceutical composition according to Claim 4, as a therapeutic agent for allergy and/or inflammation.

6. Use of the compound or the pharmaceutically acceptable salt thereof of Claim 1 for the production of therapeutic agent for allergy and/or inflammation.

7. Amethodof treatment and/orprevention for allergyand/or inflammation including administering a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of Claim 1 to a patient.