CA2188374A1 - Benzene-condensed heterocyclic derivatives and their use - Google Patents

Abstract

Novel compounds having strong TXA2 receptor antagonist activities and PGI2 receptor agonist activities, which are effective for therapy and prevention of diseases related to TXA2, are disclosed.
The compound of the present invention is represented by the following formula (I).

Description

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2 ~ 88374 - - Benzene-condensed Heterocyclic Derivatives and Their Uses TECHNICAL FIELD
The present invention relates to a novel benzene-5 condensed heterocyclic derivative and to an antagonist against thromboxane A2 (hereinafter referred to as "TXA2") receptor, comprising the compound as an active ingredient.
BACKGROUND ART
TXA2 discovered by Samuelsson et al. in 1975 has a strong platelet aggregation activity as well as vascular smooth muscle-contracting activity and bronchial smooth muscle-contracting activity (Proc. Natl. Acad. Sci.
U.S.A., 72, 2994 (1975)). On the other hand, 15 prostaglandin I2 (PGI2) is known as a compound having activities opposite to the above-mentioned activities, that is, as a compound having a strong platelet aggregation inhibiting activity and vasodilation activity (Nature, 263, 663(1976)). Since these two compounds are 20 synthesized from arachidonic acid in the body and since their activities are strong, it is said that the balance between TXA2 and PGI2 is important for keeping the homeostasis of circulatory system. Therefore, if this balance is inclined to the side of TXA2, activation of 25 platelets and subsequent thrombus formation and vasoconstriction are caused, which is thought to be a cause of circulatory disorders including ischemic heart 2 2las374 diseases such as angina pectoris and myocardial infarction, cerebrovascular diseases, renal disorders and the like. Further, since TXA2 has a strong bronchial smooth muscle-contracting activity, it is thought that TXA2 also has a relationship to bronchial asthma. Thus, inhibition of activities of TXA2 is thought to be effective for therapies of circulatory disorders including ischemic heart diseases such as angina pectoris and myocardial infarction, cerebrovascular diseases and renal disorders, as well as bronchial asthma. So far, as the drugs to inhibit the activities of TXA2, a TXA2 receptor antagonist (Circulation, 81, Suppl. I, I-69(1990); Medicinal Research Reviews, 11, 503(1991)), and an inhibitor of TXA2 synthetase have been reported.
However, no drugs which sufficiently inhibit the activities of TXA2 have been obtained yet.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide an excellent TXA2 receptor antagonist.
The present inventors searched a TXA2 receptor antagonist having a novel structure to discover benzene-condensed heterocyclic derivatives having strong TXA2 receptor antagonist activities, thereby completing the present invention.
That is, the present invention provides a benzene-condensed heterocyclic derivative of the formula (I):

3 2~88374 (I) (wherein R is -X-(CH2)nCOOR (wherein X is -O-, -S- or -CH2-, R3 is hydrogen, C1-C5 lower alkyl, or an atom or group which gives a pharmaceutically acceptable salt, and n is an integer of 1 to 3);
R is i ) -CR4=cR5-o- ~
ii) -CR =CR -O-, or iii ) -NR4-CR5R6-CHR7-(wherein R4 is - ( CH2 ) m~Y~R
(wherein m is an integer of 1 to 4, Y is 1) --O--, 2) -CH2-, 3) -S(O)p- (p is an integer of 0 to 2),

4) -CO-,

5) -CH(OH)-,

6) -NR S02- r (wherein R is a) hydrogen, b) C1-C5 alkyl, c) phenyl (which may be substituted), d) C1-C5 alkyl substituted with phenyl (which - 4 2 i 88374 may be substituted)

7) -NR9Co- (wherein R9 represents the same meanings as described above)

-8) -CONR - (wherein R represents the same meanings as described above)

9) -NR9- (wherein R represents the same meanings as described above)

10) -O-N=CR9- (wherein R9 represents the same meanings as described above), or

11) the group represented by the formula (II):

N~ N~/
(IIa) (IIb) R is 1) phenyl, thienyl, furyl, naphthyl or C3-C8 cycloalkyl, 2) substituted phenyl, substituted thienyl, substituted furyl or substituted naphthyl, 3) Cl-C5 alkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
4) C2-C5 alkenyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
5 ) C3-C5 alkynyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), -C3-C8 cycloalkyl and phenoxy;
6) C2-C8 alkoxyalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
7) C1-C5 hydroxyalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
8) C2-C8 alkylthioalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
9) Cl-C5 aminoalkyl which is substituted with one or two substituents selected from the group consisting of phenyl twhich may be substituted)j thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy; or 10) -CH2-C(O)-R1 (wherein R10 is phenyl (which may be substituted) or Cl-C5 alkyl substituted with one or two phenyl groups (which may be substituted);
Rs is 1) hydrogen, 2) Cl-C5 alkyl, 3) C1-C5 hydroxyalkyl or acetoxyalkyl, 4) C1-C5 alkyl substituted with one or two phenyl groups (which may be substituted), or 5) C2-C8 alkoxyalkyl substituted with one or two phenyl groups (which may be substituted);
-R and R represent hydrogen or R6 and R7 are covalently bonded to represent a double bond)).
The present invention also provides an antagonistagainst TXA2 receptor, comprising the above-described compound of the present invention as an active ingredient.
The compounds of the present invention have strong TXA2 receptor antagonist activities and PGI2 receptor agonist activities, so that they are effective for 7 218837~

therapy and prevention of diseases related to TXA2.
BEST MODE FOR CARRYING OUT THE INVENTION
As mentioned above, the compound of the present invention is represented by the above-described formula (I)-Although the meanings of R1 and R2 in formula (I)are described above, the meanings will now be described in more detail. It should be noted that, in the present specification, the term "lower" in phrases such as "lower alkyl" means that the number of carbon atoms is 1 to 5, unless otherwise specified.
In cases where R3 is a pharmaceutically acceptable cation, examples of the cation include metal cations, ammonium, amine cations and quaternary ammonium cations.
Especially preferred metal cations are those derived from alkaline metals such as lithium, sodium and potassium, and those derived from alkaline earth metals such as magnesium and calcium. Needless to say, cations of, for example, aluminum, zinc and iron are also included in the present invention.
The pharmaceutically acceptable amine cations are those derived from primary, secondary or tertiary amines.
Examples of the suitable amines include methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-- 8 2 ~ 88374 phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, and similar aliphatic, alicyclic and heterocyclic amines having up to 18 carbon atoms such as 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 4-dimethylpiperadine, 2-methylpiperidine and the like; and water-soluble amines and amines having hydrophilic groups, such as mono-, di-, and triethanolamine, ethyldiethylamine, N-butylethanolamine, 2-amino-1-butanol, -2-amino-2-ethyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-(p-tert-aminophenyl)diethanolamine, galactamine, N-methylglutamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like; and basic amino acids such as lysine, arginine and the like.

In cases where R3 represents a C1-C5 alkyl group, examples of R3 include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl and the like.
In cases where R5 represents a C1-C5 alkyl, examples of R5 include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl and the like.
In cases where R5 represents a C1-C5 hydroxyalkyl, examples of R5 include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 4-hydroxypentyl, 5-- 9 21~374 hydroxybutyl and the like.
In cases where R5 represents C1-C5 alkyl substituted with one or more phenyl groups (which may be substituted), examples of R5 include benzyl,phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, diphenylmethyl, 2,2-diphenylethyl, 1,3-diphenylpropyl, 3,3-diphenylpropyl, 3,3-diphenyl-2-methylpropyl, 3,3-diphenylbutyl, 1,4-diphenylbutyl, 2,4-diphenylbutyl, 3,4-diphenylbutyl, 4,4-diphenylbutyl, 4,4-diphenyl-2-methylbutyl, 4,4-diphenyl-3-methylbutyl, 4,4-diphenylpentyl, 1,5-diphenylpentyl, 4,5-diphenylpentyl, 5,5-diphenylpentyl and the like.
In cases where R5 represents C2-C8 alkoxyalkyl substituted with one or two phenyl groups (which may be substituted), examples of R5 include benzyloxyethyl, 3-methoxy-3-phenylpropyl, 2-(diphenylmethoxy)-2-methylethyl, 2-(diphenylmethoxy)-1-methylethyl, 3-(diphenylmethoxy)propyl, 4-(diphenylmethoxy)butyl, 5-(diphenylmethoxy)pentyl, 6-(diphenylmethoxy)hexyl, 7-(diphenylmethoxy)heptyl, 2-(2,2-diphenylethoxy)ethyl, (diphenylethoxy)propyl, 4-(2,2-diphenylethoxy)butyl, 6-(2,2-diphenylethoxy)hexyl and the like.
Examples of the substituents in the phenyl group in R5 include lower alkyl groups, phenyl, hydroxy, lower alkoxy, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, lower alkylamino and the like. Preferred lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.

lo 2 1 88374 Preferred lower alkoxy groups include methoxy, ethoxy, --- propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy, pentyloxy and the like. Preferred halogens include fluorine, chlorine, bromine and iodine.
Preferred lower alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, diisopropylamino, di-t-butylamino and the like.
The thienyl group in R8 is 2-thienyl or 3-thienyl;
the furyl group is 2-furyl or 3-furyl; and the naphthyl group is 1-naphthyl or 2-naphthyl.
In cases where R8 represents a Cl-Cs alkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl twhich may be substituted), C3-C8 cycloalkyl and phenoxy, examples of R8 include benzyl, phenetyl, phenylpropyl, phenylbutyl, phenylpentyl, diphenylmethyl, 2,2-diphenylethyl, 1,3-diphenylpropyl, 3,3-diphenylpropyl, 3,3-diphenyl-2-methylpropyl, 3,3-diphenylbutyl, 1,4-diphenylbutyl, 2,4-diphenylbutyl, 3,4-diphenylbutyl, 4,4-diphenylbutyl, 4,4-diphenyl-2-methylbutyl, 4,4-diphenyl-3-methylbutyl, 4,4-diphenylpentyl, 1,5-diphenylpentyl, 4,5-diphenylpentyl, 5,5-diphenylpentyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 1-naphthylmethyl, 2-naphtylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenoxymethyl, phenyl(2-thienyl)methyl, phenyl(2-11 2 1 &~374 furyl)methyl, bis(2-thienyl)methyl, bis(2-furyl)methyl, dicyclohexylmethyl and the like.
In cases where R8 represents a C2-C5 alkenyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy, examples of R8 include 2-phenylvinyl, 3-phenyl-2-propenyl, 2-phenyl-1-methylvinyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 2,2-diphenylvinyl, 3,3-diphenyl-2-propenyl, 3,3-diphenyl-1-propenyl, 4,4-diphenyl-3-butenyl, 1,4-diphenyl-3-butenyl, 2,4-diphenyl-3-butenyl, 3,4-diphenyl-2-butenyl, 4,4-diphenyl-2-butenyl, 4,4-diphenyl-2-methyl-3-butenyl, 4,4-diphenyl-3-methyl-3-butenyl, 5,5-diphenyl-4-pentenyl, 1,5-diphenyl-4-pentenyl, 4,5-diphenyl-3-pentenyl, 4,4-diphenyl-2-pentenyl, 3,3-bis(2-thienyl)-2-propynyl, 3,3-bis(2-furyl)-2-propynyl, 3,3-bis(l-naphthyl)-2-propynyl, 4-cyclopentyl-2-butenyl, 4-phenoxy-2-butenyl and the like.
In cases where R8 represents a C3-C5 alkynyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy, examples of R8 include 3-phenyl-2-propynyl, 4-phenyl-2-butynyl, 5-phenyl-3-pentynyl, 3,3-diphenyl-l-propynyl, 3,3-diphenyl-1-butynyl, 4,4-` ~ 12 2 1 88374 diphenyl-2-butynyl, 5,5-diphenyl-3-pentynyl, 4,4-bis(2-thienyl)-2-butynyl, 4,4-bis(2-furyl)-2-butynyl, 4,4-bis(1-naphthyl)-2-butynyl, 4,4-dicyclohexyl-2-butynyl, 4-phenoxy-2-butynyl and the like.
In cases where R8 represents a C2-C8 alkoxyalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy, examples of R8 include 2-benzyloxyethyl, 3-methoxy-3-phenylpropyl, 2-(diphenylmethoxy)-1-methylethyl, 3-(diphenylmethoxy)propyl, 4-(diphenylmethoxy)butyl, 5-(diphenylmethoxy)pentyl, 6-(diphenylmethoxy)hexyl, 7-(diphenylmethoxy)heptyl, 2-(2,2-diphenylethoxy)ethyl, 3-(2,2-diphenylethoxypropyl, 4-(2,2-diphenylethoxy)butyl, 6-(2,2-diphenylethoxy)hexyl, 3-(bis(2-thienyl)methoxy)propyl, 3-(bis(2-furyl)methoxy)propyl, 3-(bis(1-naphthyl)methoxy)propyl, 3-(dicyclohexylmethoxy)propyl, 3-(phenoxymethoxy)propyl and the like.
In cases where R8 represents a C1-C5 hydroxyalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy, examples of - 13 ~l~8374 R3 include 2-hydroxy-2-phenylethyl, 1-hydroxy-3-phenylpropyl, 2-hydroxy-3-phenylpropyl, 3,3-diphenyl-2-hydroxypropyl, 3,3-diphenyl-2-methyl-2-hydroxypropyl, 4,4-diphenyl-2-hydroxybutyl, 4,4-diphenyl-3-hydroxybutyl, S 4,4-diphenyl-3-methyl-2-hydroxybutyl, 5,5-diphenyl-2-hydroxypentyl, 5,5-diphenyl-3-hydroxypentyl, 1-hydroxy-3-(2-thyienyl)propyl, 1-hydroxy-3-(2-furyl)propyl, 1-hydroxy-3-(1-naphthyl)propyl, 1-hydroxy-3-cyclohexylpropyl, 1-hydroxy-3-phenoxypropyl and the like.
In cases where R represents a C2-C8 alkylthioalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy, examples of R8 include 2-(diphenylmethylthio)ethyl, 3-(diphenylmethylthio)propyl, 5-(diphenylmethylthio)pentyl, 2-(2-diphenylethylthio)ethyl, 3-(2-diphenylethylthio)propyl, 2-(bis(2-thienyl)methylthio)ethyl, 2-(bis(2-furyl)methylthio)ethyl, 2-(bis(1-naphthyl)methylthio)ethyl, 2-(dicyclohexylmethlthio)ethyl, 2-(phenoxymethylthio)ethyl and the like.
In cases where R3 represents a C1-C5 aminoalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), ` - 14 2 ~ 3 7 4 furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy, examples of R8 include diphenylaminomethyl, 2-(diphenylamino)ethyl, 3-(diphenylamino)propyl, 4-(diphenylamino)butyl, 5-(diphenylamino)pentyl, 2-(bis(2-thienyl)amino)ethyl, 2-(bis(2-furyl)amino)ethyl, 2-(bis(1-naphthyl)amino)ethyl, 2-(dicyclohexylamino)ethyl and the like.
Examples of the substituents in phenyl, naphthyl, furyl and thienyl in R8 include lower alkyl groups, phenyl, hydroxy, lower alkoxy groups, phenoxy, halogens, trifluoromethyl, cyano, nitro, amino, lower alkylamino groups and the like. Preferred examples of the lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and the like.
Preferred examples of the lower alkoxy groups include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy, pentyloxy and the like. Preferred examples of the halogens include fluorine, chlorine, bromine and iodine. Preferred examples of the lower alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, diisopropylamino, di-t-butylamino and the like.
In cases where R9 represents a Cl-C5 alkyl, examples of R9 include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl and the like.
In cases where R represents a C1-C5 alkyl substituted with phenyl (which may be substituted), _ 15 2 ~ 88374 examples of R9 include benzyl,phenethyl, 3-phenylpropyl, ---- 4-phenylbutyl, 5-phenylpentyl and the like.
Examples of the substituents in the phenyl group in R9 include lower alkyl groups, phenyl, hydroxy, lower alkoxy groups, phenoxy, halogens, trifluoromethyl, cyano, nitro, amino, lower alkylamino groups and the like.
Preferred examples of the lower alkyI groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Preferred examples of the lower alkoxy groups include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxyj t-butyloxy, pentyloxy and the like. Preferred examples of the halogens include fluorine, chlorine, bromine and iodine. Preferred examples of the lower alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, diisopropylamino, di-t-butylamino and the like.
In cases where R10 represents a Cl-C5 alkyl substituted with one or two phenyl groups (which may be substituted), examples of R10 include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, diphenylmethyl, 2,2-diphenylethyl, 1,3-diphenylpropyl, 3,3-diphenylpropyl, 3,3-diphenyl-2-methylpropyl, 3,3-diphenylbutyl, 1,4-diphenylbutyl, 2,4-diphenylbutyl, 3,4-diphenylbutyl, 4,4-diphenylbutyl, 4,4-diphenyl-2-methylbutyl, 4,4-diphenyl-3-methylbutyl, 4,4-diphenylpentyl, 1,5-diphenylpentyl, 4,5-diphenylpentyL

21 88~74 5,5-diphenylpentyl and the like.
. When R is -CR =CR -O-, the formula (I) may prefer-ably be the formula:

,SCH 2 ) m ~R (I-a) ~ (CH2 ) nCR

In the above formula ~I-a), the group -(CH2)nCOOR is prefer-ably -CH2COOR , the group (CH2)m-Y-R is preferably -CH2NHs02R ~ -CH2 ~ ~ 8 or (CH2)m-Y -R in which Y is -O-, -S(O)p-, -O-N=CR or -CH(OH)-, and R is preferably R
which is hydrogen or Cl-C5 alkyl or R5a which is Cl-C5 hydroxy-alkyl or acetoxy-Cl-C5 alkyl, such as 2-hydroxyethyl, 2-acetoxyethyl, 3-hydroxypropyl or 3-acetoxypropyl.
When R is -CR =CR -O-, the formula (I) may prefer-ably be the formula:

\ R80 (I-b) o ~ OOR

In the above formula (I-b), R is C1-C5 alkyl substituted with 15a 21~8374 one or more aryl groups (i.e., phenyl, thienyl, furyl or naphthyl, each optionally substituted) or C2-C8 alkoxyalkyl substituted with one or two such aryl groups.
When R2 is -NR4-CR5R6-CHR7-, the formula (I) may preferably be the formula:

2 ) m~Y~R ~¦CH2 ) m-Y-R8 \

2 ) nCOoR ( CH2 ) ncooR3 (I-c) (I-d) In the above formula (I-c), the group -(CH2)nCooR3 is preferably -CH2CooR3 and the group -(CH2)m-Y-R is preferably -CH2CH2NHS02R or -CH2CH2NR60-R in which R60 is hydrogen or benzyl. In the above formula (I-d), the group -(CH2)nCooR3 is preferably -CH2CooR3 and the group -(CH2)m-Y-R is preferably -CH2CH20R , -CH2CH2SR or R which is C2-C10 alkyl substituted with one or two phenyl groups which may be substituted as defined above with respect to the definition of R .

15b --- Some of the compounds represented by the formula (I) comprise asymmetric carbon atoms and include geometrical isomers. The formula (I) includes all of the possible stereo isomers and geometrical isomers.
Specific examples of the compounds according to the present invention will now be enumerated. However, the present invention is not restricted by the specific examples by any means.
(3-((phenoxyacetylamino)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-phenoxyethylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid, (3-((phenylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid, (3-((benzylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-phenylethylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid, (3-((3-phenylpropylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid, (3-((4-phenylbutylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid, (3-((5-phenylpentylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid,(3-((2-naphthylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid, 17 218 83 ~

(3-((benzylsulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-((2-phenylethylsulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-((3-phenylpropylsulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-((2-phenylethylsulfonylamino)methyl)-2-isopropylbenzofuran-7-yloxy)acetic acid, (3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(N-benzylbenzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(benzylsulfonylamino)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid, lS (3-(2-(2-phenylethylsulfonylamino)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-(2-(2,2-diphenylethylsulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(3,3-diphenylpropylsulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-(2-(2-phenylethylsulfinyl)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-(2-(2-phenylethylsulfonyl)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylideneaminoxy)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-((4-phenyloxazole-2-yl)methyl)benzofuran-7-yloxy)acetic acid, (3-((4-(2-phenylethyl)oxazole-2-yl)methyl)benzofuran-7-yloxy)acetic acid, (3-(2-(3-phenylpropyloxy)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-benzyloxyethyl)benzofuran-7-yloxy)acetic acid, (3-(2-diphenylmethoxy)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(3,3-diphenylpropyloxy)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(4-phenylbenzyloxy)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(2-oxo-2-phenylethoxy)ethyl)benzofuran-7-yloxy)acetic acid, (3-((3,3-diphenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2,2-diphenylethoxy)methyl)benzofuran-7-yloxy)acetic acid, (3-(diphenylmethoxymethyl)benzofuran-7-yloxy)acetic acid, (3-((2-phenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((1-benzyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid,(3-((1-methyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-phenyl-2-methoxy-1-methylethoxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-phenylbutyloxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-phenoxyethoxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-(diphenylmethoxy)ethoxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-methyl-2-phenoxypropyloxy)methyl)benzofuran-7-yloxy)acetic acid,(3-(2-(2-(diphenylmethoxy)ethoxy)ethyl)benzofuran-7-yloxy)acetic acid, (3-((3-diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylsulfonyl)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylthio)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(bis(4-methoxyphenyl)methylthio)ethyl)benzofuran-7-yloxy)acetic acid,(3-(2-(bis(4-hydroxyphenyl)methylthio)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(bis(4-chlorophenyl)methylthio)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(bis(4-fluorophenyl)methylthio)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylthio)ethyl)benzofuran-6-yloxy)acetic 2~ 88374 acid, (3-((3,3-diphenylpropylthio)methyl)benzofuran-7-yloxy)acetic acid, (3-(3-diphenylmethylthio)propyl)benzofuran-7-yloxy)acetic acid, (3-(3-(2,2-diphenylethylthio)propyl)benzofuran-7-yloxy)acetic acid, (3-(3-(3,3-diphenylpropylthio)propyl)benzofuran-7-yloxy)acetic acid, (3-((diphenylmethylthio)methyl)benzofuran-7-yloxy)acetic acid, (3-((2,2-diphenylethylthio)methyl)benzofuran-7-yloxy)acetic acid, (3-(2-(2,2-diphenylethylthio)ethyl)benzofuran-7-yloxy)acetic acid,(3-(2-(3,3-diphenylpropylthio)ethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylthio)ethyl)-2-hydroxymethylbenzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylthio)ethyl)-2-(2-hydroxyethyl)benzofuran-7-yloxy)acetic acid, (3-(2-(diphenylmethylthio)ethyl)-2-(3-hydroxypropyl)benzofuran-7-yloxy)acetic acid, (3-((3,3-diphenyl-2-propenyloxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-(diphenylamino)ethoxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((2-(diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid, (3-((1-methyl-2-(diphenylmethoxy)ethoxy)methyl)benzofuran-7-yloxy)acetic acid, (3-(2-hydroxy-5,5-diphenylpropyl)benzofuran-7-yloxy)acetic acid, (2-((3,3-diphenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid, (2-((2,2-diphenylethoxy)methyl)benzofuran-7-yloxy)acetic acld, (2-((3-diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid, (2-((2-diphenylmethoxy)ethoxy)methyl)benzofuran-7-yloxy)acetic acid, (2-(diphenylmethoxymethyl)benzofuran-7-yloxy)acetic acid, (1-(2-(p-tolylsulfonylamino)ethyl)indole-4-yloxy)acetic acid, (1-(2-(2-phenylethylsulfonylamino)ethyl)indole-4-yloxy)acetic acid, (1-(2-(phenylsulfonylamino)ethyl)indole-4-yloxy)acetic acid, (1-(2-(benzylsulfonylamino)ethyl)indole-4-yloxy)acetic acid, (1-(2-(3-phenylpropyloxy)ethyl)indole-4-yloxy)acetic acid, ~ 22 2188374 (1-(2-(2-phenylethoxy)ethyl)indole-4-yloxy)acetic acid, (1-(2-(2,2-diphenylethoxy)ethyl)indole-4-yloxy)acetic acid, (1-(2-(diphenylmethoxy)ethyl)indole-4-yloxy)acetic acid, (1-(2-(3,3-diphenylpropyloxy)ethyl)indole-4-yloxy)acetic acid, (1-(5-phenylpentyl)indole-4-yloxy)acetic acid, (1-(2-diphenylmethylthio)ethyl)indole-4-yloxy)acetic acid, (1-(4,4-diphenylbutyl)indole-4-yloxy)acetic acid, (1-(2-(N-(diphenylmethyl)amino)ethyl)indole-4-yloxy)acetic acid, (1-(2-(N,N-dibenzylamino)ethyl)indole-4-yloxy)acetic acid, (1-(2-(diphenylmethylthio)ethyl)indoline-4-yloxy)acetic acid, (1-(2-(diphenylmethoxy)ethyl)indoline-4-yloxy)acetic acid, (1-(2-(2,2-diphenylethoxy)ethyl)indoline-4-yloxy)acetic acid, (1-(2-(3,3-diphenylpropyloxy)ethyl)indoline-4-yloxy)acetic acid, 3-(3-(2-diphenylmethoxyethyl)benzofuran-7-yloxy)propionic acid, 4-(3-(2-diphenylmethoxyethyl)benzofuran-7-yloxy)butyric acid, (3-(2-diphenylmethoxyethyl)benzofuran-7-ylthio)acetic acid, (3-(3-(2-diphenylmethoxyethyl)benzofuran-7-ylthio)propionic acid, 4-(3-(2-diphenylmethoxyethyl)benzofuran-7-ylthio)butyric acid, 3-(3-(2-diphenylmethoxyethyl)benzofuran-7-yl)propionic acid, 4-(3-(2-diphenylmethoxyethyl)benzofuran-7-yl)butyric acid, and 5-(3-(2-diphenylmethoxyethyl)benzofuran-7-yl)valeric acid, as well as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, t-butyl ester, pentyl ester and the like of these compounds.
Examples of the process for producing some of the compounds within the scope of the present invention will now be described. However, the present invention is not restricted by these.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -CR4=CR5-o- (wherein R4 is as described above and R5 is hydrogen, Cl-C5 alkyl, or C1-C5 hydroxyalkyl) may be produced using as the starting material the intermediate (6) which may be produced by the Production Process A.
It should be noted that in the steps hereinbelow described, those for which the reaction temperature is not described can be carried out at room temperature.

(Reaction Equation 1) o ~C--R50 A~ COOMe A-2 ~ CoOR

MeO MeO MeO
(1) (2) (_) \ A-3 OH O

C 51~CoOR5l ~CRo5 MeO OOR MeO MeO

(4) (O (6) (Production Process A) (wherein R50 is hydrogen or hydroxyl group, R51 is C1-C5 alkyl, R52 is hydrogen or C1-C5 alkyl).
As the material of the Production Process A, o-vanillin (R50=H) or 3-methoxysalicylic acid (R50=oH), which are easily and commercially available, may be employed.
Step A-1 is an esterification step of 3-methoxysalicylic acid. This step may be carried out by employing various esterification reaction, and may easily be carried out by heating the starting material with a catalytic amount of an acid in methanol. The reaction temperature is preferably from 30C to the refluxing temperature of methanol. As the acid catalyst, hydrochloric acid, sulfuric acid and p-toluenesulfonic acid are best preferred.

Step A-2 is an alkylation step of o-vanillin ester or 3-methoxysalicylic acid ester. This step is carried out by reacting the hydroxyl group of o-vanillin ester or 3-methoxysalicylic acid ester with R5l ester of Cl-C6 2-bromoalkylcarboxylic acid in the presence of a base.
Preferred examples of the base include potassium carbonate, sodium hydride, potassium hydroxide and sodium hydroxide. Various polar solvents may be employed, and methanol, acetone and DMF are best preferred.
Step A-3 is a cyclization step. This step is carried out by generating an anion at the a-position of the ester by using a base, and by making the aldehyde and ester in the molecule nucleophilically attack it. As the base, various bases may be used. Although potassium t-butoxide and sodium hydride are preferably used as thebase, the base is not limited thereto. Various solvents may be employed, and toluene, THF, dimethoxyethane or DMF
is preferably employed. The reaction temperature is -preferably between -20C and 120C.
Step A-4 is an oxidation step of hydroxyl group. A
number of methods for carrying out oxidation reaction are known. This step can be sufficiently carried out by using a chromic acid-based oxidizing agent having a good ease of handling, although the oxidizing agent is not restricted thereto.
Among the compounds within the scope of the present invention, those in which Rl is -OCH2COOH- or -OCH2COOMe and R is -CR =CR5-o- (wherein R is -CH2NHS02-R or -CH2NHCO-R , and R is hydrogen or C1-C5 alkyl) may be produced by Production Process B.
(Reaction Equation 2) ~ COORsl B-l~ ~ B-2 ~ Rs3 MeO MeO MeO
O O O

B-3 ~ R52 ~ ~ R52 MeO MeO C~) NH2 NHRs4 NHR54 Rs2 ~ ~ B-7 ~ R52 ~COOMe ~) ~ ~) B-8 ~ R52 B-9 ~ R52 ~COOMe --COOH
(~L) (~) (Production Process B) (wherein R51 and R52 represent the same meanings as described above, R53 is chlorine or bromine, R54 is acyl and R8 represents the same meanings as described above).
Step B-1 is a decarboxylation step. This step is carried out by heating the starting material to reflux in water-containing dioxane, water-containing t-butyl ~ 1 88374 alcohol or acetic acid in the presence of an acid. As the acid, hydrochloric acid or sulfuric acid is especially preferably used. Among the compounds (7) obtained by this step, those in which R52 is hydrogen may also be obtained by a known method (J. Org. Chem., 53, 423-425, (1988)).
Step B-2 is a step of introducing methyl group substituted with an eliminating group R53 into the ketone (7). This step is carried out by making the ketone (7) nucleophilically attack chloromethyllithium or bromomethyllithlum. An example of the process for producing chloromethyllithium and bromomethyllithium used in this step is described in references (Tetrahedron, 27, 6109-6114(1971), and Tetrahedron, 28, 3009-3013(1972)).
As the solvent, aprotic solvents are employed. Although ether, THF or dimethoxyethane is preferably employed as the solvent, the solvent is not restricted thereto. The reaction is carried out at a temperature between -100C
and 0C, preferably between -78C and -60C.
Step B-3 is a step of introducing azide into the compound (9). This step is carried out by heating the compound (8) and sodium azide to the refluxing temperature of the solvent. As the solvent, THF/water or methanol/water mixed solvent is preferably employed.
Step B-4 is a reduction step of azide. Various reducing agents may be employed, and lithium aluminum hydride or diisobutylaluminum hydride is preferably -employed. However, the reducing agent is not restricted to these.
Step B-5 is a deprotection step of phenolic methyl ether. This step is carried out by heating the compound (10) with sodium salt or potassium salt of a thiol. As the thiol, lower alkylthiols are preferably employed, and propanethiol is best preferred. As the solvent, DMF is preferably used. The reaction temperature is 50 - 150C, preferably 80 - 120C.
Step B-6 is a step of introducing acyl groups. By this step, both of the amino group and the hydroxyl of the compound (11) are protected by the acyl groups. As the acyl group, acetyl group and benzoyl group, as well as derivatives thereof may be employed. The reaction may be carried out under normal conditions. For example, the reaction may be carried out by reacting the compound (11) with the corresponding acid chloride or acid anhydride in the presence of a tertiary amine such as triethylamine or -pyridine, in THF, dichloromethane or DMF. Alternatively, Step B-5 and Step B-6 may be successively carried out without isolating the compound (11), thereby directly deriving the compound (12) from the compound (10).
Step B-7 is a step of deprotecting the phenolic acyl group and introducing an acetic acid unit. This step is carried out by selectively deprotecting the phenolic acyl group alone using a base, and then by treating the resultant with methyl bromoacetate changing the solvent 29 2 1 &8374 to DMF. As the base, potassium carbonate, potassium hydroxide or sodium hydroxide is preferably used. As the solvent, although methanol or ethanol may preferably be used, THF or dioxane may also be used.
Step B-8 is a step for converting the amide (13) to sulfonamide (14). This step is carried out by heating the compound (13) in methanol with an acid to the refluxing temperature thereby converting the compound (13) to an amine, and then reacting the resultant with the corresponding sulfonyl chloride in the presence of triethylamine or pyridine changing the solvent to dichloromethane, DMF or THF. The reaction may also be carried out by using the amine as a solvent. As the acid, hydrochloric acid or sulfuric acid is preferably employed.
Step B-9 is a hydrolysis step of methyl ester. This step is carried out by treating the compound (14) with an aqueous solution of a base in methanol. As the base, sodium hydroxide, potassium hydroxide or lithium hydroxide is preferably employed.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe and R2 is -CR =CR5-o- (wherein R4 is -CH2-CH2-NHSO2-R8 and R5 is hydrogen or Cl-C5 alkyl) may be produced by the Production Process C.

_ 30 2 ~ 88374 (Reaction Equation 3) ~R52 r ~COOMe ~OH

MeO MeO MeO

COOMe COOMe I~_R52 C~ ~ ~ 52 C-5 MeO Ho HO

C~ , ~ C-7 HO ~COOMe ~COOMe C-8 ~--2 C-9 ~ NH2 ~COOMe COOMe --2 C-l 1 ~2 ~COOMe --COOH
~a (Production Process C) (wherein R8 and Rs2 represent the same meanings as described above, and R55 is bromine, p-toluenesulfonyloxy or methanesulfonyloxy).

Step C-1 is a step of introducing an acetic acid unit to the compound (7) which can be obtained by Production Process B. This step is carried out by Wittig reaction using methyl(triphenylphosphoranilidene)acetate or Reformatsky reaction using methyl bromoacetate and zinc, and subsequent dehydration reaction. As the solvent for the Wittig reaction, toluene or xylene is preferably employed, and the reaction may usually be carried out at the refluxing temperature. In case of employing the Reformatsky reaction, an aprotic solvent, preferably ether or THF, is employed. The reaction temperature is between -78C and 100C, preferably between -20C and 50C. The dehydration reaction is carried out by treating the obtained tertiary alcohol with an acid catalyst. As the acid catalyst, formic acid, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid may preferably be employed. However, the acid catalyst is not restricted thereto.
Step C-2 is a reduction step of the methyl ester.
Various methods for reducing esters are known and various methods may be applied to this step. A method using lithium aluminum hydride or diisobutylaluminum hydride is preferred because the process is simple and the yield is high. However, needless to say, the reduction method is not limited to this. As the solvent, ether, THF or toluene is preferably used.
Step C-3 is a deprotecting step of methyl ether.

32 21 8837~

This step is carried out in the similar manner as in Step B-5.
The compound (18) may also be obtained by Step C-4 and Step C-5.
Step C-4 is a step of deprotection of methyl ether by a Lewis acid. As the Lewis acid, various acids may be employed. Although boron tribromide is preferably used, the Lewis acid is not restricted thereto. As the solvent, benzene, toluene, dichloromethane, or tetrachloromethane is preferably employed. The reaction temperature is selected from the range between -80C and 25C.
Preferably, the Lewis acid is added at a temperature of -80C to -60C and the temperature is then raised to a temperature between 0C and 30C to complete the reaction.
Step C-5 is a reduction step of methyl ester, and may be carried out in the similar manner as in Step C-2.
Step C-6 is a step of introducing an acetic acid unit. In this step, after removing the hydrogen atom of the phenolic hydroxyl group by a base, the resultant is subjected to a coupling reaction with methyl bromoacetate.
As the base, potassium carbonate, potassium hydroxide or sodium hydroxide is preferably employed. As the reaction solvent, polar solvents may be used and DMF is preferably employed.
Step C-7 is a step of converting hydroxyl group into bromine, p-toluenesulfonyloxy or methanesulfonyloxy group.
In cases where R55 is bromine, as a brominating agent, ~ - 33 21 88374 thionyl bromide, triphenylphosphine + tetrabromomethane, or triphenylphosphine + N-bromosuccinimide is preferably employed, although the brominating agent is not restricted thereto. As a solvent, DMF, THF or ether is preferably employed. Alternatively, thionyl bromide may be used as the solvent without using a separate solvent.
The reaction temperature is selected from the range between -20C and 100C, preferably between -20C and 50C.
In cases where R55 is p-toluenesulfonyloxy or -methanesulfonyloxy, the desired product may be obtained by tosylating or mesylating the hydroxyl group by a conventional method. That is, the desired product may be obtained by tosylating or mesylating the hydroxyl group by p-toluenesulfonyl chloride or methanesulfonyl chloride in THF, DMF or dichloromethane in the presence of triethylamine or pyridine.

Step C-8 is a step of introducing an azide group.
This step may be carried out in the similar manner as in -Step B-3.
Step C-9 is a step of reducing azide. This step may be carried out by reducing the compound (22) using palladium-carbon as a catalyst in hydrogen atmosphere.
As the solvent, methanol or THF is preferably employed.
The reaction temperature is between 0C and 50C.
Step C-10 is a step of converting amino group into sulfonamide. This step is carried out by reacting the compound (33) with a corresponding sulfonyl chloride in 34 ~l 88374 the presence of a tertiary amine. As the tertiary amine, triethylamine, pyridine or diisopropylethylamine is preferably employed, although the tertiary amine is not restricted thereto. As the solvent, THF or dichloromethane is preferably employed. However, the tertiary amine may be used as the solvent.
Step C-11 is a hydrolysis step of methyl ester, and may be carried out in the similar manner as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -CR9=CR5-o- (wherein R4 is -CH2-Z-R8 and R5 is hydrogen or C1-C5 alkyl) may be produced by the Production Process D.
(Reaction Equation 4) ~ R52 D~ R8 z5zR8 MeO MeO HO
(8) (26) (27) n-3 ~~z, R8 ~R5,2R8 ~COOMe --COOH
(~
(Production Process D) (wherein R8, R52 and R53 have the same meanings as described above, and Z is oxygen or sulfur).
Step D-1 is a step of etherification or thioetherification of the compound (8) obtained by Step _ 35 2 1 88374 B-2. This step is carried out by adding the compound t8) in a preliminarily prepared sodium salt or potassium salt of R8-OH or R8-SH. As the base, potassium metal, potassium hydride, potassium t-butoxide, sodium metal, or sodium hydride may be employed, and sodium hydride or potassium t-butoxide is preferably employed. In cases where Z is sulfur, potassium carbonate as a base may be added to a mixed solution of R8-SH and the compound (8).
Aprotic solvents, preferably THF, DMF or acetone, may be used as the solvent. The reaction temperature is selected from the range between -20C and 100C, preferably between -10C and 30C.
Step D-2 is a deprotection step of methyl ether, and may be carried out in the similar manner as in Step B-5.
Step D-3 is a step of introducing an acetic acid unit, and may be carried out in the similar manner as in Step C-6.
Step D-4 is a hydrolysis step of methyl ester and may be carried out in the similar manner as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -CR4=CR5-o- (wherein R4 is -CH2-CH2-O-R8 and R5 is hydrogen or C1-C5 alkyl) may be produced by the Production Process E.

36 2 ~ 88374 (Reaction Equation 5) OH

~COOMe E-l ~ ~OOMe ~ z ~2 THPO (L) ~H e~O--R8 ~_R8 Rs60 R560 (34) -- (32) (33) E-5 ~ E-6 , ~ _R8 O - COOH
~ COOMe (35) (36) (Production Process E) (wherein R8 and R52 represent the same meanings as described above, and R56 represents methyl or tetrahydropyranyl).
Step E-1 is a step of protecting the hydroxyl group of the compound (19) which can be obtained by Step C-4, with tetrahydropyranyl group. This step may be carried out under the normal conditions for tetrahydropyranylation. That is, the step is carried out by reacting 2,3-dihydropyran with the compound (19) in the presence of a catalytic amount of p-toluenesulfonic acid.

Step E-2 is a reduction step of methyl ester and may ~ t 8~374 be carried out in the similar manner as in Step C-2.
Steps E-3 and thereafter are carried out by using the compound (31) (R56=THP) or the compound (17) (R =Me) which can be obtained by Step C-2 as a starting material.
Step E-3 is a step of introducing a side chain into the compound (32). This step is carried out by converting the hydroxyl group of the compound (32) into an alkoxide by a base and then by adding R8-Cl or R8-Br.
As the base, potassium metal, potassium hydride, potassium t-butoxide, sodium metal, and sodium hydride may be employed, and potassium t-butoxide or sodium hydride is preferably employed. As the solvent, an aprotic solvent is used, and preferably THF or DMF is employed, although the solvent is not restricted thereto.
The reaction temperature is selected from the range between -20C and 100C, preferably between -10C and 30C.
Step E-4 is a deprotection step of the protected _ hydroxyl group. In cases where R56 is tetrahydropyranyl, this step is carried out by treating the compound (33) with an acid. As the acid, hydrochloric acid, sulfuric acid and acetic acid may be employed. As the solvent, THF, DMF, methanol, ethanol or dioxane, or a mixed solvent of one or more of these solvents and water is employed. The reaction temperature is selected from the range between 0C and 100C, preferably between 10C and 50C. In cases where R56 is methyl, this step may be carried out in the similar manner as in Step B-5.

38 2 ~ ~8374 Step E-5 is a step of introducing an acetic acid unit into the compound (34), and may be carried out in the similar manner as in Step C-6.
Step E-6 is a hydrolysis step of methyl ester, and may be carried out in the similar manner as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -CR4=CR5-o- (wherein R4 is -CH2-CH2-O-N=CPh2 or -CH2-CH2-S(O)p-R (wherein p is an integer of O - 2) and R5 is hydrogen or C1-C5 alkyl) may be produced by the Production Process F.

~ ~ 39 ~1 8~374 (Reaction Equation 6) ~ OH ~ F-2 ~ /2 R560 R560 (38) (321 R57 R57 ~2R57 HO (40) --COOH

$~--2 ~COOMe (21) o ~O

S--R8 ~ _R8 -/s - R8 F-6 ~ R52 F-7 ~R52 ~COOMe ~COOMe COOH
(42) (~) (44) S_R8 ~S~ ~S~
F-8 ~--2 F-9 ~--/2 ~COOMe ~COOMe COOH
(42) (45) (46) (Production Process F) (wherein R , R , R and R56 represent the same meanings as described above, and R57 is -O-N=CPh2 or -S-R8).
Step F-1 is a step of converting hydroxyl group into an eliminating group R55, and may be carried out in the similar manner as in Step C-7.
Step F-2 is a step of introducing a side chain into the compound (37). This step is carried out by removing the hydrogen atom of the hydroxyl group or thiol group of Ph2C=N-OH or R~-SH by a base and by adding the compound (37). As the base, potassium metal, potassium hydride, potassium t-butoxide, sodium metal, or sodium hydride may be employed, and potassium t-butoxide or sodium hydride is preferably employed, although the base is not restricted thereto. As the solvent, an aprotic solvent is used, and preferably THF or DMF is employed, although the solvent is not restricted thereto. The reaction temperature is selected from the range between -20C and 100C, preferably between -10C and 25C.
Step F-3 is a step of deprotecting the methyl or tetrahydropyranyl group, and may be carried out in the similar manner as in Step B-5 or Step E-4.
Step F-4 is a step of introducing an acetic acid unit into the compound (39), and may be carried out in the similar manner as in Step C-6.
The compound (40) obtained by Step F-4 may also be obtained by introducing a side chain into the compound (21) obtained by the Production Process C, in the similar manner as in Step F-2.
Step F-5 is a hydrolysis step of methyl ester, and may be carried out in the similar manner as in Step B-9.
Step F-6 is a step of oxidizing the sulfide (42) ` - 41 21 88374 into a sulfoxide (43). This step is carried out by treating the compound (42) with N-bromosuccinimide in methanol.
Step F-8 is a step of converting the sulfide (42) into a sulfone (45). This step is carried out by treating the compound (42) with a peracid in dichloromethane. As the peracid, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and trifluoroperacetic acid may be employed, and m-chloroperbenzoic acid may preferably be employed.
However, the peracid is not restricted to these. As the solvent, dichloromethane is preferably used. The reaction temperature may be -20C to 50C, preferably 0C
to 25C.
Step F-7 and Step F-9 are hydrolysis steps of methyl ester and are carried out in the similar manner as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R is -CR4=CR5-o- (wherein R4 is -CH2-CH2-S-R8 and R
is hydroxymethyl) may be produced by the Production Process G.

- 42 2 1 8~3 74 (Reaction Equation 7) ~$~ a-l . ~,OH G-2, ~ ~,OMOM

Me Me Me (48) (49) COOMe OH
G-3 ~ OMOM G-4 ~ ~OMOM G 5 Me Me (50) ~) - ~$ Rss ~ G-7 .

Me Me (53) ~$ 8--R: G 8 ~OH G-9 ~ Ç~U - R8 MeO COOMe (~COOH
(54) (55) (56) (Production Process G) (wherein R8, R51 and R55 have the same meanings as described above) Step G-1 is a reduction step of ester. This step is carried out by firstly treating the compound (47) obtainable by the Step A with a base to convert the compound into an enolate, and then reducing the ester alone by a reducing agent. As the base, sodium metal and sodium hydroxide may preferably be employed. As the reducing agent, various compounds may be employed.
Preferred reducing agents are lithium aluminum hydride ` - q3 2 ~ 8~374 and diisobutylalminum hydride. An aprotic solvent is used as the solvent and ether, THF and dioxane may preferably be employed. The reaction temperature is selected from the range between -78C and 100C.
Preferably, the step may be carried out by heating the reaction mixture to refluxing temperature after adding the base and then by cooling the reaction mixture to 0C
followed by adding the reducing agent.
Step G-2 is a step of protecting the hydroxyl group of the compound (48) with methoxymethyl group. This step is carried out by treating the compound (48) with dimethoxymethane in the presence of phosphorus pentoxide.
As the solvent, dichloromethane is preferably employed.
Step G-3 is a step of introducing an acetic acid unit, and may be carried out in the similar manner as in Step C-1.
Step G-4 is a reduction step of the ester, and may be carried out in the similar manner as in Step C-2.
Step G-5 is a step of converting the hydroxyl group of the compound (51) into an eliminating group, and is carried out in the similar manner as in Step C-7.
Step G-6 is a step of introducing thioether, and is carried out as in Step D-1.
Step G-7 is a deprotection step of methoxymethyl group. This step is carried out by treating the compound (53) with a catalytic amount of an acid. As the acid, p-toluenesulfonic acid or pyridinium p-toluenesulfonate is 44 2i 88374 preferably employed. As the solvent, various alcohols are preferred, and t-butyl alcohol is especially preferred. The reaction is carried out at a temperature of 0C to 200C. Preferably, the reaction is carried out at the refluxing temperature using t-butyl alcohol as the solvent.
Step G-8 is a step of deprotecting methyl ether and introducing acetic acid into phenol. This step may be carried out in the similar manner as in Step B-5 or Step C-6.
Step G-10 is a hydrolysis step of ester and may be carried out as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -CR4=CR5-o- (wherein R4 is -CH2-CH2-S-R8 and R5 is hydroxyethyl) may be produced by the Production Process H.

~ &~374 (Reaction Equation 8) MeO ~ooR5l ~ oR51 H-2 (~Z) (~Z) (~) COOMe COOMe H-3 ~ H4 ~ H-5 MeO HO
~) ~
_ ~ OH ~ OH OTHP
H-6 ~ H-7 ~ H-8 HO O ~
~ ~ COOMe OOMe ~) ~) OTHP ~ OTHP ~ OTHP
H-9 ~ ~ OH r ~ OAc ~ COOMe ~ COOMe ~ COOMe ~) ~) ~
~ OH R55 H-ll ~ H-12 ~ H-13 ~ COOMe COOMe H-14 ~ H

~ COOMe - COOH
~) (Production Process H) (wherein R8, R5l and R55 have the same meanings as 2 ~ 88374 described above) Step H-1 is a step of introducing an allyl group.
This step is carried out by converting the compound (47) into an enolate using a base, and then by treating the enolate with allyl bromide. As the base, sodium hydrlde is best preferred, although the base is not restricted to it. Various solvents may be used as the solvent, and DMF, THF, ether and toluene are preferred. This step may also _ be carried out by recovering by filtration the metal salt of the compound (47) obtained after completion of Step A-3, and treating the obtained metal salt with allyl bromide. Although a mixture of C-allyl compound and O-allyl compound is obtained by this Step, the O-allyl compound may be converted into the C-allyl compound by carrying out Claise rearrangement after extraction. The Claise rearrangement may easily be carried out by treating the mixture of the C-allyl compound and O-allyl _ compound in benzene or toluene at the refluxing temperature.
Step H-2 is a decarboxylation step and may be carried out in the similar manner as ln Step B-1.
Step H-3 is a step of introducing an acetic acid unit and may be carried out as in Step C-1.
Step H-4 is a deprotection step of methyl group and may be carried out as in Step C-4.
Step H-5 is a reduction step of ester and may be carried out as in Step C-2.

Step H-6 is a step of introducing an acetic acid unit and may be carried out as in Step C-6.
Step H-7 is a step of protecting the hydroxyl group of the compound (62) with tetrahydropyranyl ether. This step is carried out by treating the compound (62) with dihydropyran in the presence of a catalytic amount of an acid. As the acid, hydrochloric acid, sulfuric acid and p-toluenesulfonic acid may preferably be employed. As _ the solvent, various solvents may be employed, and THF
and dichloromethane are preferred.
Step H-8 is a step of cleaving the allyl group.
This step is carried out by oxidatively cleaving the double bond by treating the compound (63) with an oxidizing agent. As the oxidizing agent, osmium tetroxide/sodium periodide or potassium permanganate is preferably used. As the solvent, dichloromethane and t-butyl alcohol are best preferred. The reaction _ temperature is preferably between -20C and 50C.
Step H-9 is a reduction step of aldehyde. This step is a step of selectively reducing the aldehyde alone of the compound (64). As the reducing agent, sodium borohydride is preferably employed. As the solvent, methanol, ethanol, or THF/water mixture is preferably employed. The reaction temperature is preferably between -20C and 30C.
Step H-10 is a step of protecting the hydroxyl group of the compound (65) with acetyl group. This step may be ~ 48 21 38374 carried out by applying an ordinary acetylation reaction.
The system of acetic anhydride/pyridine, acetyl chloride/triethylamine, and acetyl chloride/pyridine are preferred. As the solvent, dichloromethane, ether or THF
is preferably employed. The reaction temperature is preferably -20C to 30C.
Step H-ll is a step of deprotecting the tetrahydropyranyl group, and may be carried out in the similar manner as in Step E-4.
Step H-12 is a step of converting the hydroxyl group of the compound (67) to an eliminating group, and may be carried out as in Step C-7.
Step H-13 is a step of introducing a thioether side chain, and may be carried out as in Step D-l.
Step H-14 is a hydrolysis step of methyl ester. By this step, the acetyl group is also eliminated simultaneously. This step may be carried out as in Step B-9.
Among the compounds within the scope of the present invention, those in which Rl is -OCH2COOH or -OCH2COOMe, and R2 is -CR4=CR5-o- (wherein R4 is -CH2-CH2-S-R8 and R
is hydroxypropyl) may be produced by the Production Process I.

(Reaction Equation 9) pH OH
~e I I ~ 1-2 ~, MeO MeO HO '72' (59) (71) ~ OH ~OTHP
1-3 ~ 4 ~ 1 5 COOMe COOMe ~ (~) ~

~PTHP ~OTHP
1-6 ~ OAc ~COOMe ~COOMe ~) ~) ~)H Rs5 ,OAc ~~OAc ~COOMe ~COOMe ~) ~) $~, 1-10 ~--. OH

~COOMe COOH
(79) (~) (Production Process I) (wherein R8 and R55 have the same meanings as described above) ` - 50 ~l &~374 Step I-1 is a reduction step of ester, and may be carried out in the same manner as in Step C-2.
Step I-2 is a deprotection step of methyl group, and may be carried out as in Step B-5. By this step, isomerization of the double bond of the 2-allyl group is also carried out simultaneously.
Step I-3 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6.
Step I-4 is a step of protecting the hydroxyl group of the compound (73) with tetrahydropyranyl group, and may be carried out as in Step H-7.
Step I-5 is a step of introducing bromine into the compound (74). In this step, bromine is introduced into the allyl group which is a side chain at the 2-position, by using N-bromosuccinimide. As the solvent, benzene, tetrachloromethane or chloroform is preferably employed, and the reaction is preferably carried out at the _ refluxing temperature of the solvent. The reaction may also be carried out adding a peracid or azoisobutylonitrile (AIBN) as a radical initiator.
Step I-6 is a step of introducing an acetoxy group.
This step is carried out by treating the compound (75) with a metal salt of acetic acid. As the metal, sodium and potassium are preferred. As the solvent, DMF or THF
is preferably employed. The reaction may be carried out at a temperature between 20C and 100C.
Step I-7 is a reduction step of the double bond.

~ ~ &8374 This step may be carried out by catalytic hydrogenation using a catalyst. As the catalyst, palladium metal and platinum oxide, as well as these catalysts carried on a carrier are preferred. As the solvent, methanol, ethanol and THF are preferred. The reaction temperature may be 0C to 50C. By this step, deprotection of the tetrahydropyranyl group is also carried out simultaneously.
_ Step I-8 is a step of converting the hydroxyl group of the compound (77) into an eliminating group, and may be carried out in the similar manner as in Step C-7.
Step I-9 is a step of introducing a thioether side chain, and may be carried out as in Step D-1.
Step I-10 is a hydrolysis step of methyl ester. By this step, the acetyl group is also eliminated simultaneously. This step may be carried out as in Step B-9.
_ Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R is -CR4=CR5-o- (wherein R4 is -CH2-CH2-CH2-S-R ) may be produced by the Production Process J.

~ 52 2 1 88374 (Reaction Equation 10) OH

~ R52 J-l, ~ 52 J-2, ~ R52 MeO MeO MeO
(7) (81) (82) ~ H ~ OH
J-3 ~ ~_R52 J~ ~ ~ 52 J~S >

HO
(83) C(84)Me --R5s J-7 ~ ~R8 ~COOMe ~COOMe --COOH
(85) (86) (87) (Production Process J) (wherein R8, R52 and R55 have the same meanings as described above) Step J-1 is a step of introducing an allyl group.
_ This step may be carried out by reacting the compound (7) with allyllithium or an allyl Grignard reagent in the presence of cerium chloride, and by dehydrating the generated tertiary alcohol. As the solvent, aprotic solvents may be employed and THF and ether are preferred.
The reaction temperature is selected from the range between -78C and 10C. The dehydration reaction may preferably be carried out by refluxing the resultant in benzene in the presence of an acid catalyst. As the acid catalyst, p-toluenesulfonic acid is preferably employed.

53 21 ~8374 Step J-2 is a step of oxidizing the double bond of the compound (81). This step is carried out by hydroboration and subsequent oxidation reaction. As the borane derivative, various borane derivatives such as diborane, borane complexes, and alkyl boranes may be employed, and complex between borane and dimethylsulfide, and complex between borane and THF are preferred. As the solvent, THF or ether is preferably employed. The reaction temperature is preferably -20C to 50C. The oxidation reaction is preferably carried out by using a peracid or hydrogen peroxide under alkyl condition. As the solvent, methanol or ethanol is preferably employed.
The reaction temperature is preferably 10C to 50C.
Step J-3 is a deprotection step of methyl group, and may be carried out in the similar manner as in Step C-4.
Step J-4 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6.
Step J-5 is a step of converting the hydroxyl group of the compound (84) into an eliminating group, and may be carried out as in Step C-7.
Step J-6 is a step of introducing a thioether side chain, and may be carried out as in Step D-1.
Step J-7 is a hydrolysis step of methyl ester, and may be carried out as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -CR4=CR5-o- (wherein R4 is -CH2-CH(OH)-R8 and R

` - 54 ~l 883 7~

is hydrogen or C1-C5 alkyl) may be produced by the Production Process K.
(Reaction Equation 11) R8 COOMe M~HO ~<20H

( I 6) (88) (89) K-3 ~H K-4 ~OAc K-S

HO AcO
(90) (91) ~H K-6 ~ ~OH K-7 ~ ~OH

HO ~COOMe --COOH
(92) (93) (94) (Production Process K) (wherein R8 and R52 have the same meanings as described - above) Step K-1 is a step of reducing methyl ester into aldehyde. Various reducing agents may be employed, and diisobutylaluminum hydride is preferably employed. As the solvent, aprotic solvents may be employed, and dichloromethane and THF are preferred. The reaction may be carried out at a temperature of -100C to 10C.
Step K-2 is a step of introducing a side chain.
This step may be carried out by reacting R8-Li or R8-Mg-R58 (wherein R58 is chlorine or bromine) with the compound 2 t &8374 (88). As the solvent, aprotic solvents may be employed, and THF and ether are especially preferred. The reaction may be carried out at a temperature of -78C to 10C.
Step K-3 is a deprotection step of methyl ether and may be carried out in the similar manner as in Step B-5.
Step K-4 is a step of protecting hydroxyl group with acetyl group, and may be carried out as in Step H-10.
Step K-5 is a deprotection step of acetyl group.
_ This step is carried out by treating the compound (91) with a base. As the base, potassium carbonate, potassium hydroxide and sodium hydroxide are preferred. As the solvent, methanol, ethanol and mixtures of each of these alcohols with water are best preferred. The reaction may be carried out at a temperature of 0C to 50C.
15Step K-6 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6.
Step K-7 is a hydrolysis step of methyl ester, and - may be carried out as in Step B-9.
Among the compounds within the scope of the present invention, those in which Rl is -OCH2COOH or -OCH2COOMe, and R2 is -CR9=CR5-o- (wherein R4 is -O-CH2-W-R8 (wherein W is represented by formula (IIa) and R5 is hydrogen or Cl-C5 alkyl) may be produced by the Production Process L.

56 21 &8374 (Reaction Equation 12) OOMe OOH ~R8 ~ L-l~ ~ L-2 MeO MeO MeO (96) (94) (95) L-3 ~ ~ 8 L~, ~R` L-5 MeO HO
(97) (98) ~5~ ~R~

COOMe --COOH
(99) (100) (Production Process L) (wherein R8 and R52 have the same meanings as described above) Step L-1 is a hydrolysis step of methyl ester, and _ may be carried out in the similar manner as in Step B-9.
Step L-2 is an alkylation step of the carboxylic acid (95). This step is carried out by converting the IO carboxylic acid (95) into a salt using a base and then by condensing the resultant with R8-CO-CH2-OH.
Alternatively, this step is carried out by condensing R8-CO-CH2-OH and the carboxylic acid using a dehydrating agent. As the base, potassium carbonate, potassium hydroxide, sodium hydroxide and sodium hydride are preferably employed, although the base is not restricted thereto. As the dehydrating agent, dicyclohexylcarbodiimide is preferably used, although the dehydrating agent is not restricted thereto. As the solvent used when using the base, THF or DMF is preferably employed. Alternatively, after converting the carboxylic acid into a salt in methanol, the reaction may be carried out using the methanol as a solvent. The reaction temperature is preferably 0C to 50C. As the solvent used when the dehydrating agent is used, THF, DMF, benzene or toluene is preferably employed. The reaction temperature is preferably 0C to 50C.
Step L-3 is a step of constructing oxazole ring.
This step is carried out by heating the compound (96) with ammonium acetate to reflux in acetic acid.
Step L-4 is a deprotection step of methyl ether, and may be carried out in the similar manner as in Step B-5.
Step L-5 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6.
Step L-6 is a hydrolysis step of methyl ester, and may be carried out as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOEt, and R2 is -CR5=CR4-o- (wherein R4 is -CH2-O-R8 and R is hydrogen) may be produced by the Production Process M.

_ 5821 88374 (Reaction Equation 13) ~ CHO ~ M-2j ~ H

MeO MeO MeO
~) C~) M-3 r~CI M-4 ~ M-S

MeO MeO
(103) (104) --~~R80 ~`R80- ~ ~ `R80 HO Q Q
COOEt ~-~OOH

~QO (l07) (Production Process M) (wherein R80 represents C1-C5 alkyl substituted with one or two aryl groups, or C1-C8 alkoxyalkyl substituted with one or two aryl groups).
Step M-1 is a step of converting o-vanillin to benzofuran. In this step, by heating o-vanillin and ethyl bromoacetate in the presence of a base, O-alkylation of o-vanillin, cyclization and dehydration are attained so that the benzofuran ring is constructed in a single step. As the base, potassium carbonate is preferably employed, although the base is not restricted thereto. As the solvent, DMF is preferably employed.
The reaction temperature may be 50C to 150C, preferably 80C to 120C.
Step M-2 is a reduction step of ethyl ester, and may be carried out in the similar manner as in Step C-2.

_ 59 ` 2l a83 74 Step M-3 is a step of converting hydroxyl group into chlorine. This step is carried out by treating the compound ~102) with thionyl chloride. Pyridine may be added to the reaction solution. As the solvent, dichloromethane or DMF is preferably employed, and pyridine may also be used as the solvent. The reaction may also be carried out by adding thionyl chloride to the compound (102) without using a solvent.
_ Step M-4 is a step of introducing a side chain, and may be carried out as in Step D-1.
Step M-5 is a deprotection step of methyl ether, and may be carried out as in Step B-5.
Step M-6 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6 except that ethyl bromoacetate is used in place of methyl bromoacetate.
Step M-7 is a hydrolysis step of methyl ester, and may be carried out as in B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -NR4-CR5R6-CHR7- (wherein R6 and R represent covalent bond, R4 is -CH2-CH2-NHSO2-R8 and R5 is hydrogen) may be produced by the Production Process N.

21 883?4 (Reaction Equation 14) __/OTHP
H N-l ~ H N-2 ~ N-3 OH BnO BnO
~) ~) __/OH /__/OH /__/Br N-4 ~ N-5 HO O O
(l lo) ~COOMe ~COOMe (~) (~) ~ N3 /__/NH2 N-6 ~ N-7 ~ N-8 ~COOMe ~COOMe (1 14) __/NHS02R8 ~NHSO2R8 N-9 ~

~ COOMe - COOH
~) ~L) (Production Process N) (wherein R8 represents the same meanings as described above) As the starting material of this production process, easily and commercially available 4-hydroxyindole is used.

_ 61 21 88374 Step N-1 is a step of protecting the hydroxyl group in 4-hydroxyindole with benzyl ether. This step is carried out under usual benzylation conditions. Although this reaction may preferably be carried out in DMF using sodium hydroxide as a base, the reaction conditions are not restricted thereto.
Step N-2 is an N-alkylation step of the compound (108). This step is carried out by eliminating the hydrogen atom in NH by uslng a base, and then reacting the resultant with tetrahydropyranyl ether of ethylene bromohydrin. As the base, potassium metal, potassium hydride, potassium t-butoxide, sodium metal, sodium hydride and the like may be employed. Among these, sodium hydride is preferred, although the base is not restricted to this. As the solvent, THF, DMF, ether or dimethoxyethane is employed, and DMF is preferred. The reaction may be carried out at a temperature of -20C to _ 50C, preferably -10C to 10C.
Step N-3 is a deprotection step of benzyl ether.
This step is carried out by catalytic hydrogenation using palladium-carbon as a catalyst. By this step, not only the benzyl ether, but also the tetrahydropyranyl ether may be deprotected. As the solvent, methanol or ethanol is preferably employed. The reaction may be carried out at a temperature of 0C to 50C.
Step N-4 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6.

~~ 62 21 88374 Step N-5 is a step of converting hydroxyl group into bromine, and may be carried out as in Step C-7.
Step N-6 is a step of introducing an azide group, and may be carried out as in B-3.
Step N-7 is a reduction step of azide group, and may be carried out as in Step C-9.
Step N-8 is a step of converting the amino group of the compound (114) into sulfonamide, and may be carried out as in Step C-10.
Step N-9 is a hydrolysis step of methyl ester, and may be carried out as in Step B-9.
Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R is -NR -CR R -CHR7- (wherein R4 is -CH2-CH2-O-R8 R5 is hydrogen, and both of R6 and R7 represent hydrogen or covalent bond) may be produced by the Production Process 0.

(Reaction Equation 15) ~H 0-1 [~H 0-2 ~>H

HO Rs90 Rs90 (117) (118) ~OTHP ~` R8 ~_ 0-3 ~_R6 or ~R6 Rs90 R7 Rs90 R7 Rs90 R
(~or 118) (119) (120) ~OTHP ~OH O~R8 R~ 6 0-4 $~_ 6 0-5 ~--R6 22) ~) R8 ~ R8 ~~R8 0-6 ~ 6 0-7 ~ 6 0-8 ~ R6 HO R O R O
~COOMe --COOH
(~) (L~) (125) (Production Process O) (wherein R6 and R7 represent the same meanings as described above, and R59 represents methyl or benzyl).
Step 0-1 is a step of protecting the hydroxyl group of 4-hydroxyindole with benzyl ether or methyl ether.
This step may be carried out by reacting 4-hydroxyindole with methyl iodide or benzyl chloride in the presence of a base. As the base, potassium hydroxide or sodium hydroxide is preferably employed, although the base is not restricted thereto. As the solvent, DMF and methanol are preferred.
Step O-2 is a step of reducing indole ring into indoline ring. This step is carried out by adding hydrochloric acid and borane-trimethyl amine complex to the reaction system using dioxane as a solvent and heating the reaction mixture to reflux.
Step 0-3 is a step of introducing a side chain.
This step is carried out by eliminating the hydrogen atom in NH of indole (117) or indoline (118) by using a base, and adding R -O-CH2-CH2-Br. As the base, sodium hydride or phenyllithium is preferably employed, although the base is not restricted thereto. As the solvent, an aprotic solvent, preferably DMF, may be employed. The reaction temperature is between -20C and 50C.
Preferably, the base and the material of the side chain are added at 0C and then the temperature is raised to -_ room temperature to complete the reaction. The compound (120) obtained by this step may also be obtained by the same method as described above except that tetrahydropyranyl ether of ethylenebromohydrine is used in place of R8-O-CH2-CH2-Br to obtain the compound (119), and then by carrying out Steps 0-4 and O-S described below.
Step 0-4 is a deprotection step of tetrahydropyranyl ether. This step is carried out by hydrolyzing the compound (121) with an acid. As the acid, hydrochloric - 65 2 i 883 74 acid or sulfuric acid is preferably employed. As the solvent, THE, methanol, ethanol, or a mixture of each of these solvents and water is preferably employed.
Step 0-5 is an 0-alkylation step of the compound (122), and may be carried out in the similar manner as in Step E-3.
Step 0-6 is a deprotection step of R59. In cases where R59 is methyl, the step may be carried out as in B-_ 5. In cases where R59 is benzyl, the step may be carried out as in Step N-3.
Step 0-7 is a step of introducing acetic acid unit, and may be carried out as in Step C-6.
Step 0-8 is a hydrolysis step of methyl ester, and may be carried out as in Step B-9.
15Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -NR4-CR5R6-CHR7- (wherein R6 and R7 represent -- covalent bond, R4 is -CH2-CH2-NR6-R8 and R5 is hydrogen) may be produced by the Production Process P.

66 21 &8374 (Reaction Equation 16) ~~NH2 ~~NR60_R8 ~--COOMe ~--COOMe ll4) (126) ~~NR61)--R8 COOH
~) (Production Process P) (wherein R8 represents the same meanings as described above, and R60 represents hydrogen or benzyl).
Step P-1 is an N-alkylation step of the compound (114). In cases where R60 is hydrogen, this step is carried out by reacting the compound (114) with R8-Cl or -- R8-Br in the presence of a base. In cases where R60 is benzyl, this step is carried out by using benzyl bromide.
As the base, various tertiary amines and potassium carbonate may be employed, and potassium carbonate, pyridine, triethylamine and diisopropylethylamine are preferred. As the solvent, DMF and acetonitrile are preferred. The reaction temperature is preferably 20C
to 150C.
Step P-2 is a hydrolysis step of methyl ester, and may be carried out as in Step B-9.

Among the compounds within the scope of the present invention, those in which R1 is -OCH2COOH or -OCH2COOMe, and R2 is -NR4-CR5R6-CHR7- (wherein R is C2-C10 alkyl substituted with one or two phenyl groups (which may be - 5 substituted), R5 is hydrogen, and both of R6 and R7 represent hydrogen or covalent bond) may be produced by the Production Process Q.
(Reaction Equation 17) - ,R61 R61 ~6 Q-l ~ ~ 6 Q-2 ~6 Rs9 R7 Rs9 R7 H R7 (128) (129) (130 Q~3 ~ ~R6 Q~4 ~ ~R6 COOMe --COOH
C~) ~) - 10(Production Process Q) (wherein R6, R7 and R59 represent the same meanings as described above, and R6l represents C2-C10 alkyl substituted with one or two phenyl groups (which may be substituted).
15Step Q-1 is a step of introducing a side chain.
This step is carried out by eliminating the hydrogen atom of NH in indole or indoline by using a base and by adding R61-Br or R6l-Cl. As the base, sodium hydride or phenyllithium is preferably employed, although the base 68 2 ~ 88374 is not restricted thereto. As the solvent, aprotic solvents may be employed, and DMF is preferably employed.
The reaction temperature is selected from the range between -20C and 50C.
Step Q-2 is a deprotection step of R59. In cases where R59 is methyl, this step may be carried out as in Step B-5. In cases where R59 is benzyl, this step may be carried out as in Step N-3.
Step Q-3 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6.
Step Q-4 is a hydrolysis step of methyl ester, and may be carried out as in Step B-9.
Among the compounds withln the scope of the present invention, those in which Rl is -OCH2COOH or -OCH2COOMe, and R is -NR -CR5R6-CHR7- (wherein R4 is -CH2-CH2-S-R8 R5 is hydrogen, and both of R6 and R7 represent hydrogen or covalent bond) may be produced by the Production Process R.

(Reaction Equation 18) ~ R6 Rl ~ ~ 6 ~ ~ R-3 R59 R H R ~COOMe (122) (133) R55~ S -R8 6S- R`

~COOMe ~COOMe --COOH
(1 35) (I 36) (1 37) (Production Process R) R6 R7 R8 R5s and R5 represent t meanings as described above).
Step R-1 is a step of deprotecting R59 of the compound (122) which can be obtained by Step O-4. In cases where R59 is methyl, this step may be carried out as in Step B-5. In cases where R59 is benzyl, this step may be carried out as in Step N-3.
- Step R-2 is a step of introducing an acetic acid unit, and may be carried out as in Step C-6.
Step R-3 is a step of converting hydroxyl group into eliminating group R55, and may be carried out as in Step C-7.
Step R-4 is a step of introducing a side chain, and may be carried out as in Step D-1.
Step R-5 is a hydrolysis step of methyl ester, and may be carried out as in Step B-9.
Although the compound of the present invention is 70 2 1 ~8374 represented by a structural formula of an optically active compound, the general formula includes d-, 1- and d,l-isomers. The processes A to R can be equally applied to d-, l- and dl-isomers.
In cases where the processes A to R are carried out using a dl compound, the compound represented by the formula ~I] obtained in the form of racemate may easily be separated into d- or l-isomer by column chromatography or the like.
The compounds of the present invention have strong TXA2 receptor antagonist activities and PGI2 receptor agonist activities, so that they have pharmacological activities such as activity to inhibit platelet aggregation, vasoconstriction inhibition activity and activity to inhibit contraction of bronchial muscle.
Therefore, they are effective in therapy and prevention of hypertension, myocardial infarction, angina pectoris, _ thrombus formation after PTCA, cerebral infarction, transient cerebral ischemic attack, peripheral circulatory disturbance (Buerger's disease, Raynaud's disease, Behcet's disease, thrombotic thrombocytopenic purpura, hepatic disorders, renal disorders and the like), arteriosclerosis, platelet function disorder accompanied by diabetes, retinal vascular occlusion, hyperlipidemia, lupus nephritis, vibration disease, bronchial asthma, allergies and the like. To this end, the compound according to the present invention may usually be administered by intravenous, intraarterial, intramuscular, percutaneous, subcutaneous or oral administration. In case of oral or rectal administration, the compound is usually administered 1 to 4 times a day at a dose of 1 ,ug/kg/day to 100 mg/kg/day. In case of intravenous drip infusion or intraarterial injection, good results are obtained by administering the compound at a dose of 1 ng/kg/min. to 100 ug/kg/min. In case of usual _ intravenous, intramuscular or subcutaneous injection, the compound is usually administered 1 to 4 times a day at a dose of 0.1 ,ug/kg/day to 100 mg/kg/day. When the compound is administered, the dose is selected from the ranges mentioned above depending on the age, sex and conditions of the patient and on the times of administration.
The compounds of the present invention may be orally administered in the form of a solid containing a vehicle - such as starch, lactose, sucrose, glucose, microcrystalline cellulose or a kind of clay, a coloring agent, lubricant, binding agent, disintegrating agent, or a coating agent. Alternatively, the compounds of the present invention may be administered parenterally in the form of a sterilized solution. The solution may contain another solute, such as sodium chloride or glucose enough to make the solution isotonic. Since the compounds of the present invention have chemical structural stabilities, there is no difficulties in formulating the 72 21~8374 compounds. Thus, the compounds may be formulated into a wide variety of preparations such as formulations for oral administration (tablets, powder, granules),-various injection solutions, suppositories, ointments, lotions and the like.

Examples of a part of the present invention will now be described.
Reference Example 1 Methyl 3-methoxy salicylate ~ COOMe MeO
3-methoxysalicylic acid (23.8 g) was dissolved in anhydrous methanol (400 ml) and concentrated sulfuric acid (2.5 ml) was added, followed by stirring the mixture for 25 hours. After evaporating the solvent under reduced pressure, the residue was poured into water and the resultant was extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution, water and with saturated brine, and then dried over magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated off. The obtained compound was recrystallized from ethyl acetate/n-hexane to obtain the desired product (24.6 g, yield: 96%).
m.p.: 64.0-64.5 C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3342,1688,1628,1597,1510,1466,1379,1346,1274,1224,1191, 1145,1079,998,940,853,789,762,741,723,679,650,586,528,441 N M R(300MHz CDC13 ) 11.01(1H,s),7.44(1H,dd,J=2,8Hz),7.05(1H,dd,J=2,8Hz), 6.83(1H,t,J=8Hz),3.96(3H,s),3.91(3H,s) EI-MS m/e 182(M+) Reference Example 2 Methyl 2-methoxycarbonylmethyloxy-3-methoxy benzoate O ~ COOMe MeO
Methyl 3-methoxysalicylic acid (22.5 g) and methyl bromoacetate (20.4 g) were dissolved in DMF (370 ml) and anhydrous potassium carbonate (20.2 g) was added, followed by stirring the mixture at room temperature for 30 hours. After removing the solvent by evaporation under reduced pressure, the residue was poured into water and the resultant was extracted with ethyl acetate. The _ 15 organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated off. The obtained residue was purified by distillation under reduced pressure (bp. 157-159C/6 mmHg) to obtain the desired compound (23.2 g, yield: 91%).
m.p.: 71C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3342,1688,1628,1597,1510,1466,1379,1346,1274,1224,1191,11 45,1079,998,940,853,789,762,741,723,679,650,586,528,441 2 ~ 88374 NMR(300MHz CDCl3 ) ~ 7-33tlH,dd,J=2,8Hz),7.12(lH,t,J=8Hz),7.06(1H,dd, J=2,8Hz),4.69(2H,s),3.89(3H,s),3.86(3H,s),3.82(3H,s) EI-MS m/e 254(M+) Reference Example 3 Methyl 3-hydroxy-7-methoxybenzofuran-2-carboxylate OH

COOMe ~ O
MeO
Sodium hydride (752 mg) was washed with n-hexane and dried under reduced pressure. Methyl 2-methoxycarbonylmethyloxy-3-methoxy benzoate (4.68 g) was dissolved in toluene (50 ml) and the solution was added to the sodium hydride, followed by stirring the mixture at 100C for 22 hours. The reaction solution was poured into lN hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated off. The obtained residue was recrystallized from ethyl acetate/n-hexane to obtain the desired compound (2.53 g, yield: 63%).
m.p.: 114C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3342,1688,1628,1597,1510,1466,1379,1346,1274,1224,1191, 76 ~l 88374 1145,1079,998,940,853,789,762,741,723,679,650,586,528,441 cm-l NMR(300MHz CDCl3 ) ~ 8.07(lH,bs),7.32(lH,dd,J=1,8Hz),7.22(lH,t,J=8Hz), 6.97(1H,dd,J=1,8Hz),4.00(3H,s),3.99(3H,s) EI-MS m/e 222(M+) Reference Example 4 Methyl 7-methoxy-3-oxo-2-(2-propenyl)-2,3-_ dihydrobenzofuran-2-carboxylate MeO
Methyl 3-methoxy-2-(methoxycarbonylmethoxy) benzoate (19.39 g) was dissolved in toluene (200 ml). To this solution, sodium hydride (3.36 g) was added and the resultant was stirred at room temperature for 20 minutes, - 15 followed by refluxing the mixture for 2 hours. Toluene was evaporated off under reduced pressure and the residue was dissolved in DMF (150 ml). To this solution, acetic acid (2 ml) was added and the solvent was evaporated off under reduced pressure. The residue was dissolved in toluene (200 ml) and the solution was refluxed for 1 hour.
The reaction solution was cooled to room temperature and poured into water (150 ml), followed by separating the organic layer. The aqueous layer was extracted with ethyl acetate (100 ml) and the organic layers were 77 2i 8 83 74 combined. The resultant was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated off, and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate = 3/1) using silica gel to obtain the desire compound (18.42 g, yield: 92%).
_ IR (liquid film method) 2970,1745,1718,1640,1617,1600,1506,1440,1350,1261,1194, 1170,1153,1125,1081,1065,1013,965,936,888,847,808,771,731 cm~l NMR(300MHz CDCl3 ) ~ 7.24(1H,dd,J=7.7,1.4Hz),7.15(1H,dd,J=8.0,1.4Hz), 7.06(1H,t,J=7.7Hz), 5.67(1H,ddt,J=17.3,10.1,7.1Hz),5.27-5.20(lH,m),5.11-5.07(lH,m),3.99,3.75(each3H,s), 3.08(lH,ddt,J=14.5,7.2,1.1Hz),2.91(1H,ddt,J=14.6,7.7.4, -- l.lHz) EI-MS m/e 262(M+) Reference Example 5 7-methoxy-3-oxo-2-(2-propenyl)-2,3-dihydrobenzofuran ~0~
MeO
Methyl 7-methoxy-3-oxo-2-(2-propenyl)-2,3-dihydrobenzofuran-2-carboxylate (18.42 g) and ~1 88374 concentrated sulfuric acid (2 ml) were dissolved in t-butyl alcohol (150 ml) and the solution was refluxed for 22.5 hours. After cooling the reaction solution to room temperature, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and then washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=4/1) using silica gel to obtain the desired compound (11.39 g, yield: 79%).
IR (liquid film method) 3080,3014,2940,2844,1717,1644,1603,1506,1441,1352,1319, 1270,1209,1185,1168,1091,1064,1029,1011,922,876,855,797, 752,733cm 1 NMR(300MHz CDC13 ) 7.24(1H,dd,J=7.7,1.1Hz),7.15(1H,dd,J=7.7,1.1Hz), 7.02(1H,t,J=7.7Hz), 5.82(1H,ddt,J=17.3,10.1,6.9Hz), 5.24(lH,ddd,J=7.3,1.6,1.4Hz)),5.14-5.09(1H,m), 4.68(lH,dd,J=6.8,4.7Hz),3.96(3H,s),2.89-2.78(lH,m), 2.66-2.55(lH,m) EI-MS m/e 204(M+) Reference Example 6 3-bromomethyl-7-methoxybenzofuran _ 79 2 1 88374 ~ Br MeO
7-methoxy-2,3-dihydrobenzofuran-3-one (1.00 g) which is obtained by the process described in a reference (J.
Org. Chem. 53, 423-425(1988) and dibromomethane (1.3 ml) were dissolved in tetrahydrofuran (30 ml) and the _ solution was cooled to -78C. To this solution, n-butyllithium (1.62 M, 14.8 ml) was added dropwise for 10 minutes, and the resulting solution was stirred at -78C
for 30 minutes. To this reaction solution, acetic acid (2 ml) was added and the solution was poured into water layer (30 ml). The water layer was extracted twice with ethyl acetate (20 ml) and the organic layers were combined. The resultant was washed with saturated brine and dried over sodium sulfate. After removing sodium _ 15 sulfate by filtration, the solvent was evaporated off.
The obtained residue was dissolved in benzene (30 ml) and p-toluenesulfonic acid (121 mg) was added thereto, followed by stirring the mixture at room temperature for 10.5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=15/1) using silica gel to obtain the desired compound (607 mg, yield:
41%).
m.p.: 66-67C (recrystallized from hexane/ethyl acetate) 80 21 ~8374 IR (KBr method) 3118,1626,1595,1493,1468,1433,1361,1286,1270,1216,1203, 1178,1149,1108,1046,922,822,783,741,719,681,656,607,582 cm NMR(90MHz CDCl3 ) ~ 7.69(lH,s),7.29-7.22(2H,m),6.85(lH,dd,J=2.9,6.0Hz), 4.61(2H,d,J=0.7Hz),4.01(3H,s) EI-MS m/e 241(M+) _ Reference Example 7 3-chlromethyl-7-methoxybenzofuran S~CI

MeO
The same procedure as in Reference Example 6 was repeated except that chlorobromomethane was used in place of dibromomethane to obtain the desired compound (2.23 g, _ 15 yield: 37%) from 7-methoxy-2,3-dihydrobenzofuran-3-one (5.03 g)-IR (KBr method) 3120,2966,1626,1595,1495,1466,1456,1435,1363,1288,1272, 1203,1180,1156,1133,1112,1060,1044,924,824,783,737,721, 694,677,627,605 cm~
NMR(90MHz CDCl3 ) 7.67(lH,s),7.28-7.21(2H,m),6.89(lH,m,), 4.74(2H,d,J=0.7Hz),4.01(3H,s) EI-MS m/e 196(M+) 81 2 1 ~374 Reference Example 8 3-azidomethyl-7-methoxybenzofuran ~ N3 MeO
3-bromomethyl-7-methoxybenzofuran (565 mg) and sodium azide (230 mg) were dissolved in methanol-water - (5:1, 10 ml) and the solution was refluxed for 1 hour.
After cooling the reaction solution to room temperature, the reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl - 15 acetate=9/1) using silica gel to obtain the desired compound (452 mg, yield: 95~).
IR (liquid film method) 2944,2844,2104,1628,1593,1495,1437,1361,1344288,1270, 1245,1212,1180,1149,1106,1052,787,729 cm~
NMR(90MHz CDCl3 ) 7.66(1H,s),7.26-7.19(2H,m),6.90-6.80(lH,m),4.45(2H,s).03(3H,s) EI-MS m/e 203(M+) Reference Example 9 82 2 i 88374 7-acetoxy-3-((acetylamino)methyl)benzofuran ~ NHAc AcO

3-azidomethyl-7-methoxybenzofuran (325 mg) was dissolved in diethyl ether (10 ml) and the solution was cooled to 0C. To this solution, lithium aluminum - hydride (91 mg) was added and the resulting solution was stirred at 0C for 1 hour and then at room temperature for 1.5 hours. To the reaction solution, saturated aqueous sodium hydrogen carbonate was added and the solution was dried over magnesium sulfate, followed by filtration. After concentrating the filtrate, the residue was dissolved in dimethylformamide (7 ml). To this solution, potassium t-butoxide (415 mg) and n-propanethiol (0.34 ml) were added and the solution was - 15 stirred at 100C for 1.5 hours. After the reaction, the reaction solution was cooled to 0C and pyridine (1.2 ml) and acetyl chloride (1.05 ml) were added, followed by stirring the resulting solution for 40 minutes. The reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with lN hydrochloric acid (20 ml) and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under ` - 83 2 1 &8374 reduced pressure and the residue was purified by column chromatography (solvent: chloroform/methanol=95/5) using silica gel to obtain the desired compound (260 mg, yield:
66%).
m.p.: 138-139C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3298,1763,1651,1591,lS60,1522,1510,1493,1475,1460,1437, - 1375,1344,1296,1284,1251,1218,1191,1170,1145,1098,1083, 1052,1019,967,899,876 cm~
NMR(90MHz CDCl3 ) ~ 7.57(lH,s),7.54-7.03(3H,m),4.55(2H,d,J=5.7Hz), 2.40(3H),2.01(3H,s) EI-MS m/e 247(M+) Reference Example 10 7-phenoxyacetoxy-3-((phenoxyacetylamino)methyl)benzofuran - ~ OPh ~ OPh The same procedure as in Reference Example 4 was repeated except that phenoxyacetyl chloride was used in place of acetyl chloride to obtain the desired compound (278 mg, yield: 29%) from 3-azidomethyl-7-84 2 1 ~8374 methoxybenzofuran (452 mg).
m.p.: 117-118C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3622,3418,3126,1794,1783,1688,1626,1601,1589,1535,1491, 1458,1437,1365,1344,1301,1290,1249,1236,1197,1172,1149, 1089,1075,1060,1015,967,851,837,824,801,768,750 cm NMR(90MHz CDCl3 ) - ~ 7.56(lH,s),7.53-6.83(13H,m?,4.99(2H,s), 4.65(2H,d,J=5.5Hz),4.55(2H,s) EI-MS m/e 431(M+) Reference Example 11 3-(diphenylmethylthiomethyl)-7-methoxybenzofuran ~ Ph MeO
~ 15 Under argon atmosphere, diphenylmethanethiol (121 mg) was dissolved in DMF (2 ml) and the solution was stirred at room temperature. To this solution, potassium t-butoxide (81 mg) and 3-chloromethyl-7-methoxybenzofuran (118 mg) were added and the solution was stirred at room temperature. After confirming vanishment of the materials, the reaction solution was poured into saturated aqueous ammonium chloride solution (5 ml) and the resulting solution was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium-sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=20/1) using silica gel to obtain the desired compound (183 mg, yield:
85%).
IR (liquid film method) - 1626,1589,1493,1452,1433,1354,1274,1203,1180,1156,1100, 1046,789,739,704 cm NMR(400MHz CDC13 ) ~ 7.39-7.15(13H,m),6.83(1H,dd,J=7.8,1.0Hz), 5.00(lH,s),4.02(3H,s),3.63(2H,s) EI-MS m/e 360(M+) Reference Example 12 3-(diphenylmethylthiomethyl)-7-hydroxybenzofuran Ph ~S~

HO
Under argon atmosphere, 3-(diphenylmethylthiomethyl)-7-methoxybenzofuran (45 mg) was dissolved in DMF (3 ml) and the solution was stirred at room temperature. To this solution, n-propanethiol (0.20 ml) and potassium t-butoxide (47 mg) were added and the resulting solution was stirred at 100C. After confirming vanishment of the materials, the reaction mixture was poured into saturated aqueous ammonium chloride solution (5 ml) and the resulting solution was extracted three times with ethyl acetate (10 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate.
After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
- hexane/ethyl acetate-5/1 - 3/1) using silica gel to obtain the desired compound (26 mg, yield: 60%).
IR (liquid film method) 3400,1622,1491,1448,1357,1274,1222,1183,1096,969,785,733, 702cm~1 NMR(400MHz CDCl3 ) ~ 7.39-7.09(13H,m),6.85(1H,dd,J=7.8,1.0Hz), 5.47(lH,br s),5.02(lH,s),3.63(3H,d,J=l.OHz) EI-MS m/e 346(M+) -- Reference Example 13 Methyl 7-methoxybenzofuran-3-acetate ~ COOMe MeO
7-methoxy-2,3-dihydrobenzofuran-3-one (10.36 g) and methyl(triphenylphosphoranilidene)acetate (26.92 g) were added to xylene (200 ml) and the mixture was refluxed for 28 hours. After cooling the reaction solution to room 87 2 1 &8374 temperature, cyclohexane (100 ml) was added to the reaction solution, and the resultant was filtered. The filtrate was concentrated and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (12.37 g, yield: 91%).
IR (liquid film method) 2956,1738,1628,1591,1495,1437,1363,1319,1270,1207,1168, - 1100,1050,1009,787,733,625 cm~
NMR(90MHz CDCl3 ) ~ 7.63(1H,s),7.25-7.13(2H,m),6.80(1H,dd,J=5.5,3.3Hz), 4.00(3H,s),3.72(3H,s),3.69(2H,d,J=l.lHz) EI-MS m/e 220(M+) Reference Example 14 Methyl (7-methoxy-2-(2-propenyl)benzofuran-3-yl)acetate ~ COOMe MeO
THF (10 ml) was added to zinc powder (5.92 g) and then a catalytic amount of iodine was added. While vigorously stirring the resulting solution, a small amount of a solution of 7-methoxy-3-oxo-2-(2-propenyl)-2,3-dihydrobenzofuran (6.16 g) and methyl bromoacetate (8.9 ml) in THF (90 ml) was added at room temperature.

After confirming generation of heat, the reaction 2 ~ 88374 solution was cooled to 0C and the remainder of the solution was added dropwise for 15 minutes. The reaction solution was stirred at 0C for 3 hours, cooled to room temperature and was stirred for another 2.5 hours.
Acetic acid (5.5 ml) was added to the reaction solution and the resultant was filtered through Celite. After removing the solvent under reduced pressure, the residue was dissolved in toluene (100 ml) and p-toluenesulfonic - acid (536 mg) was added thereto, followed by stirring the resulting mixture at room temperature for 2 hours. The reaction solution was poured into water (150 ml) and the resultant was extracted twice with ethyl acetate (50 ml).
After combining the organic layers, the resultant was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the - residue was purified by column chromatography (solvent:
hexane/ethyl acetate=3/1) using a silica gel to obtain the desired compound (5.23 g, yield: 67%).
m.p.: 65-66C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2998,2950,1735,1628,1591,1498,1441,1425,1386,1329,1308, 1280,1266,1231,1213,1198,1181,1166,1144,1094,1069,1007, 992,916,899,849,827,783,761,726 cm~
NMR(300MHz CDCl3 ) ~ 7.15(1H,t,J=7.7Hz),7.09(1H,dd,J=7.7,1.4Hz), _ 89 2~8~374 6.77(1H,dd,J=7.4,1.4Hz), 5.82(1H,ddt,J=17.2,10.2,6.3Hz), 5.15(lH,dq,J=25.6,1.6Hz),3.99,3.68(each3H,s),3.63(2H,s), 3.57(2H,dt,J=6.3,1.6Hz) EI-MS m/e 260(M+) Reference Example 15 Methyl (7-hydroxybenzofuran-3-yl)acetate COOMe HO
Methyl (7-methoxybenzofuran-3-yl)acetate (12.37 g) was dissolved in dichloromethane (50 ml) and the solution was cooled to -78C. To this solution, boron tribromide (1.0 M, 120 ml) was added dropwise for 50 minutes.
Thereafter, the temperature was raised to room temperature and the reaction solution was stirred at this temperature for 3 hours. After completion of the -- 15 reaction, the reaction solution was cooled to -78C and methanol (100 ml) was added thereto. After neutralizing the reaction mixture by adding sodium hydrogen carbonate, the resulting solution was filtered. The filtrate was concentrated and poured into water layer (300 ml) and the resultant was extracted twice with ether (150 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate.
After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the -- go 2 1 88374 residue was purified by column chromatography (solvent:
hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (10.53 g, yield: 91%).
m.p.: 58-59C (recrystallized from cyclohexane/ethyl acetate) IR (KBr method) 3284,1698,1593,1495,1473,1365,1294,1261,1180,1129,1093, 1015,977,772,727 cm~
_ NMR(90MHz CDCl3 ) ~ 7.66(1H,s),7.31-7.09(2H,m),6.87(lH,dd,J=4.2,4.8Hz), 5.58(lH,brm),3.79(3H,s),3.75(2H,d,J=l.lHz) Reference Example 16 7-hydroxy-3-(2-hydroxyethyl)benzofuran OH

HO
Methyl (7-hydroxybenzofuran-3-yl)acetate (1.46 g) was dissolved in THF (30 ml) and the solution was cooled to 0C. To this solution, lithium aluminum hydride (269 mg) was added and the solution was stirred for 3.5 hours.
After making the pH of the reaction solution not more than 2 by adding lN hydrochloric acid, the reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml).
After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate.

After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=l/l) using silica gel to obtain the desired compound (1.09 g, yield: 86%).
m.p.: 116-117C (recrystallized from hexane/ethyl acetate) IR (KBr method) _ 3416,3090,2982,2940,1597,1491,1477,1408,1363,1319,1267, 1185,1168,1137,1098,1054,1017,980,934,855,799,787,739, 704,634,572,557,545cm~
NMR(90MHz CDC13 ) ~ 7.48(lH,s),7.08-7.02(2H,m),6.92-6.75(lH,m), 3.89(2H,t,J=6.6Hz),2.90(2H,t,J=5.5Hz) EI-MS m/e 178(M+) Reference Example 17 Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate ~ ~ OH

~ COOMe 7-hydroxy-3-(2-hydroxyethyl)benzofuran (1.09 g), methyl bromoacetate (0.86 ml) and potassium carbonate (930 mg) were added to DMF (50 ml) and the mixture was stirred at room temperature for 18 hours. After filtering the reaction solution, the filtrate was concentrated and added to water layer (150 ml), followed by extracting the resultant twice with ethyl acetate (20 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=1/1) using silica gel to obtain the _ desired compound (1.48 g, yield: 97%).
IR (KBr method) 3500,3456,3422,2860,1746,1715,1673,1630,1586,1495,1481, 1450,1435,1379,1270,1207,1156,1098,1085,1062,1040,1009, 953,868,830,787,745,731 cm~
NMR(90MHz CDCl3 ) ~ 7.53(1H,s),7.26-7.13(2H,m),6.78(1H,dd,J=6.6,2.6Hz), 4.88(2H,s),4.03-3.89(2H,m),3.81(3H,s), 2.93(2H,dt,J=6.2,0.9Hz) Reference Example 18 Methyl (3-(2-bromoethyl)benzofuran-7-yloxy)acetate ~ Br ~ COOMe Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (1.30 g) was dissolved in THF (15 ml) and the solution was cooled to 0C. To this solution, triphenylphosphine (2.05 g) and N-bromosuccinimide (NBS, 1.39 g) were added and the resulting solution was stirred for 1 hour.
Hexane (10 ml) was added to the reaction solution and the reaction solution was filtered through Celite. The filtrate was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate.
_ After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (1.39 g, yield: 85%).
m.p.: 58 - 59C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3110,2956,2916,1767,1628,1591,1499,1435,1390,1365,1296, - 1278,1214,1203,1149,1116,1085,988,948,905,84583,745,729, 650,590,545cm~1 NMR(9OMHz CDCl3 ) ~ 7.54(lH,s),7.20-7.14(2H,m),6.81(lH,m),4.88(2H,s), 3.81(3H,s),3.73-3.56(2H,m),3.32-3.24(2H,m) EI-MS m/e 312(M+) Reference Example 19 Methyl (3-(2-methanesulfonyloxyethyl)benzofuran-7-yloxy)acetate 21 &837~
OMs ~ COOMe Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (4.12 g) was dissolved in dichloromethane (120 ml) and triethylamine (3 ml) and methanesulfonyl chloride (1.35 - S ml) were added to the solution, followed by stirring the resulting solution at 0C for 1.5 hours. The reaction mixture was then poured into lN hydrochloric acid and the resultant was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and with saturated saline, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure. The residue was ~~ recrystallized from n-hexane/ethyl acetate to obtain the desired compound (5.25 g, yield: 97%).
m.p.: 102.0C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3130,1763,1630,1586,1493,1439,1354,1288,1203,1172,1091, 984,963,907,843,793,758,735,717,526,472cm~
NMR(300MHz CDCl3 ) ~ 7.56(1H,s),7.21(1H,dd,J=2,8Hz),7.17(1H,t,J=8Hz), 6.79(dd,1H,J=2,8Hz),4.89(2H,s),4.48(2H,t,J=7Hz), 9S 21 8837~

3.92(3H,s),3.81(3H,s),3.15(2H,dt,J=1,7Hz) EI-MS m/e 328(M+) Reference Example 20 Methyl (3-(2-azidoethyl)benzofuran-7-yloxy)acetate ~ N3 _ 5 ~ COOMe By the similar method as in Reference Example 8, the desired compound (654 mg, yield: 90%) was obtained from methyl (3-(2-bromoethyl)benzofuran-7-yloxy)acetate (830 mg).
IR (KBr method) 3114,2914,2086,1771,1630,1593,1576,1493,1448,1435,1392, 1365,1288,1270,1245,1210,1187,1149,1096,1062,1040,949, 903,855,777,741,729,665,630,605cm~
NMR(90MHz CDC13 ) ~ 7.51(1H,s),7.20-7.14(2H,m),6.78(lH,dd,J=5.4,3.5Hz), 4.88(2H,s),3.80(3H,s),3.58(2H,t,J=7.1Hz), 2.94(2H,t,J=7.lHz) Reference Example 21 Methyl (3-(2-hydroxyethyl)-2-(2-propenyl)benzofuran-7-yloxy)acetate _ 96 21 88374 ~ COOMe Methyl (7-methoxy-2-(2-propenyl)benzofuran-3-yl)acetate (464 mg) was dissolved in dichloromethane (4 ml) and the solution was cooled to 0C. To this solution, _ 5 boron tribromide (1.0 M, 3.9 ml) was added and the solution was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and the resulting solution was poured into water layer (50 ml), followed by extracting the resultant twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was dissolved in THF (15 ml). This solution was cooled to 0C and lithium aluminum hydride (91 mg) was added, followed by stirring the resulting mixture at 0C for 30 minutes and then at room temperature for 1.5 hours. Ethyl acetate was added to the reaction solution to quench the lithium aluminum hydride, and water (0.2 ml) and acetic acid (0.5 ml) were added, followed by stirring the solution at room temperature for 30 minutes. To this solution, sodium hydrogen carbonate (600 mg) and magnesium sulfate were added and the solution was filtered through Celite.
After removing the solvent under reduced pressure, the residue was dissolved in DMF (5 ml). To this solution, methyl bromoacetate (0.5 ml) and potassium carbonate (606 mg) were added and the solution was stirred at room temperature for 17 hours. The reaction solution was poured into water (80 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturate brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using silica gel to obtain the desired compound (450 mg, yield: 87%).
IR (liquid film method) 3402,3012,2956,2884,1744,1628,1591,1493,1441,1381,1294, 1203,1085,1048,996,919,855,781,733 cm~
NMR(300MHz CDCl3 ) ~7.16-7.08(2H,m),6.73(lH,dd,J=7.1,1.6Hz), 5.99(1H,ddt,J=17.0,10.2,6.3Hz),5.19-5.10(2H,m), 4.89(2H,s),3.85(2H,t,J=6.3Hz),3.81(3H,s), 3.56(2H,dt,J=6.3,1.6Hz),2.89(2H,t,J=6.3Hz) EI-MS m/e 290(M+) Reference Example 22 Methyl (2-(2-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate ` - 98 21 88374 ~ COOMe Methyl (3-(2-hydroxyethyl)-2-(2-propenyl)benzofuran-yloxy)acetate (450 mg) was dissolved in THF (2 ml). To this solution, 2,3-dihydropyrane (0.212 ml) and p-toluenesulfonic acid (15 mg) were added and the solutionwas stirred at room temperature for 1.5 hours. The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml).
The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (544 mg, yield:
94%).
IR (liquid film method) 2946,2872,1767,1742,1628,1591,1493,1441,1381,1352,1292, 1201,1137,1122,1079,1035,994,971,907,870,855,781,733 cm~
NMR(300MHz CDCl3 ) ~7.16(1H,dd,J=8.0,1.1Hz),7.09(1H,t,J=8.0Hz), 6.70(1H,dd,J=8.0,1.1Hz), 5.98(lH,ddt,J=17.0,10.2,6.3Hz), 5.20-5.09(2H,m),4.88(2H,s),4.59-4.57(lH,brm), ^ - 99 21 88374 3.94(lH,dt,J=9.6,6.9Hz),3.81t3H,s),3.80-3.72(lH,m), 3.61-3.53(3H,m),3.49-3.41(1H,m),2.92(2H,t,J=6.9Hz), 1.84-1.45(6H,m) EI-MS m/e 374(M+) Reference Example 23 Methyl (2-(2-hydroxyethyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yl)acetate C ~ ~ ~ ; H

~ COOMe Methyl (2-(2-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (0.97 g) and osmium tetroxide (0.07 M solution in t-butyl alcohol, 0.37 ml) were dissolved in dioxane/water (3:1) and the solution was cooled to 0C. To this solution, - sodium periodate (1.38 g) was added for 10 minutes.
After stirring the reaction solution at 0C for 30 minutes, the solution was stirred at room temperature for additional 30 minutes. The reaction solution was filtered through Celite and the precipitate was washed with THF (12 ml). The filtrate was cooled to 0C and sodium borohydride (98 mg) was added, followed by stirring the resultant for 40 minutes. The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The loo 21 88374 organic layers were combined and washed with lN
hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=l/l) using silica gel to obtain the desired compound (412 mg, yield:
42%).
IR (liquid film method) 3444,2952,2874,1765,1744,1628,1591,1493,1441,1381,1354, 1325,1288,1203,1137,1122,1104,1069,1035,971,907,870,814, 781,735cm~l NMR(300MHz CDCl3 ) ~ 7.14(1H,dd,J=8.0,1.4Hz),7.09(1H,t,J=7.7Hz), 6.70(1H,dd,J=7.7,1.4Hz), 4.87(2H,s),4.54-4.52(1H,brm),4.11-4.04(1H,m),3.93(2H,t,J=5.8Hz), 3.81(3H,s),3.71-3.58(3H,m),3.43-3.35(lH,m), 3.05(2H,t,J=5.8Hz),2.96(2H,t,J=6.31Hz),1.76-1.42(6H,m) EI-MS m/e 378(M+) Reference Example 24 Methyl (2-(2-acetoxyethyl)-3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate - lol 2 1 88374 ; ~ ~OAc ~ COOMe Methyl (2-(2-hydroxyethyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (403 mg), pyridine (0.13 ml) and acetic anhydride (0.3 ml) were dissolved in THF (5 ml) and the solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 ml) and the organic layer was separated, followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with lN hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, - the solvent was removed under reduced pressure and the residue was dissolved in methanol (4 ml). To this solution, lN hydrochloric acid (1 ml) was added and the solution was stirred at room temperature for 2 hours.
The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate - 102 2~ 88374 by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/2) using silica gel to obtain the desired compound (412 mg, yield:
42%).
m.p.: 80 - 81C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3322,3220,2960,1734,1632,1497,1475,1452,1439,1371,1311, 1296,1270,1247,1210,1174,1102,1067,1052,1011,864,777, 733cm~l NMR(300MHz CDCl3 ) ~ 7.14-7.09(2H,m),6.74(lH,dd,J=7.4,2.5Hz),4.88(2H,s), 4.43(2H,t,J=6.6Hz),3.87(2H,t,J=6.3Hz),3.81(3H,s), 3.13(2H,t,J=6.6Hz),2.90(2H,t,J=6.3Hz),2.03(3H,s) EI-MS m/e 336(M+) Reference Example 25 - Methyl (3-(2-hydroxyethyl)-2-(1-propenyl)benzofuran-7-yloxy)acetate -COOMe 3-(2-hydroxyethyl)-7-methoxy-2-(2-propenyl)benzofuran (1.43 g), n-propanethiol (0.84 ml) and potassium t-butoxide (968 mg) were dissolved in DMF

- 103 21 ~8374 (15 ml) and the solution was stirred at room temperature for 5 minutes and then at 100C for 5 hours. After cooling the reaction temperature to room temperature, methyl bromoacetate (0.87 ml) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (150 ml) and the resultant was extracted twice with ethyl acetate (20 ml).
The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (630 mg, yield:
35%)-IR (liquid film method) -- 3380,3042,2956,2880,1742,1624,1593,1493,1437,1377,1299, 1205,1110,1085,1048,959,781,735cm~
NMR(300MHz CDCl3 ) ~ 7.14-7.08(2H,m),6.76(1H,dd,J=7.1,1.6Hz),6.61-6.38(2H,m),4.92(2H,s),3.85(2H,t,J=6.6Hz),3.82(3H,s), 2.93(2H,t,J=6.3Hz),1.94(2H,dd,J=6.6,1.4Hz) EI-MS m/e 290(M+) Reference Example 26 Methyl (2-(1-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate OTHP

~ COOMe By the method similar to Reference Example 22, the desired compound (741 mg, yield: 93%) was obtained from methyl (3-(2-hydroxyethyl)-2-(1-propenyl)benzofuran-7-_ 5 yloxy)acetate (620 mg).
IR (liquid film method) 3042,2928,2862,1763,1742,1624,1593,1493,1437,1381,1352, 1290,1191,1120,1067,1033,963,938,907,870,814,781,733 cm-NMR(300MHz CDCl3 ) ~ 7.15(lH,dd,J=8.0,1.lHz),7.07(lH,t,J=8.OHz), 6.73(1H,dd,J=7.7,1.1Hz),6.56-6.35(2H,m),4.91(2H,s),4.59-4.56(lH,brm),3.93(lH,dt,J=9.6,6.9Hz),3.81(3H,s),3.82-3.72(lH,m),3.58(lH,dt,J=9.6,6.9Hz),3.48-3.40(lH,m), - 2.95(2H,t,J=6.9Hz),1.93(2H,d,J=5.2Hz),1.86-1.44(6H,m) EI-MS m/e 374(M+) Reference Example 27 Methyl (2-(3-acetoxy-1-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate OTHP

OAc ~ COOMe _ 105 2188374 Methyl (2-(1-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (523 mg) was dissolved in benzene (5 ml) and NBS (299 mg) and azoisobutylonitrile (23 mg) were added, followed by stirring the mixture for 4 hours. The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, _ followed by drying the resultant over sodium sulfate.
After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was dissolved in DMF (4 ml). Potassium acetate (205 mg) was added to this solution and the solution was stirred at room temperature for 50 minutes. The reaction solution was added to water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine and _ dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (217 mg, yield:
36%).
IR (liquid film method) 2948,2872,1734,1688,1626,1593,1493,1437,1381,1205,1122, 1081,1033,963,907,870,814,783,735cm-NMR(30OMHz CDCl3 ) - 106 21 ~8374 ~ 7.18(1H,dd,J=7.9,1.1Hz),7.10(1H,t,J=7.9Hz), 6.77(1H,dd,J=7.9,1.1Hz),6.69(1H,dt,J=15.7,1.4Hz),6.52(1H, dt,J=15.7,6.3Hz),4.90(2H,s),4.77(2H,dd,J=16.0,1.4Hz), 4.57(1H,brm),3.95(1H,dt,J=9.3,6.9Hz),3.82(3H,s), 3.77-3.69(lH,brm),3.59(lH,dt,J=9.6,6.9Hz), 3 47-3.39(lH,brm),2.98(2H,t,J=6.9Hz),2.12(3H,s), 1.84-1.44(6H,m) EI-MS m/e 432(M+) Reference Example 28 Methyl (2-(3-acetoxypropyl)-3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate OH

OAc ~ COOMe Methyl (2-(3-acetoxy-1-propenyl)-3-(2-- tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (199 mg) was dissolved in methanol (4 ml) and 5% Pd/C (28 mg) was added to the solution, followed by stirring the solution at room temperature for 1.5 hours under hydrogen atmosphere. After filtering the reaction solution through Celite, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using silica gel to obtain the desired compound (80 mg, yield:
50%)-IR (liquid film method) 3410,2958,1734,1628,1591,1493,1441,1369,1247,1199,1106, 1046,861,i81,756,735,665 cm~
NMR(300MHz CDCl3 ) ~ 7.14-7.07(2H,m),6.71(1H,dd,J=6.9,2.2Hz),4.88(2H,s), 4.12(2H,t,J=6.3Hz),3.86(2H,t,J=6.6Hz),3.81(3H,s), 2.87(4H,m),2.09(2H,quint,J=7.1Hz),2.03(3H,s) EI-MS m/e 350(M+) - Reference Example 29 Methyl (7-tetrahydropyranyloxybenzofuran-3-yl)acetate ~ COOMe THPO
By the method similar to Reference Example 22, the desired compound (606 mg, yield 87%) was obtained from - - 15 methyl (7-hydroxybenzofuran-3-yl)acetate (492 mg).
IR (llquid film method) 2878,2854,1734,1628,1591,1491,1458,1437,1390363,1319, 1259,1166,1100,1077,1052,1023,988,946,903,874,82089,735, 627,567cm-1 NMR(9OMHz CDCl3 ) ~ 7.63(1H,s),7.21-7.11(3H,m),5.68(lH,m),4.15-3.50(2H,m).73(3H,s),3.70(2H,d,J=l.lHz),2.10-1.60(6H,m) EI-MS m/e 290(M+) Reference Example 30 ` - 108 2i88374 3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran ~ OH

THPG
Methyl (7-tetrahydropyranyloxybenzofuran-3-yl)acetate (355 mg) was dissolved in THF (4 ml) and the solution was cooled to 0C. To this solution, lithium - aluminum hydride (47 mg) was added and the solution was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution and the solution was filtered through Celite. The filtrate was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated saline, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate 15 by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (289 mg, yield:
90% ) .
IR (liquid film method) 3348,2950,2878,1628,1589,1491,1435,1390,1359286,1259, 1183,1145,1116,1096,1025,944,949,903,872,787,735,408 cm~
NMR(90MHz CDCl3 ) ~ 7.50(1H,s),7.26-7.06(3H,m),5.68(lH,m),4.16-log 2i 88374 3.48(4H,m).91(2H,t,J=6.4Hz),2.25-1.70(6H,m) EI-MS m/e 262(M+) Reference Example 31 3-(2-propenyl)-7-methoxybenzofuran MeO
- Cerium chloride (5.63 g) was placed in a dry eggplant type flask, and stirred at 150C under reduced pressure for 4 hours to dry. After replacing the atmosphere with nitrogen, the reaction mixture was cooled to room temperature. THF (30 ml) was added and the flask was left to stand overnight. The reaction mixture was cooled to 0C and allylmagnesium bromide (0.79 M solution in ether, 28.9 ml) was added dropwise. To this, 2,3-dihydro-3-oxo-7-methoxybenzofuran (2.5 g) was added and - 15 the resulting mixture was stirred at 0C for 1.5 hours.
The reaction solution was poured into water (200 ml) and acetic acid (3 ml), and the resultant was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated off to obtain brown syrup (4.52 g). This syrup (4.52 g) was dissolved in benzene (20 ml) and p-toluenesulfonic acid monohydrate llo 2188374 (50 mg) was added to the solution, followed by stirring - the resulting solution at 60C for 30 minutes. The reaction solution was poured into 5~ sodium hydrogen carbonate solution, and extracted with ethyl acetate.
The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, - the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
cyclohexane/diethyl ether=5/1 - 2/1) using silica gel.
The main fraction was further purified by column chromatography (solvent: n-hexane/ethyl acetate=20/1) to obtain the desired compound (2.05 g, yield: 72%).
IR (liquid film method) 2914,1738,1628,1591,1495,1437,1361,1284,1267,1096,1048, 919,785,731cm~1 NMR(300MHz CDCl3 ) ~ 7.42(1H,s),7.13-7.16(2H,m),6.80(1H,dd,J=3, 6Hz),5.95-6.10(lH,m),5.09-5.23(2H,m),4.10(3H,s),3.40-3.44(2H,m) EI-MS m/e 188(M+) Reference Example 32 3-(3-hydroxypropyl)-7-methoxybenzofuran / OH

MeO

111 21 8837~

3-(2-propenyl)-7-methoxybenzofuran (2.19 g) was dissolved in anhydrous tetrahydrofuran (25 ml) under argon atmosphere and the solution was cooled to-0C.
Borane dimethylsulfide complex (2M solution in THF, 6.1 ml) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was cooled to 0C and ethanol (20 ml), 3N aqueous sodium hydroxide solution (1.3 ml) and 30% hydrogen peroxide - solution (1.5 ml) were added. After stirring the reaction solution at room temperature for another 15 minutes, the reaction mixture was poured into saturated aqueous ammonium chloride solution, and the resultant was extracted with ethyl acetate. The organic layer was washed with water and with saturated brine, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column - chromatography (solvent: cyclohexane/ethyl acetate=3/1 -2/1) to obtain the desired compound (1.42 g, yield: 59%).
IR (liquid film method) 3378,2944,1626,1589,1493,1437,1361,1286,1267,1203,1180, 1143,1094,1060,1038,924,785,733cm~
NMR(300MHz CDCl3 ) ~ 7.44(lH,s),7.16(1H,m),6.81(1H,m),4.01(3H,s), 3.74(2H,t,J=6Hz),2.77(2H,dt,J=1,8Hz),1.98(2H,m), 1.49(lH,bs) EI-MS m/e 206(M+) Reference Example 33 3-(3-hydroxypropyl)-7-hydroxybenzofuran ~ OH
S~

By the similar method as in Reference Example 15, the desired compound (996 mg, yleld: 90%) was obtained - from 3-(3-hydroxypropyl)-7-methoxybenzofuran (1.187 g).
m.p.: 101.0 - 101.5C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3446,3140,1493,1379,1299,1272,1185,1098,1046,975,911,783, 727,567,509cm~1 NMR(300MHz CDC13 ) ~ 7.49(1H,d,J=7Hz),7.03(2H,m),6.70(1H,dd,J=2,7Hz), 3.62(2H,t,J=7Hz),2.72(2H,t,J=7Hz),1.90(2H,quint,J=7Hz) EI-MS m/e 192(M~) Reference Example 34 Methyl (3-(3-hydroxypropyl)benzofuran-7-yloxy)acetate _ ~ ; ~ OH

~ COOMe By the method similar to Reference Example 17, the desired compound (884 mg, yield: 83%) was obtained from ` - 113 21 ~8374 3-(3-hydroxypropyl)-7-hydroxybenzofuran (777 mg).
m.p.: 72 - 73C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3506,1715,1493,1458,1435,1340,1315,1265,1203,1145,1087, 1058,1009,729cm~1 NMR(300MHz CDCl3 ) ~ 7.45(1H,s),7.22(1H,m),7.14(1H,m),6.78(1H,d,J=7Hz), - 4.89(2H,s),3.82(3H,s),3.74(2H,t,J=6Hz),2.78(2H,t,J=6Hz), 1.98(2H,quint,J=6Hz) EI-MS m/e 264(M+) Reference Example 35 Methyl (3-(3-bromopropyl)benzofuran-7-yloxy)acetate Br ~ COOMe - 15 By the method similar to Reference Example 18, the desired compound (837 mg, yield: 95%) was obtained from (3-(3-hydroxypropy)benzofuran-7-yloxy)acetate (710 mg).
IR (liquid film method) 1769,1626,1584,1491,1437,1284,1270,1214,1205,1141,1085, 783,743cm~1 NMR(300MHz CDC13 ) ~ 7.48(lH,s),7.21(1H,dd,J=1,8Hz),7.15(1H,t,J=8Hz3, 6.78(1H,dd,J=1,8Hz),4.89(2H,s),3.82(3H,s), 3.45(2H,t,J=6Hz),2.86(2H,t,J=6Hz),2.24(2H,quint,J=6Hz) EI-MS m/e 326, 328(peak height ratio=l:l)(M+) Reference Example 36 3-(2-hydroxy-5,5-diphenylpentyl)-7-methoxybenzofuran - Ph C Ph MeO
- 5 Under argon atmosphere, methyl (7-methoxybenzofuran-3-yl)acetate (82 mg) was dissolved in methylene chloride (2 ml) and the solution was stirred at -78C. To this solution, diisobutylaluminum hydride (1.01 M solution in toluene (0.40 ml)) was added, and the resulting solution was stirrèd at -78C. After confirming vanishment of the materials, saturated aqueous sodium sulfate solution (5 ml) was gradually added to the reaction solution and the resultant was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure to obtain a partially purified product. Under argon atmosphere, the obtained partially purified product was dissolved in THF (2 ml) and the solution was stirred at -78C. To this solution, 3,3-diphenylmagnesium bromide was added and the temperature of the solution was gradually raised to room temperature. After confirming ~ 115 2 1 ~8374 vanishment of the materials, saturated aqueous ammonium chloride solution (5 ml) was added to the reaction solution, and the resulting solution was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was - purified by Lovar column chromatography (solvent:
hexane/ethyl acetate=10/1) to obtain the desired compound (36 mg, yield: 25%).
IR (liquid film method) 2942,1694,1626,1591,1495,1454,1437,1361,1284,1267,1205, 1180,1143,1096,1058,926,785,733,702cm~
NMR(300MHz CDCl3 ) ~ 7.45(1H,s),7.40-6.94(12H,m),6.81(1H,d,J=7.5Hz), 4.01(3H,s),4.07-3.07(2H,m),2.82(1H,dd,J=14.4,3.9Hz), - 2.68(lH,dd,J=14.4,8.4Hz),2.33-2.07(2H,m),1.70-1.40(2H,m) EI-MS m/e 386(M+) Reference Example 37 3-(2-acetoxy-5,5-diphenylpentyl)-7-acetoxybenzofuran Ph T

ACO

Under argon atmosphere, 3-(2-hydroxy-5,5-~ 116 2188374 diphenylpentyl)-7-methoxybenzofuran (130 mg) was dissolved in DMF and the solution was stirred at room temperature. To this solution, n-propanethiol (0.30 ml) and potassium t-butoxide (153 mg) were added and the solution was stirred at 100C. After confirming vanishment of the materials, saturated aqueous ammonium chloride solution (5 ml) was added to the reaction solution and the resulting solution was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by Lovar column chromatography (solvent: hexane/ethyl acetate=2/1), thereby purifying the residue. The obtained compound was dissolved in methylene chloride (2 ml) and the solution was stirred at room temperature. To this solution, - acetic anhydride (0.10 ml) and pyridine (0.10 ml) were added and the solution was stirred at room temperature.
After confirming vanishment of the materials, saturated aqueous ammonium chloride solution (5 ml) was added to the reaction solution, and the resultant was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (184 mg, yield: 100%).

NMR(300MHz CDC13 ) ~ 7.46(1H,d,J=7.5Hz),7.33(1H,s),7.29-7.12(11H,m), 7.05(1H,d,J=7.5Hz),5.17(1H,tt,J=6.0,6.0Hz), 3.84(lH,t,J=7.8Hz),2.91(1H,dd,J=14.4,5.7Hz), 2.82(1H,dd,J=14.4,6.0Hz),2.41(3H,s), - 2.20-2.00(2H,m),2.01(3H,s),1.62-1.54(2H,m) EI-MS m/e 456(M+) Reference Example 38 Ethyl 2-(2-formyl-6-methoxyphenoxy) propionate ~ CHO

O COOEt MeO

o-vanillin (24.20 g) was dissolved in DMF (300 ml) 15 and potassium carbonate (15.4 g) and ethyl 2-bromopropionate (24.8 ml) were added to the solution, followed by stirring the solution at room temperature for 19.5 hours. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was distilled to obtain the desired compound (36.98 g, yield:
93~).
b.p.: 129 - 130C/0.4 mmHg IR (liquid film method) 2988,2944,2900,1744,1694,1586,1483,1458,1394,1377,1309, 2i 88374 1251,1205,1131,1096,1067,1044,1019,913,785,764,743 cm~
NMR(90MHz CDCl3 ) ~ 10.61(1H,s),7.50-7.09(3H,m),5.05(1H,q,J=7.0Hz), 4.16(2H,q,J=7.OHz),3.88(3H,s),1.63(3H,d,J=7.0Hz), 1.23(3H,t,J=7.lHz) EI-MS m/e 252(M+) Reference Example 39 Ethyl 7-methoxy-2-methyl-3-oxo-2,3-- dihydrobenzofuran-2-carboxylate ~ COOEt MeO
Sodium hydride (60~ dispersion in oil, 6.61 g) was added to DMF (250 ml). To this solution, a solution of ethyl 2-(2-formyl-6-methoxyphenoxy)-propionate (34.56 g) in DMF (150 ml) was added dropwise at room temperature -- 15 for 1 hour, and the resulting solution was stirred for another 30 minutes. Acetic acid (12 ml) was added to the reaction solution and the solution was concentrated. The solution was poured into water layer (300 ml) and the resultant was extracted twice with ethyl acetate (150 ml).

The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate.
After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in dichloromethane (600 ml). To this solution, Celite (105 g) and pyridinium chlorochromate (44.52 g) were added and the solution was stirred at room temperature for 21 hours. Isopropyl alcohol (20 ml) was added to the reaction solution and the resulting solution was stirred for 15 minutes. One liter of hexane was added to the reaction solution and the resultant was filtered through Celite, followed by washing the precipitate with one liter of ether. The - filtrate was washed with water (500 ml) and the aqueous layer was extracted with ether (200 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1 - 3/1) using silica gel to obtain the desired compound (20.39 g, yield: 60~).
m.p.: 81-82C (recrystallized from hexane/ether) IR (KBr method) 2978,1717,1657,1649,1618,1603,1508,1466,1439,1375,1284, 1253,1199,1176,1127,1110,1077,1065,1009,980,940,853,841, 774,750,727,671,629cm~
NMR(90MHz CDCl3 ) ~ 7.33-6.97(3H,m),4.21(2H,q,J=7.3Hz),3.99(3H,s), 1.77(3H),1.23(3H,t,J=7.0Hz) EI-MS m/e 250(M+) Reference Example 40 7-methoxy-2-methyl-2,3-dihydrobenzofuran-3-one .
S~~~
MeO
Methyl 7-methoxy-2-methyl-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (18.38 g) was dissolved in dioxane-water (5:1, 300 ml) and 0.5 N sulfuric acid - (37 ml) was added to the solution, followed by refluxing the resulting solution for 16 hours. The reaction solution was concentrated and poured into water layer (300 ml), followed by extracting the resultant three times with ether (150 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=9/1 - 5/1) using florisil to obtain the desired compound (4.69 g, yield: 36%).
m.p.: 60-61C (recrystallized from hexane/ether) IR (KBr method) 2988,2936,1713,1657,1638,1615,1603,1560,1543,1510,1468, lg41,1375,1350,1317,1305,1265,1210,1185,1170,1145,1081, 1065,973,917,899,866,824,799,758,679,642,598,555cm~
NMR(90MHz CDCl3 ) - 121 -21 ~8~74 7.31-6.99(3H,m),4.68(lH,q,J=7.2Hz),3.97(3H,s), 1.56(3H,J=7.2Hz) EI-MS m/e 178(M+) Reference Example 41 3-azidomethyl-7-methoxy-2-methylbenzofuran S~N3 -- MeO
7-methoxy-2-methyl-2,3-dihydrobenzofuran-3-one (2.97 g) and dibromomethane (2.4 ml) were dissolved in THF (80 ml) and the solution was cooled to -78C. To this solution, n-butyllithium (1.62 M, 21 ml) was added dropwise for 30 minutes, and the mixture was stirred at -78C for 20 minutes. Acetic acid (5 ml) was added to the reaction solution and the resultant was poured into water layer (100 ml). The aqueous layer was extracted - 15 twice with ethyl acetate (50 ml) and the organic layers were combined. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The obtained residue was 20 dissolved in benzene (50 ml) and p-toluenesulfonic acid (286 mg) was added, followed by stirring the solution at 50C for 1.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (30 ml). The organic layers 122 2 i &8374 were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drylng over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The obtained residue was dissolved in methanol-water (5:1, 100 ml) and sodium azide (1.63 g) was added to the solution, followed by refluxing the resulting solution for 1 hour. The - reaction solution was cooled to room temperature and then poured into water layer (100 ml), followed by extraction twice with ethyl acetate (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=9/1) using silica gel to obtain the desired compound (1.70 g, yield:
47%)-IR (liquid film method) 2942,2108,1628,1595,1495,1439,1321,1278,1232,1210,1178, 1114,1091,1062,1044,864,781,733,634, cm~
NMR(9OMHz CDCl3 ) ~ 7.20-6.77(3H,m),4.39(2H,s),4.01(3H,s),2.50(3H,s) EI-MS m/e 217(M+) Reference Example 42 7-acetoxy-3-(acetylamino)methyl-2-methylbenzofuran 2 1 &8374 ~ NHAc AcO
By the method similar to Reference Example 9, the desired compound (1.27 g, yield: 62%) was obtained from 3-azidomethyl-7-methoxy-2-methylbenzofuran (1.70 g).
m.p.: 139 - 141C (recrystallized from cyclohexane/ethyl - acetate) IR (KBr method) 3328,2930,1760,1642,1595,1537,1491,1466,1444,1373,1265, 1218,1193,1174,1154,1079,1017,855,791,745,73380cm~
NMR(90MHz CDCl3 ) ~ 7.35(1H,dd,J=7.4,1.5Hz),7.13(1H,d,J=7.4Hz), 6.96(1H,dd=7.4,1.6Hz),5.8-5.6(1H,brm), 4.43(2H,d,J=5.3Hz),2.39(3H,s),1.95(3H,s) EI-MS m/e 261(M+) - 15 Reference Example 43 Methyl (7-methoxy-2-methylbenzofuran-3-yl)acetate ~ COOMe MeO
By the method similar to Reference Example 13, the desired compound (3.29 g, yield: 67%) was obtained from 7-methoxy-2-methyl-2,3-dihydrobenzofuran-3-one (3.74 g).
NMR(90MHz CDCl3 ) ~ 7.15-7.08(2H,m),6.78(lH,dd,J=6.3,2.4Hz),4.00(3H,s), 3.68(3H,s),3.60(2H,s~,2.45(3H,s) Reference Example 44 3-(2-hydroxyethyl)-7-methoxy-2-methylbenzofuran ~ OH

MeO
- By the method similar to Reference Example 30, the desired compound (1.70 g, yield: 47~) was obtained from methyl (7-methoxy-2-methylbenzofuran-3-yl) acetate.
m.p.: 58 - 59C (recrystallized from hexane/ether) IR (KBr method) 3356,3272,2970,2946,2920,1624,1591,1493,1468,1450,1441, 1282,1214,1187,1170,1093,1062,1046,864,775,729 cm~
NMR(90MHz CDCl3 ) ~ 7.13-7.07(2H,m),6.74(lH,dd,J=6.3,2.6Hz),4.00(3H,s), - 15 3.82(2H,m),2.87(2H,t,J=6.6Hz),2.44(3H,s),1.48(lH,brm) EI-MS m/e 206(M+) Reference Example 45 Methyl (3-(2-hydroxyethyl)-2-methylbenzofuran-7-yloxy)acetate ~ OH

~ COOMe 3-(2-hydroxyethyl)-7-methoxy-2-methylbenzofuran - (2.34 g) was dissolved in DMF (60 ml) and-potassium t-butoxide (2.71 g) and n-propanethiol (2.2 ml) were added to the solution, followed by stirring the resulting solution at 100C for 5 hours. The reaction mixture was cooled to room temperature and acetic acid (3 ml) was added. The reaction solution was concentrated, and poured into water layer (100 ml). The aqueous layer was -~ extracted twice with ethyl acetate (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The obtained residue was dissolved in DMF (50 ml), and potassium carbonate (1.66 g ) and methyl bromoacetate (1.7 ml) were added, followed by stirring the resulting solution at room temperature for 17.5 hours. The reaction solution was concentrated - and poured into water layer (100 ml), followed by extraction twice with ether (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1 - 1/1) using silica gel to obtain the desired compound (2.29 g, yield: 75%).
IR (liquid film method) 126 21 ~8374 3568,3390,2956,2882,1760,1626,1591,1493,1437290,1261, 1205,1108,1050,855,779,733,640,cm~
- NMR(90MHz CDCl3 ) ~ 7.13-6.65(3H,m),4.86(2H,s),3.85(1H,t,J=6.8Hz), 3.80(3H),2.84(2H,d,J=6.8Hz),2.43(3H,s),1.58(lH,brs) Reference Example 46 Methyl (3-(2-azidoethyl)-2-methylbenzofuran-7-yloxy)acetate ~ COOMe Methyl (3-(2-hydroxyethyl)-2-methylbenzofuran-7-yloxy acetate (390 mg) was dissolved in dichloromethane (7 ml) and the obtained solution was cooled to 0C. To this solution, triethylamine (0.43 ml) and p-toluenesulfonyl chloride (443 mg) were added and the resulting solution was stirred at 0C for l hour and then at room temperature for 23 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (15 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The residue was dissolved in THF-water (5:1, 10 ml) and sodium azide (354 mg) was added, followed by refluxing the resulting solution for 24 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column - chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (250 mg, yield:
58%).
m.p.: 62 - 63C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2110,1773,1622,1586,1491,1437,1278,1255,1226,1209,1197, 1172,1114,791,737cm~
NMR(9OMHz CDCl3 ) ~ 7.13-7.07(2H,m),6.70(1H,dd,J=5.3.3.5Hz), 4.87(2H,s),3.81(3H,s),3.50(2H,t,J=7.2Hz), 2.88(2H,t,J=7.OHz),2.45(3H,s) EI-MS m/e 289(M+) Reference Example 47 - Methyl (3-(2-bromoethyl)-2-methylbenzofuran-7-yloxy)acetate Br ~ COOMe By the method similar to Reference Example 18, the desired compound (346 mg, yield: 88%) was obtained from methyl (3-(2-hydroxyethyl)-2-methylbenzofuran-7-yloxy)acetate (318 mg).
m.p.: 96 - 97C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2964,2920,1729,1632,1591,1493,1450,1433,1381,1367,1307, 1267,1218,1207,1180,1152,1093,1069,1019,1009,965,866,781, 762,729,662 cm~1 NMR(90MHz CDCl3 ) ~ 7.13-7.06(2H,m),6.69(1H,dd,J=5.5,3.7Hz), - 4.87(2H,s),3.81(3H,s),3.49 (2H,dt,J=6.1,0.9Hz), 3.17(2H,t,J=6.8Hz),2.44(3H,s) EI-MS m/e 326(M+) Reference Example 48 Methyl 2-(2-formyl-6-methoxyphenoxy) isovalerate ~ CHO
b~O~
MeO
The same method as in Reference Example 38 was 129 ;~188374 repeated except that methyl 2-bromoisovalerate (10.20 g) was used in place of ethyl 2-bromopropionate, to obtain the desired compound (6.78 g, yield: 54%) from o-vanillin (7.14 g)-b.p.: 121 - 122C/0.2 mmHg IR (liquid film method) 2970,2882,1746,1694,1586,1483,1392,1371,1309,1249,1212, 1185,1131,1114,1085,1067,1019,913,787,766cm~
- NMR(90MHz CDCl3 ) ~ 10.64(lH,s),7.50-7.07(3H,m),4.96(1H,d,J=4.6Hz), 3.85(3H,s),3.66(3H,s),2.32(1H,m),1.14(3H,d,J=6.9Hz), 1.10(3H,d,J=7.0Hz) EI-MS m/e 266(M+) Reference Example 49 Methyl 2-isopropyl-7-methoxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate .~,-4 - ~ ~ OMe MeO
Potassium t-butoxide (5.62 g) was dissolved in DMF
(150 ml) and the obtained solution was cooled to 0C. To this solution, methyl 2-(2-formyl-6-methoxyphenoxy)-isovalerate (11.10 g) solution in DMF (50 ml) was added dropwise for 40 minutes, and the resulting solution was stirred for another 30 minutes. Acetic acid (4 ml) was added to the reaction solution and the solution was - 130 ~188374 concentrated. The resultant was poured into water layer (300 ml) and extracted twice with ethyl acetate (150 ml).
The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate.
After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in dichloromethane (250 ml). To this solution, Celite (70 g) and pyridinium ~ dichromate (23.55 g) were added and the solution was stirred at room temperature for 19 hours. Isopropyl alcohol (20 ml) was added to the reaction solution and the solution was stirred for 15 minutes. Ether (200 ml) was added to the solution and the solution was filtered through Celite, followed by washing the obtained precipitate with ether (100 ml twice). The filtrate was concentrated and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1 - 3/1) ~ using silica gel to obtain the desired compound (7.26 g, yield: 66%).
m.p.: 87 - 88C (recrystallized from cyclohexane/chloroform) IR (KBr method) 2980,2964,2940,1744,1717,1620,1601,1508,1473,1444,1348, 1255,1187,1172,1145,1087,1071,1042,1000,959,934,849,835, 799,756,731,675,667cm~
NMR(9OMHz CDCl3 ) ~ 7.29-7.02(3H,m),4.00(3H,s),3.76(3H,s),2.90(1H,m), 131 ~l ~8374 1.15(3H,d,J=6.8Hz),0.79(3H,d,J=6.8Hz) EI-MS m/e 264(M+) Reference Example 50 2-isopropyl-7-methoxy-2,3-dihydrobenzofuran-3-one o MeO
By the method similar to Reference Example 40, the desired compound (2.47 g, yield: 60%) was obtained from methyl 2-isopropyl-7-methoxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate.
m.p.: 46 - 47C (recrystallized from hexane) IR (KBr method) 2972,1717,1613,1601,1506,1462,1439,1286,1265,1249,1210, 1181,1170,1089,1067,1052,980,909,760 cm~
NMR(90MHz CDCl3 ) - 15 ~ 7.29-6.98(3H,m),4.47(lH,d,J=3.8Hz),3.97(3H,s), 2.40(lH),1.17(3H,d,J=7.1Hz),0.92(3H,d,J=6.8Hz) EI-MS m/e 206(M+) Reference Example 51 3-azidomethyl-2-isopropyl-7-methoxybenzofuran MeO
By the method similar to Reference Example 41, the 132 2 i 8837~

desired compound (672 mg, yield: 30%) was obtained from 2-isopropyl-7-methoxy-2,3-dihydrobenzofuran-3-one (1.90 g) .

IR (liquid film method) 2976,2936,2116,2098,1624,1591,1495,1458,1439,1340,1330, 1284,1243,1214,1187,1151,1075,1044,870,806,775,733 cm~
NMR(90MHz CDC13 ) ~ 7.25-7.12-(2H,m),6.78(1H,dd,J=5.5,3.5Hz),4.40(2H,s), 4.01(3H,s),3.23(lH,sept,J=6.8Hz),1.40(3H,d,J=6.8Hz) EI-MS m/e 245(M+) Reference Example 52 2-hydroxymethyl-2,3-dihydro-3-oxo-7-methoxybenzofuran o ~ OH

MeO
Sodium hydride (440 mg) was washed with n-hexane and -dried under reduced pressure. Methyl 3-hydroxy-7-methoxybenzofuran-2-carboxylate (2.33 g) was dissolved in THF (200 ml) and the solution was added to the sodium hydride, followed by refluxing the resulting solution for 80 minutes. After cooling the solution to 0C, aluminum lithium hydride (404 mg) was added, and the resulting solution was stirred at 0C for 2 hours. To the reaction solution, a 1:1 mixture (200 ml) of lN hydrochloric acid and saturated brine was added and the organic layer was 2~ 88374 separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine, followed by drying over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: ethyl acetate) to obtain the desired compound (1.76 g, yield: 87%).
m.p.: 103 - 104C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3426,1696,1615,1603,1510,1437,1274,1185,1168,1100,1079, 1052,1027,959,876,833,777,733,683,605,588,468cm~
NMR(300MHz CDCl3 ) ~ 7.27(lH,dd,J=1,8Hz),7.14(lH,dd,J=1,8Hz), 7.06(lH,t,J=8Hz),4.72(lH,t,J=4Hz),4.15(2H,m),3.98(3H,s), 1.97(lH,t,J=7Hz) EI-MS m/e 194(M+) Reference Example 53 2,3-dihydro-2-methoxymethoxymethyl-3-oxo-7-methoxybenzofuran o ~ OMOM

MeO
2,3-dihydro-2-hydroxymethyl-3-oxo-7-methoxybenzofuran (1.79 g) and dimethoxymethane (10 ml) were dissolved in dichloromethane (25 ml) and phosphorus pentoxide (3.47 g) was added to the obtained solution, followed by stirring the resulting solution at room temperature for 3.5 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layers were combined and washed with water and with saturated brine, followed by drying over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=1/1) to obtain the desired compound (912 mg, yield: 58%).
m.p.: 71 - 72C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 2960,1715,1615,1603,1510,1448,1282,1181,1077,1064,1038, 1000,953,920,868,772,735,565cm~
NMR(300MHz CDCl3 ) ~ 7.26(lH,dd,J=1,7Hz),7.13(lH,dd,J=1,7Hz), 7.03(lH,t,J=7Hz),4.76(lH,dd,J=3,5Hz),4.61(lH,d,J=7Hz), 4.58(lH,d,J=7Hz),4.08(2H,m),3.97(3H,s),3.31(3H,s) EI-MS m/e 238(M+) Reference Example 54 Methyl (2,3-dihydro-2-methoxymethyl-3-hydroxy-7-methoxybenzofuran-3-yl)acetate 135 21 &83?4 ~~COOMe ~ > ~OMOM

MeO
Zinc powder (793 mg) was stirred under reduced pressure for 1 hour to dry the powder. THF (5 ml) was added and the resultant was stirred at 0C. 2,3-dihydro-2-methoxymethoxymethyl-3-oxo-7-methoxybenzofuran (815 mg) and methyl bromoacetate (1.5 ml) in THF (11 ml) were added dropwise at 0C. Reaction was started by slightly heating the mixture and the mixture was stirred at 0C
for 15 minutes and then at room temperature for 2.5 hours.
A small amount of 5% aqueous citric acid solution was added to the reaction solution and the solvent was evaporated off. The residue was poured into 5% aqueous citric acid solution and the extracted with ethyl acetate.
The organic layers were combined and washed with water and with saturated brine, followed by drying over -magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent:
n-hexane/ethyl acetate=3/2) to obtain the desired compound (990 mg, yield: 93%).
IR (liquid film method) 3474,1738,1624,1599,1497,1462,1441,1280,1212,1154,1114, 1042,994,919,895,874,737cm~
NMR(300MHz CDCl3 ) ~ 6.94(lH,dd,J=2,8Hz),6.90(lH,t,J=8Hz), 6.83(lH,dd,J=2,8Hz),4.90(lH,t,J=4Hz),4.67(lH,d,J=6Hz), 4.64(lH,d,J=6Hz),4.14(lH,d,J=lHz),4.11(2H,d,J=4Hz), 3.88(3H,s),3.74(3H,s),3.35(3H,s),3.07(lH,dd,J=1,16Hz), 2.87(lH,dd,J=1,16Hz) EI-MS m/e 312(M+) Reference Example 55 Methyl (2-methoxymethoxymethyl-7-methoxybenzofuran-3-yl)acetate COOMe ~ OMOM

MeO
Methyl (2,3-dihydro-2-methoxymethoxymethyl-3-hydroxy-7-methoxybenzofuran-3-yl)acetate (990 mg) was dissolved in THF (25 ml) and formic acid (15 ml), and the obtained solution was stirred at room temperature for 15 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and with saturated brine and dried over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=l/l) to obtain the desired compound (789 mg, yield: 75%).
IR (liquid film method) 2~ 88374 2954,1742,1626,1593,1497,1439,1359,1274,1216,1100,1081, 1038,922,857,785,733cm-NMR(300MHz CDCl3 ) ~ 7.18(lH,t,J=8Hz),7.13(lH,dd,J=2,8Hz), 6.82(lH,dd,J=2,8Hz),4.74(2H,s),4.69(2H,s),4.00(3H,s), 3.76(2H,s),3.69(3H,s),3.41(3H,s) EI-MS m/e 294(M+) Reference Example 56 2-methoxymethoxymethyl-3-(2-hydroxyethyl)-7-methoxybenzofuran OH

~ OMOM

MeO
By the method similar to Reference Example 30, the desired compound (204 mg, yield: 95~) was obtained from methyl (2-methoxymethoxymethyl-7-methoxybenzofuran-3-yl)acetate (237 mg).
IR (liquid film method) 3404,2946,1626,1591,1495,1439,1359,1284,1216,1154,1098, 1038,920,859,783,735cm~
NMR(300MHz CDCl3 ) ~ 7.17(1H,t,J=8Hz),7.12(1H,dd,J=2,8Hz), 6.83(1H,dd,J=2,8Hz),4.73(2H,s),4.72(2H,s),4.01(3H,s), 3.87(2H,q,J=6Hz),3.42(3H,s),2.98(2H,t,J=6Hz), 2.14(lH,t,J=6Hz) EI-MS m/e 266(M+) - 138 21883~4 Reference Example 57 2-methoxymethoxymethyl-3-(2-methanesulfonyloxyethyl)-7-methoxybenzofuran OMs ~ OMOM

MeO
By the method similar to Reference Example 19, the desired compound (258 mg, yield: 99%) was obtained from 2-methoxymethoxymethyl-3-(2-hydroxyethyl)-7-methoxybenzofuran.
IR (liquid film method) 2950,1626,1591,1497,1466,1441,1357,1284,1214,1176,1102, 1038,1006,973,955,905,814,799,785,735cm-NMR(300MHz CDCl3 ) ~ 7.20(1H,t,J=7Hz),7.14(lH,dd,J=1,7Hz), 6.83(1H,dd,J=1,7Hz),4.71(4H,s),4.44(2H,t,J=7Hz), _ 15 4.01(3H,s),3.43(3H,s),3.18(2H,t,J=6Hz),2.85(3H,s) EI-MS m/e 344(M+) Reference Example 58 2-methoxymethoxymethyl-3-(2-(diphenylmethylthio)ethyl)-7-methoxybenzofuran Ph SlPh ~ OMOM

MeO

Sodium hydride (85 mg) was washed with n-hexane and dried under reduced pressure. Diphenylmethanethiol (396 mg) was dissolved in DMF (8 ml) and the obtained solution was added to the sodium hydride. 2-methoxymethoxymethyl-3-(2-methanesulfonyloxyethyl)-7-methoxybenzofuran (437 mg) was dissolved in DMF (6 ml) and the obtained solution was added to the above-mentioned solution, and the resulting solution was stirred at 60C for 15 hours.
After evaporating off the solvent of the reaction mixture, the residue was poured into 5% aqueous citric acid solution and extracted with ethyl acetate. The organic layers were combined and washed with water and with saturated brine, followed by drying over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=2/1) to obtain the desired compound (406 mg, yield: 71%).
m.p.: 110C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 2930,1624,1589,1493,1452,1439,1375,1346,1284,1212,1135, ~~ 140 2~ 88374 1077,1029,1013,917,857,754,743,735,704,692,625,588,511, 497cm~l NMR(300MHz CDCl3 ) ~ 7.37-7.41(4H,m),7.19-7.33(6H,m),7.08(lH,t,J=8Hz), 6.83(lH,dd,J=1,8Hz),6.78(lH,dd,J=1,8Hz),5.15(lH,s), 4.64(2H,s),4.62(2H,s),3.99(3H,s),3.39(3H,s), 2.95(2H,t,J=7Hz),2.66(2H,t,J=7Hz) EI-MS m/e 448(M+) Reference Example 59 Methyl (2-methoxymethoxymethyl)-3-(2-diphenylmethylthio)ethyl)-benzofuran-7-yloxy)acetate Ph S--~Ph OMOM

~ COOMe Potassium t-butoxide (465 mg) was dried under reduced pressure. n-propanethiol (0.4 ml) was dissolved in DMF (5-ml) and the obtained solution was stirred at room temperature. 2-methoxymethoxymethyl-3-(2-(diphenylmethylthio)ethyl-7-methoxybenzofuran (803 mg) was dissolved in DMF (6 ml) and the obtained solution was added to the above-mentioned solution, followed by stirring the resulting solution at 90C for 6 hours. The reaction mixture was poured into 5% aqueous citric acid solution and extracted with ethyl acetate. The organic - 141 21~8374 layer was washed with water and with saturated brine and dried over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off.
The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=l/l) to obtain the phenolic compound (406 mg, yield: 52%). This phenolic compound (406 mg) was dissolved in ethanol (50 ml) and 4N
aqueous potassium hydroxide solution (0.3 ml) was added, followed by stirring the resulting solution at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure. DMF (20 ml) was added to the residue to dissolve the same and methyl bromoacetate (0.20 ml) was added to the solution, followed by stirring the resulting solution at room temperature for 90 minutes.
The reaction solution was poured into 5% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and with saturated brine and dried over magnesium sulfa-te. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=l/l) to obtain the phenolic compound (403 mg, yield: 84%).
IR (liquid film method) 3450,1760,1591,1493,1437,1388,1288,1209,1096,1004,785, 752,733,704cm~l NMR(300MHz CDCl3 ) ~ 7.38-7.18(lOH,m),7.08(lH,t,J=8Hz),6.93(lH,dd,J=1,8Hz), - 142 2 ~ 883 74 6.77(1H,dd,J=1,8Hz),5.03(1H,s),4.89(2H,s), 4.67(2H,d,J=6Hz),3.80(3H,s),2.92(2H,t,J=7Hz), 2.68(2H,t,J=7Hz),2.18(lH,t,J=6Hz) Reference Example 60 (7-methoxy-benzofuran-3-yl)acetic acid ~ COOH
~ 0 MeO
Methyl (7-methoxy-benzofuran-3-yl)acetate (1.12 g) was dissolved in methanol (20 ml). To this solution, 2N
aqueous sodium hydroxide solution (5 ml) was added and the resulting solution was stirred at room temperature for 13.5 hours. To this solution, lN hydrochloric acid (12 ml) was added and the reaction solution was poured into water layer (200 ml), followed by extraction twice with ethyl acetate (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The residue was recrystallized from hexane/chloroform to obtain the desired compound (0.95 g, yield: 91~).
m.p.: 143 - 145C (recrystallized from hexane/chloroform) IR (KBr method) 2912,1715,1626,1595,1497,1435,1400,1284,1267,1230,1178, 1094,1048,924,779,733,673c m~1 - 143 ~8~374 N M R (9OMHz CDCl3 ) ~ 8.78(1H,brm),7.64(1H,s),7.19-6.75(3H,m),4.00(3H,s), 3.69(2H,d,J=l.lHz) Reference Example 61 3-((4-phenyloxazole-2-yl)methyl)-7-methoxybenzofuran ~ ~l ~ Ph _ MeO
7-methoxy-benzofuran-3-carboxylic acid (294 mg) was dissolved in DMF (5 ml). To this solution, potassium carbonate (237 mg) and phenacyl bromide (342 mg) were added, and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration -and the solvent was removed under reduced pressure. The residue was dissolved in acetic acid (5 ml) and ammonium acetate (551 mg) was added, followed by refluxing the resulting solution for 4 hours. After cooling the reaction solution to room temperature, the solution was poured into water layer (100 ml) and extracted twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by 144 2i88374 filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (203 mg, yield:
47%)-m.p.: 101- 103C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3118,2968,2844,1628,1591,1568,1497,1477,1450,1437,1417, 1363,1332,1317,1288,1272,1224,1209,1183,1170,1147,1112, 1100,1065,1050,1033,959,942,919,905,820,789,754,733,690, 673,632 cm-1 NMR(9OMHz CDCl3 ) ~ 7.83(lH,s),7.78-6.82(9H,m),4.23(2H,d,J=l.lHz), 4.01(3H) EI-MS m/e 305(M+) Reference Example 62 3-((4-phenyloxazole-2-yl)methyl)-7-hydroxybenzofuran ~ J: Ph HO

By the method similar to Reference Example 12, the desired compound (242 mg, yield: 91%) was obtained from 3-(4-phenyloxazole-2-yl)methyl-7-methoxybenzofuran (279 mg).

- 145 21 ~8374 m.p.: 180 - 181C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3126,3050,1597,1572,1491,1448,1421,1365,1346,1325,1272, 1181,1135,1108,1075,971,951,795,756,731,690,677 cm-NMR(90MHz CDCl3 ) ~ 8.23(1H,m),7.84-6.84(10H,m),4.22(2H,d,J=0.9Hz) EI-MS m/e 291(M+) Reference Example 63 3-((4-phenyl-2-oxobutoxy)carbonylmethyl)-7-methoxybenzofuran o Ph S~
MeO
7-methoxybenzofuran-3-carboxylic acid (220 mg) was dissolved in THF (5 ml). To this solution, 4-phenyl-2-oxo-1-butanol (211 mg) and dicyclohexylcarbodiimide (330 mg) were added and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was filtered and the filtrate was poured into water layer (50 ml), followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate.
After removing the sodium sulfate by filtration, the ~ 146 2188374 solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (178 mg, yield: 47%).
m.p.: 68 - 69C (recrystallized from hexane/ethyl acetate) IR (KBr method) 1760,1725,1589,1497,1439,1417,1390,1270,1205,1189,1160, 1096,1048,990,779,733cm~
NMR(90MHz CDC13 ) ~ 7.67(1H,s),7.29-6.81(8H,m),4.67(2H,s),4.01(3H,s), 3.82(2H,d,J=l.lHz),3.02-2.58(4H,m) EI-MS m/e 352(M+) Reference Example 64 3-((4-(2-phenylethyl)oxazole-2-yl)methyl)-7-methoxybenzofuran C ~ r / ~ Ph MeO

3-((4-phenyl-2-oxo-butoxy)carbonylmethyl-7-methoxy-benzofuran (176 mg) was dissolved in acetic acid (3 ml) and ammonium acetate (373 mg) was added to the solution, followed by refluxing the resulting solution for 4 hours.

After cooling the reaction solution to room temperature, the solution was poured into water layer (100 ml) and extracted twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (96 mg, yield: 58%).
m.p.: 69 - 70C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3112,1628,1591,1564,1497,1456,1439,1363,1286,1270,1209, 1183,1145,1094,1048,789,754,733,712,692,663,625,603cm~
NMR(9OMHz CDCl3 ) ~ 7.60(1H,s),7.25-6.75(9H,m),4.14(2H,d,J=l.lHz), 4.00(3H),2.95-2.70(4H) EI-MS m/e 333(M+) Reference Example 65 3-(2-(2,2-ethylenedioxy-2-phenylethoxy)ethyl)-7-tetrahydropyranyloxybenzofuran ~O
O ~ Ph THPO
3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran ~ 148 21 8~374 (319 mg) was dissolved in DMF (2 ml). To this solution, sodium hydride (60%, 59 mg) was added and the solution was stirred at room temperature for 1 hour. To this reaction solution, 1-bromo-acetophenoneethylene acetal (445 mg) was added and the resulting solution was stirred at room temperature for 1 hour and then at 100C for 2.5 hours. After cooling the reaction solution to room temperature, the solution was added to water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (239 mg, yield: 46%).
Reference Example 66 3-(2-(2,2-ethylenedioxy-2-phenylethoxy)-ethyl)-7-hydroxybenzofuran ~0 ~ O ~ Ph Ç~
HO
3-(2-(2,2-ethylenedioxy-2-phenylethoxy)ethyl)-7-tetrahydropyranyloxybenzofuran (239 mg) was dissolved in 149 2~1 88374 THF (3 ml). To this solution, 6N hydrochloric acid (1 ml) was added and the resulting solution was stirred at room temperature for 30 minutes. The reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (189 mg, yield:
98%).
IR (liquid film method) 3550,2956,2898,1624,1593,1491,1448,1363,1313,1238,1183, 1122,1093,1044,973,948,878,785,770,735,706 cm~
NMR(400MHz CDCl3 ) ~ 7.51-7.49(2H,m),7.36-7.33(4H,m),7.11-7.04(2H,m), 6.80 (lH,dd,J=8.3Hz),5.59(lH,s),4.08-4.05(2H,m), 3.87-3.84(2H,m),3.79(2H,t,J=6.4Hz),3.71(2H,s).88(2H,t, J=6.4HZ) Reference Example 67 3-(2-(2-oxo-2-phenylethoxy)ethyl)-7-hydroxybenzofuran -~ 150 21 88374 o O ~ Ph 1~\ ~~ .

HO
3-(2-(2,2-ethylenedioxy-2-phenylethoxy)ethyl)-7-hydroxybenzofuran (185 mg) was dissolved in THF (3 ml).
To this solution, one drop of concentrated hydrochloric acid was added and the solution was stirred at 50C for 29 hours, followed by refluxing the solution for 3 hours.
The reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired -compound (111 mg, yield: 69%).

m.p.: 114-115C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3300,1702,1622,1597,1479,1446,1408,1371,1274,1226,1187, 1131,1087,1075,1044,1017,984,971,946,849,785,758,733,688, 669,619,598 cm~l NMR(9OMHz CDC13 ) ~ 7.96-6.97(9H,m),5.60(1H,brs),4.77(2H,s), 3.88(2H,t,J=6.9Hz),3.01(2H,t!J=6.8Hz) EI-MS m/e 296(M+) Reference Example 68 3-((3,3-diphenylpropyloxy)methyl)-7-methoxybenzofuran Ph ~ Ph O

MeO

3,3-diphenyl-1-propanol (550 mg) was dissolved in DMF (5 ml) and the obtained solution was cooled to 0C.
To this solution, potassium t-butoxide (291 mg) was added and the solution was stirred at 0C for 10 minutes. To the reaction solution, 3-chloromethyl-7-methoxybenzofuran (339 mg) solution in DMF (4 ml) was added dropwise and -the resulting solution was stirred at 0C for 30 minutes.
After neutralizing the reaction solution with lN
hydrochloric acid, the solution was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate.
After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=9/1) using silica gel to obtain the 152 2~ 88374 desired compound (547 mg, yield: 85%).
- IR (liquid film method) 3062,3030,3006,2942,2866,1628,1593,1493,1451,12435,1359, 1286,1270,1201,1180,1151,1096,1054,843,789,731,704 cm~
NMR(90MHz CDCl3 ) ~ 7.50(lH,s),7.25-6.78(13H,m),4.56(2H,d,J=0.9Hz), 4.11(lH,m),4.01(3H,s),3.43(2H,t,J=6.8Hz),2,46-2.23(2H,m) EI-MS m/e 372(M+) Reference Example 69 3-((2-(N,N-diphenylamino)ethoxy)methyl)-7-methoxybenzofuran Ph ~ N _Ph MeO
By the method similar to Reference Example 68, the desired compound (185 mg, yield: 70%) was obtained from 2-(N,N-diphenylamino)-1-ethanol (139 mg).
IR (liquid film method) 3062,2944,2864,1628,1576,1491,1464,1437,1363,1253,1201, 1180,1152,1054,992,926,748,731,696 cm~
NMR(300MHz CDCl3 ) ~7.49(1H,brs),7.25-6.81(13H,m),4.64(2H,d,J=l.lHz), 3.96(2H,t,J=6.6Hz),3.72(2H,t,J=6.6Hz) EI-MS m/e 373(M+) _ 153 2 1 88374 Reference Example 70 4-benzyloxyindole ~ NH
W

BnO

Potassium hydroxide (0.42 g) was added to 4-hydroxyindole (1.00 g) in DMF (25 ml), and the solution - was stirred at room temperature for 15 minutes. Benzyl bromide (1.00 ml) was added to the solution, and the solution was stirred at room temperature for 1.5 hours.
Since the reaction was not completed, benzyl bromide (0.20 ml) was further added and the solution was stirred for 5 hours. After removing the solvent under reduced pressure, water (50 ml) was added to the residue and the resultant was extracted with ether (3 x 50 ml). The organic layers were washed with saturated brine, and 15 dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by silica gel column chromatography to obtain the desired product (1.43 g, yield: 85%).

IR (liquid film method) 3418,1589,1504,1361,1243,1087,1050,739cm~
NMR(90MHz CDCl3 ) ~ 8.16(lH,brs),7.60-7.00(8H,m),6.80-6.50(2H,m), 5.23(2H,s) Mass(m/e) 223 (M+) - Reference Example 71 1-(2-tetrahydropyranyloxyethyl)-4-benzyloxyindole OTHP

BnO

Under argon atmosphere, sodium hydride (121 mg) in DMF (2 ml) was cooled to 0C and 4-benzyloxyindole (501 mg) in DMF (S ml) was added thereto, followed by stirring the resulting solution at 0C for 5 minutes. To this solution, 2-tetrahydropyranyloxy-1-bromoethane (599 mg) in DMF (2 ml) was added and the solution was stirred at 0C for 30 minutes. The reaction mixture was added to saturated aqueous NH4Cl solution (30 ml) cooled at 0C, and the resultant was extracted with ethyl acetate (3 x 20 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (722 mg, yield: 92%).
IR (liquid film method) 2944,1578,1497,1441,1369,1232,1125,1035,737 cm~
NMR ( 90MHz CDC13 ) ~ 7.60-6.50(lOH,m),5.22(2H,s),4.60-3.20(7H,m), 1.90-1.30(6H,m) Mass(m/e) 351(M+) Reference Example 72 Methyl (1-(2-hydroxyethyl)indole-4-yloxy)acetate ~ OH

~--COOMe Under argon atmosphere, 1-(2-tetrahydropyranyloxyethyl)-4-benzyloxyindole (85 mg) and 5% Pd-C (10 mg) were added to ethanol (5 ml), and the atmosphere in the reaction vessel was replaced with hydrogen. The mixture was stirred at room temperature for 3 hours and solids were removed by filtration through Celite. The solvent was removed under reduced pressure and the obtained oil was transferred to a reaction vessel having argon atmosphere, followed by dissolving the oil in DMF (2 ml). To this, potassium carbonate (26 mg) was added and the resultant was stirred at room temperature for 10 minutes. Methyl bromoacetate (0.03 ml) was added to the mixture and the resultant was stirred at room temperature for 80 minutes. Since the reaction had not been completed, methyl bromoacetate (0.03 ml) was added and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, saturated aqueous NH4Cl solution (5 ml) was added to stop the reaction, and the resultant was extracted with ethyl acetate (3 x 10 ml).
The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (25 mg, yield: 41%).
IR (liquid film method) 3520,2934,1750,1578,1499,1354,1220,1151,748 cm-NMR(90MHz CDCl3 ) ~ 7.20-7.00(3H,m),6.69(lH,d,J=3.lHz),6.50-6.30(lH,m), 4.79(2H,s),4.40-40(2H,m),4.10-3.80(2H,m),3.80(3H,s), 1.56(lH,brs) EI-MS 249(M+) Reference Example 73 Methyl (1-(2-bromoethyl)indole-4-yloxy)acetate Br S~~
"~--COOMe Under argon atmosphere, triphenylphosphine (1.05 g) and tetrabromomethane (2.00 g) were added to methyl (1-(2-hydroxyethyl)indole-4-yloxy)acetate (500 mg) in methylene chloride (10 ml) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. Slnce the reaction had not been completed, triphenylphosphine (1.00 g) was added and the reaction mixture was stirred at room temperature for 30 minutes.
To the reaction mixture, aqueous sodium hydrogen carbonate solution (5 ml) and water (10 ml) were added and the resultant was extracted with ethyl acetate (3 x 20ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (602 mg, yield: 96%).
IR (liquid film method) 1752,1578,1497,1439,1257,1220,1087,737cm~
NMR(90MHz CDC13 ) ~ (ppm)7.30-6.90(3H,m),6.68(lH,d,J=3.1,0.7Hz), 6.50-6.30(1H,m),4.78(2H,s),4.46(2H,t,J=6.8Hz),3.79(3H,s), 3.60(2H,t,J=6.8Hz) EI-MS 311(M+) Reference Example 74 Methyl (1-(2-azidoethyl)indole-4-yloxy)acetate o~~N3 ~ COOMe By the method similar to Reference Example 8, the 158 21 ~38374 desired compound (597 mg) was obtained from methyl (1-(2-bromoethyl)indole-4-yloxy)acetate (598 mg).
EI-MS 274 (M+) Reference Example 75 1-(5-phenylpentyl)-4-benzyloxyindole ~ Ph BnO

By the method similar to Reference Example 71, the desired compound (330 mg, yield: 100%) was obtained from 4-benzyloxyindole (200 mg).
IR (liquid film method) 2934,1580,1497,1456,1371,1234,1058,735,698 cm-1 NMR(90MHz CDCl3 ) ~(ppm)7.60-6.90(12H,m),6.70-6.50(2H,m),5.22(2H,s),4.10-3.90(2H,m),3.51(2H,t,J=6.4Hz),2.80-2.40(2H,m),2.20--1.15(6H,m) EI-MS 369(M+) Reference Example 76 1-(5-phenylpentyl)-4-hydroxyindole ~ Ph HO

2~ 88374 Under argon atmosphere, 1-(5-phenylpentyl)-4-benzyloxyindole (330 mg) and 5% Pd-C (10 mg) were added to methanol (5 ml) and the atmosphere in the reaction vessel was replaced with hydrogen. The mixture was stirred at room temperature for 2 hours and solids were removed by filtration through Celite. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (178 mg, yield: 71%).
IR (liquid film method) 3394,2936,1580,1495,1357,1257,982,737,700 cm~
NMR(90MHz CDCl3 ) ~(ppm)7.40-6.90(4H,m),6.60-6.40(lH,m),5.34(lH,brs), 4.02(2H,t,J=6Hz),2.56(2H,t,J=7.7Hz),2.00-1.20(6H,m) EI-MS 279(M+) Reference Example 77 1-(2-(3-phenylpropyloxy)ethyl)-4-benzyloxyindole Ph 0~

BnO
Under argon atmosphere, sodium hydride (40 mg) was added to 1-(2-hydroxyethyl)-4-benzyloxyindole (52 mg) in DMF (3 ml) and the mixture was stirred at room temperature for 15 minutes. To the mixture, 3-phenyl-1-bromopropane (0.15 ml) was added and the resultant was -stirred at room temperature for another 18 hours. The reaction mixture was added to saturated aqueous NH4Cl solution (5 ml) to stop the reaction, and the resultant was extracted with ethyl acetate (3 x 10 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (72 mg, yield: 96%).
IR (liquid film method) 2866,1686,1560,1543,1491,1056,735 cm~
NMR(9OMHz CDC13 ) ~(ppm)7.60-6.90(13H,m),6.75-6.50(2H,m),5.21(2H,s), 4.24(2H,t,J=5.6Hz),3.68(2H,t,J=5.6Hz),3.33(2H,t,J=6.2Hz), 2.68-2.48(2H,m),2.00-1.62(2H,m) EI-MS 385(M+) Reference Example 78 -1-(2-(3-phenylpropyloxy)ethyl)-4-hydroxyindole Ph ~/~

HO
By the method similar to Reference Example 76, the desired compound (180 mg, yield: 74%) was obtained from 1-(2-(3-phenylpropyloxy)ethyl)-4-benzyloxyindole (318 mg).

IR (liquid film method) 3382,1582,1495,1473,1263,1114,737 cm~
NMR(90MHz CDCl3 ) ~(ppm)7.30-6.90(8H,m),6.60-6.40(2H,m),5.15(lH,brs), 4.26(2H,t,J=5Hz),3.71(2H,t,J=5.6Hz),3.35(2H,t,J=6.3Hz), 2.60(2H,t,J=7.6Hz),1.90-1.70(2H,m) EI-MS 295(M+) Reference Example 79 4-methoxyindole -MeO

Potassium hydroxide (2.12 g) was added to 4-hydroxyindole (4.99 g) in DMF (100 ml) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (2.80 ml) was added to the mixture and the resultant was stirred at room temperature for 150 minutes.
- Since the reaction had not been completed, potassium hydroxide (0.64 g) was added and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and water (20 ml) was added to the residue, followed by extraction with ether (3 x 30 ml).
The organic layers were washed with saturated brine, and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by ~ 162 2188374 silica gel column chromatography to obtain the desired product (3.38 g, yield: 61%).
IR (KBr method) 3400,1591,1497,1361,1284,1249,1083,727 cm~
5 NMR(90MHz CDCl3 ) ~8.50-7.90(lH,m),7.20-7.00(3H,m),6.70-6.40(2H,m), 3.96(3H,s) EI-MS 147(M+) Reference Example 80 4-methoxyindoline MeO
Borane-trimethylamine complex (3.00 g) and 10.5N
hydrochloric acid (2.25 ml) were added to 4-methoxyindole (1.29 g) in dioxane (20 ml), and the mixture was heated to reflux for 30 minutes. To this mixture, 6N
hydrochloric acid (7.00 ml) was added and the mixture was heated to reflux for 15 minutes. The solvent was removed under reduced pressure and lN aqueous sodium hydroxide solution was added to change the aqueous layer to alkaline condition, followed by extracting the aqueous layer with ether (3 x 20 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column - 2l88374 chromatography to obtain the desired compound (1.08 g, yield: 83%).

IR (KBr method) 3378,2943,1611,1468,1336,1247,1091,772,704cm~
NMR(90MHz CDCl3 ) ~(ppm)6.98(1H,t,J=8.0Hz),6.40-6.20(2H,m),3.80(3H,s), 3.70-3.40(2H,m),3.10-2.80(2H,m) EI-MS 149(M+) Reference Example 81 1-(2-diphenylmethoxy)ethyl)-4-methoxyindoline Ph ~ ~h MeO
Under argon atmosphere, 4-methoxyindoline (1.08 g) in ether (10 ml) was cooled to 0C and phenyllithium (1.77 M solution in ether, 6.0 ml) was added thereto, followed by stirring the resulting mixture at 0C for 30 .
minutes. To this mixture, 2-diphenylmethoxy-1-bromoethane (3.18 g) was added and the mixture was gradually heated to room temperature. After stirring the mixture at room temperature for 1 hour, water (5 ml) was added to the reaction mixture to stop the reaction and the resultant was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced 21 8~3374 pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (1.58 g, yield: 58%).
IR (liquid film method) 2838,1618,1458,1340,1230,1073,743,511 cm~
NMR(90MHz CDCl3 ) ~(ppm)7.50-7.20(10H,m),7.02(lH,t,J=8.4Hz), 6.24(1H,t,J=8.4Hz),6.15(1H,d,J=8.4Hz),5.38(1H,s), 3.80(3H,s),3.80-3.20(6H,m),3.00-2.80(2H,m) EI-MS 359(M+) Reference Example 82 1-(2-(diphenylmethoxy)ethyl)-4-hydroxyindoline ~0~/

-~h HO
By the method similar to Reference Example 12, the desired compound (855 mg, yield: 89%) was obtained from (2-(diphenylmethoxy)ethyl)-4-methoxyindoline (1.00 g).
IR (liquid film method) 3500,2858,1630,1599,1466,1222,1098,760,741,704cm~
NMR(9OMHz CDCl3 ) ~(ppm)7.40-7.10(lOH,m),6.92(lH,t,J=8.OHz), 6.11(1H,t,J=8.0Hz),6.08(1H,d,J=8.0Hz),5.38(1H,s), 4.60(lH,brs),3.80-3.20(6H,m),3.10-2.80(2H,m) EI-MS 345(M+) 2 1 8~3374 Reference Example 83 1-(2-hydroxyethyl)-4-methoxyindole - OH
~~
MeO
Under argon atmosphere, NaH (283 mg) was added to 4-methoxyindole (516 mg) in DMF (10 ml) and the mixture was stirred at 0C for 15 minutes. To this mixture, 2-tetrahydropyranyloxy-1-bromoethane (890 mg) was added and the mixture was gradually heated to room temperature, followed by stirring the mixture at room temperature for 90 minutes. The reaction mixture was added to saturated aqueous NH4Cl solution (5 ml) cooled at 0C to stop the reaction, and the resultant was extracted with ethyl acetate (3 x 10 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate.
After removing solids by filtration, the solvent was .
removed under reduced pressure. The obtained oil was transferred to a reaction vessel and dissolved in methanol (10 ml), followed by cooling the obtained solution to 0C. To this solution, lN hydrochloric acid (1 ml) was added and the solution was stirred at 0C for 2 hours. After removing the solvent under reduced pressure, water (5 ml) was added and the resultant was extracted with ethyl acetate (3 x 20 ml). The obtained organic layers were washed with saturated brine and dried 21 8837~

over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (547 mg, yield: 82%).
IR (liquid film method) 3500,1580,1497,1446,1359,1257,1064,739cm~
NMR(90MHz CDC13 ) ~(ppm)7.39-6.95(3H,m),6.70-6.40(2H,m),4.30-3.70(4H,m), 3.94(3H,s),1.90-1.50(lH,m) EI-MS l91(M+) Reference Example 84 Methyl (1-(2-hydroxyethyl)indole-4-yloxy)acetate S~

~ COOMe By the method similar to Reference Examples 83 and 45, the desired compound (112 mg, yield: 55%) was obtained from 4-methoxyindole (121 mg).
IR (liquid film method) 2934,1742,1615,1576,1495,1437,1354,1210,1060,737cm~
NMR(300MHz CDCl3 ) ~ 7.14-7.02(3H,m),6.69(1H,dd,J=3.0,0.9Hz), 6.42(1H,dd,J=7.5,0.9Hz),4.80(2H,s),4.26(2H,t,J=5.4Hz), 3.97-3.92(2H,m),3.81(3H,s),1.70-1.50(lH,br s) EI-MS m/e 249(M+) Reference Example 85 Methyl (1-(2-hydroxyethyl)indoline-4-yloxy)acetate OH

~ COOMe Under argon atmosphere, 1-(2-hydroxyethyl)-4-benzyloxyindoline (369 mg) was dissolved in ethanol and the obtained solution was stirred at room temperature.
To this solution, 5% Pd/C (46 mg) was added and the atmosphere in the reaction vessel was replaced with hydrogen. After confirming vanishment of the materials, the atmosphere of the reaction vessel was replaced with argon. Solids were removed by filtration through Celite and the solvent was removed under reduced pressure to obtain a crude product. The crude product was dissolved in DMF and the obtained solution was stirred at room temperature. To this solution, potassium carbonate (368 mg) and methyl bromoacetate (0.26 ml) were added and the mixture was stirred at room temperature. After confirming vanishment of the materials, saturated aqueous ammonium chloride solution (5 ml) was added to the reaction solution and the resultant was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed ~ ~ 88374 .

by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using - 5 silica gel to obtain the desired compound (151 mg, yield:
45%).
IR (liquid film method) 2934,1763,1655,1618,1466,1437,1340,1296,1212,1098,866, 756,706 cm~1 NMR(300MHz CDCl3 ) ~ 7.02(1H,t,J=8.1Hz),6.28(1H,d,J=8.1Hz), 6.16(lH,d,J=8.lHz),4.65(2H,s),3.90-3.70(2H,m), 3.79(3H,s),3.43(2H,t,J=8.4Hz),3.24(2H,t,J=5.4Hz), 3.03(2H,t,J=8.4Hz) EI-MS m/e 251(M+) Reference Example 86 1-(2-(diphenylmethoxy)ethyl)-4-methoxyindole o~/Ph ~ Ph MeO
By the method similar to Reference Example 77, the desired compound (309 mg, yield: 55%) was obtained from 1-(2-hydroxyethyl)-4-methoxyindole.
IR (liquid film method) 1686,1560,1543,1491,1458,1257,737 cm~

NMR(90MHz CDC13 ) ~(ppm)7.40-6.80(13H,m),6.70-6.45(2H,m),5.24(lH,s), 4.32t2H,t,J=5.6Hz),3.96(3H,s),3.74(2H,t,J=5.6Hz) EI-MS 357(M+) Reference Example 87 1-(2-(diphenylmethoxy)ethyl)-4-hydroxyindole HO
By the method similar to Reference Example 12, the desired compound (263 mg, yield: 42%) was obtained from 1-(2-(diphenylmethoxy)ethyl)-4-methoxyindole (650 ml).
IR (liquid film method) 3400,1493,1456,1263,1085,739,702cm~
NMR(90MHz CDCl3 ) ~(ppm)7.50-6.75(13H,m),6.60-6.40(2H,m),5.19(lH,s), 4.24(2H,t,J=5.2Hz),3.69(2H,t,J=5.2Hz),1.80-1.40(1H,m) EI-MS 343(M+) Reference Example 88 1-(4,4-diphenylbutyl)-4-methoxyindole Ph ~ h MeO

By the method similar to Reference Example 71, the - 2~ 88374 desired compound (176 mg, yield: 36%) was obtained from 4-methoxyindole (200 mg).
IR (liquid film method) 2942,1736,1582,1495,1454,1375,1255,1183,1164,1139,1065, 911,845,735,702cm~
NMR(300MHz CDCl3 ) ~ 7.27-7.06(llH,m),6.94(lH,d,J=3.3Hz), 6.87(lH,d,J=8.lHz),6.57(lH,dd,J=3.0,0.9Hz), 6.50(lH,d,J=7.5Hz),4.07(2H,t,J=6.9Hz),3.95(3H,s), 3.84(lH,t,J=7.8Hz),2.09-2.00(2H,m),1.85-1.75(2H,m) EI-MS m/e 355(M+) Reference Example 89 1-(4,4-diphenylbutyl)-4-hydroxyindole Ph HO
By the method similar to Reference Example 12, the desired compound (16 mg, yield: 83%) was obtained from 1-(4,4-diphenylbutyl)-4-methoxyindole (20 mg).
IR (liquid film method) 3028,2940,1700,1624,1582,1495,1452,1375,1249,1031,980, 737,702 cm~l NMR(300MHz CDC13 ) ~ 7.28-7.13(10H,m),7.03(1H,d,J=8.0Hz), 6.97(lH,d,J=3.0Hz),6.85(lH,d,J=8.lHz), 6.52-6.49(2H,m),4.96(1H,s),4.08(2H,t,J=6.9Hz), 3.85(1H,t,J=7.8Hz),2.10-2.02(2H,m),1.85-1.76(2H,m) EI-MS m/e 341(M+) Reference Example 90 3-(2-(3-phenylpropyloxy)ethyl)-7-hydroxybenzofuran Ph /\~~

HO

Sodium hydride (60%, 27 mg) was suspended in DMF (1 ml) and the obtained suspension was cooled to 0C. To this solution, a solution of 3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran (118 mg) in DMF (0.5 ml) was added dropwise and the obtained mixture was stirred at 0C for 10 minutes. To this solution, 1-bromo-3-phenyl-propane (0.27 ml) was added and the solution was stirred at 0C for 1 hour and then at room temperature for 45 hours. A catalytic amount of concentrated hydrochloric acid was added to the reaction solution and the solution was stirred for 2 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (15 ml).
The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate.
After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:

hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (106 mg, yield: 80%).

IR (liquid film method) 3210,3064,3030,2944,2868,1624,1595,1495,1448,1363,1317, 1241,1185,1143,1091,1048,971,946,847,787,733,700,679 cm~
NMR(90MHz CDCl3 ) ~ 7.46(1H,s),7.28-7.16(7H,m),6.80(1H,dd,J=5.3,4.0Hz), 5.63(1H,brs),3.71(2H,t,J=7.3Hz),3.48(2H,t,J=6.4Hz), 3.01-2.59(4H,m),2.05-1.82(2H,m) -EI-MS m/e 296(M+) Reference Example 91 3-(2-(4-phenylbenzyloxy)ethyl)-7-methoxybenzofuran MeO

3-(2-hydroxyethyl)-7-methoxybenzofuran (373 mg) was dissolved in DMF (7 ml) and potassium t-butoxide (261 mg) -was added to the obtained solution, followed by stirring the resulting solution at room temperature for 20 minutes.
To this reaction solution, 4-phenylbenzyl chloride (511 mg) was added and the solution was stirred at room temperature for 1 hour. Acetic acid was added to the reaction solution and the resultant was poured into water layer (50 ml), followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (613 mg, yield:
88%).
m.p.: 77-78C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2864,1624,1589,1491,1462,1446,1435,1369,1280,1267,1210, 1180,1152,1122,1106,1091,1060,1035,1009,828,783,760,746, 733,698,681,611cm~
NMR(90MHz CDC13 ) ~ 7.64-6.75(13H,m),4.58(2H,s),3.99(3H,s), 3.80(2H,t,J=6.8Hz),2.99(2H,dd,J=7.3,6.4Hz) EI-MS m/e 358(M+) Reference Example 92 Ethyl 7-methoxybenzofuran-2-carboxylate ~ COOEt MeO

To N,N-dimethylformamide (300 ml), o-vanillin (25.2 g), ethyl chloroacetate (23.5 ml) and potassium carbonate (45 mg) were added and the resulting mixture was stirred at 120C for 14 hours. The reaction mixture was filtered to remove insoluble inorganic salts, and lN hydrochloric acid (50 ml) was added to the mixture to stop the _ 174 21 88374 reaction. Distilled water (250 ml) was added and the resulting mixture was extracted 4 times with totally 150 ml of ethyl acetate containing 15% of n-hexane. The organic layers were washed with distilled water (100 ml) and with saturated brine (100 ml), and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the solvent was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=10/1 to 5/1) using silica gel to obtain the desired compound (17.4 g, yield: 48%) in the form of colorless needle-shaped crystals.
m.p.: 86.5-87C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3132,3000,2970,2846,1976,1912,1711,1622,1582,1495,1468, 1446,1371,1317,1270,1224,1203,1091,1058,1027,975,942,857, 779,762,733,704,625,572,534 cm~
NMR(9OMHz CDC13 ) ~ 7.52(1H,s),7.26-7.19(2H,m),6.91(1H,dd,J=3.5,5.5Hz), 4.44(2H,q,J=7.1Hz),4.02(3H.s.),1.42(3H,t,J=7.1Hz) EI-MS m/e 220(M+) Reference Example 93 7-methoxy-(2-hydroxymethyl)benzofuran 2~ 8837~

MeO

By the method similar to Reference Example 30, the desired compound (11.2 g, yield: 79%) was obtained from ethyl 7-methoxy-benzofuran-2-carboxylate (17.3 g).

IR (liquid film method) 3370,2926,2484,2044,1636,1605,1499,1454,1379,1336,1319, 1284,1257,1195,1168,1123,1050,1017,959,909,735,646 cm~
NMR(90MHz CDC13 ) ~ 7.17-7.11(2H,m),6.87-6.73(lH,m),6.64(lH,s), 4.76(2H,d,J=5.9Hz),3.99(3H,S),2.32(1H,t,J=5.9Hz) EI-MS m/e 178(M+) Reference Example 94 7-methoxy-2-chloromethylbenzofuran ¢~ ~CI

MeO

7-methoxy-(2-hydroxymethyl)benzofuran (2.25 g), pyridine (1.12 ml) and thionyl chloride (0.9 ml) were dissolved in dichloromethane (60 ml) and the obtained solution was refluxed under stirring for 23 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution (30 ml) and the resulting mixture was separated into aqueous and organic layers, ` 2188374 followed by washing the aqueous layer with dichloromethane (30 ml). The organic layers were combined and washed with saturated brine (30 ml), followed by drying over anhydrous sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure to dry the residue and the residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=10/1) using silica gel to obtain the desired compound (2.2 g, yield: 87%).

m.p.: 44.5-45C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3002,2960,2942,2838,1918,1721,1626,1601,1586,1495,1466, 1433,1361,1330,1294,1270,1253,1212,1187,1174,1145,1129, 1098,1062,982,955,903,845,816,764,733,700,644,621,574,553 cm~l NMR(90MHz CDC13 ) ~ 7.19-7.13(2H,m),6.82(1H,dd,J=4.4,5.0Hz),6.74(1H,s), 4.71(2H,s),4.01(3H,S) EI-MS m/e 196(M+) Reference Example 95 2-((3,3-diphenylpropyloxy)methyl)-7-methoxybenzofuran ~ Ph MeO

3,3-diphenylpropanol (324 mg) and sodium hydride (60% dispersion in mineral oil, 54 mg) were added to DMF
(5 ml) and the obtained mixture was stirred at room temperature for 15 minutes. 7-methoxy-2-chloromethylbenzofuran (250 mg) was then added and theresulting mixture was stirred at room temperature for 3 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution (15 ml) to neutralize the mixture. Distilled water (20 ml) was added to the mixture and the resultant was extracted with 20 ml of ethyl acetate containing 15% of n-hexane three times.
The organic layers were combined and washed with distilled water (10 ml) and with saturated brine (10 ml), followed by drying over anhydrous sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure to dry the residue and the residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=10/1) using silica gel to obtain the desired compound (394 mg, yield: 83%).
IR (liquid film method) 3062,3030,2944,1951,1893,1810,1738,1624,1603,1589,1491, 1452,1437,1357,1330,1292,1270,1245,1209,1183,1139,1094, 1060,1029,977,938,855,818,775,750,735,702,632,617 cm~
NMR(9OMHz CDC13 ) ~ 7.23-7.06(12H,m),6.79(lH,dd,J=4.0,4.8Hz),6.59(lH,s), 4.53(2H,s),4.15(1H,t,J=7.9Hz),4.00(3H,S), 3.46(2H,t,J=6.4Hz),2.34(2H,dt,J=6.4,7.9Hz) EI-MS m/e 372(M+) Reference Example 96 2-((2,2-diphenylethoxy)methyl)-7-methoxybenzofuran Ph O ~ Ph ~ 0 MeO

The same procedure as in Reference Example 95 was repeated except that 2,2-diphenylethanol (303 mg) was used in place of 3,3-diphenylpropanol to obtain the desired compound (387 mg, yield: 85%) in the form of a colorless oily product.
IR (liquid film method) 3064,3030,2906,1951,1885,1812,1738,1624,1603,1589,1495, 1452,1437,1357,1330,1290,1270,1243,1207,1183,1139,1102, 1060,1046,975,938,853,818,775,737,702,630 cm-NMR(90MHz CDCl3 ) ~ 7.25-7.10(12H,m),6.76(1H,dd,J=3.8,5.0Hz),6.56(1H,s), 4.64(2H,d,J=0.4Hz),4.42-4.24(lH,m),4.10-4.00(2H,m), 4.03(3H,S) EI-MS m/e 358(M+) Reference Example 97 2-((diphenylmethoxy)methyl)-8-methoxybenzofuran - 2l88374 C~
MeO

The same procedure as in Reference Example 95 was repeated except that benzhydrol (281 mg) was used in place of 3,3-diphenylpropanol to obtain the desired compound (280 mg, yield: 64%) in the form of a colorless oily product.
IR (liquid film method) 3064,3030,2942,2842,1891,1812,1624,1589,1495,1454,1437, 1388,1330,1288,1270,1209,1183,1139,1093,1060,1029,1004, 977,942,853,816,764,737,704,623,603 cm~
NMR(90MHz CDC13 ) ~ 7.40-7.11(12H,m),6.80(1H,q,J=4.3Hz),6.68(1H,s), 5.54(1H,s),4.64(2H,d,J=0.7Hz),4.00(3H,s) EI-MS m/e 344(M+) Reference Example 98 2-((3,3-diphenylpropyloxy)methyl)-7-hydroxybenzofuran --<

By the method similar to Reference Example 12, the desired compound (242 mg, yield: 64%) was obtained from 2-((3,3-diphenylpropyloxy)methyl)-7-methoxybenzofuran (394 mg)-m.p.: 105-106C (recrystallized from n-hexane/ethyl acetate) IR (KBr method) 3234,2926,2362,1607,1497,1448,1386,1373,1332,1286,1259, 1228,1147,1083,1052,975,938,861,820,770,731,698 cm -1 NMR(9OMHz CDCl3 ) ~ 7.24-7.00(13H,m),6.85(1H,q,J=4.4Hz),6.60(1H,s), 4.53(2H,d,J=0.4Hz),4.14(lH,t,J=7.9Hz),3.47(2H,t,J=6.4Hz), -2.35(2H,dt,J=6.4,7.9Hz) EI-MS m/e 358(M+) Reference Example 99 2-((2,2-diphenylethoxy)methyl)-7-hydroxybenzofuran Ph O ~ Ph yO
HO
By the method similar to Reference Example 12, the desired compound (115 mg, yield: 35%) in the form of pale yellow oil was obtained from 2-((2,2-diphenylethoxy)methyl)-7-methoxybenzofuran (345 mg).
IR (liquid film method) 3280,3064,3030,2868,1951,1897,1808,1603,1495,1450,1361, 1307,1220,1189,1162,1139,1081,940,859,820,739,702 cm~
NMR(9OMHz CDC13 ) ~ 7.23-7.03(12H,m),6.80(lH,q,J=4.3Hz),6.57(lH,s), 5.71(lH,brs),4.58(2H.s),4.30(lH,m),4.01(2H,m) EI-MS m/e 344(M+) Reference 100 2-((diphenylmethoxy)methyl)-7-hydroxybenzofuran Ph HO

By the method similar to Reference Example 12, the desired compound (227 mg, yield: 85%) in the form of pale yellow oil was obtained from 2-((diphenylmethoxy)methyl)-7-methoxybenzofuran (280 mg). The product was recrystallized from n-hexane/ethyl acetate to obtain colorless crystals.
m.p.: 45-47C
EI-MS m/e 330(M ) Reference Example 101 Methyl (3-((acetylamino)methyl)benzofuran-7-yloxy)acetate Ac ~ COOMe 7-acetoxy-3-((acetylamino)methyl)benzofuran (258 mg) and potassium carbonate (82 mg) were added to methanol (5 ml) and the obtained mixture was stirred at room temperature for 1 hour. After removing methanol under reduced pressure, DMF (5 ml) and methyl bromoacetate (0.15-ml) were added to the residue, followed by stirring the resultant for 18 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over anhydrous sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was -purified by column chromatography (solvent:
chloroform/methanol=95/5) using silica gel to obtain the desired compound (227 mg, yield: 78%).
m.p.: 139-140C (recrystallized from cyclohexane/chloroform) IR (KBr method) 3292,1752,1738,1649,1636,1545,1510,1495,1460,1433,1381, 1365,1321,1280,1224,1193,1154,1106,1087,783,729cm~
NMR(9OMHz CDCl3 ) , ~ 7.60(1H,s),7.59-7.06(2H,m),6.80(1H,dd,J=6.8,2.2Hz), 4.88(2H,s),4.54(2H,d,J=5.1Hz),3.81(3H,s),2.01(3H,s) EI-MS m/e 277(M+) Reference Example 102 Methyl (3-((acetylamino)methyl)-2-methylbenzofuran-7-yl-oxy)acetate 183 2 1 8~3374 NHAc ~ COOMe By the method similar to Reference Example 101, the desired compound (1.38 g, yield: 85%) was obtained from 7-acetoxy-3-((acetylamino)methyl)-2-methylbenzofuran (1.46 g).
m.p.: 179-181C (recrystallized from hexane/chloroform) IR (KBr method) 3250,3080,3038,2980,2960,2928,2884,1750,1620,1589,1549, 1493,1435,1379,1344,1299,1263,1228,1203,1183,1158,1106, 1093,1058,1040,984,946,853,779,737,716,649,621,603cm~
NMR(90MHz CDC13 ) ~ 7.15-7.09(2H,m),6.71(1H,dd,J=5.3,3.8Hz), 5.70-5.50(1H,brm),4.86(2H,s),4.45(2H,d,J=5.3Hz), 3.80(3H,s),2.45(3H,s),1.98(3H,s) EI-MS m/e 291(M+) Reference Example 103 Methyl (3-((acetylamino)methyl)-2-isopropylbenzofuran-7-yloxy)acetate / NHAc ~ COOMe By the method similar to Reference Examples 9 and 101, the desired compound (425 mg, yield: 37%) was obtained from 3-azidomethyl-2-isopropyl-7-methoxybenzofuran (882 mg).
m.p.: 132-133C (recrystallized from hexane/chloroform) IR (KBr method) 3314,2976,1742,1642,1630,1593,1531,1495,1470,1446,1435, 1371,1288,1243,1201,1085,1050,1023,996,725 cm-NMR(90MHz CDCl3 ) ~ 7.15-7.09(1H!m),6.74(lH,dd,J=5.5,3.7Hz),5.67(lH,brm), 4.90(2H,s),4.43(2H,d,J=5.lHz),3.81(3H,s),3.27(lH,m), 1.98(3H,s),1.34(3H,d,J=6.8Hz) EI-MS m/e 319(M+) Example 1 Methyl (3-((phenoxyacetylamino)methyl)benzofuran-7-yloxy)acetate o OPh ~N~

~ COOMe The same procedure as in Reference Example 101 was repeated except that 7-(phenoxyacetoxy)-3-(phenoxyacetylamino)methylbenzofuran (269 mg) was used inplace of 7-acetoxy-3-(acetylamino)methylbenzofuran to obtain the desired compound (202 mg, yield: 87%).

m.p.: 101-102C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3266,3106,1721,1659,1630,1601,1591,1545,1495,1450,1433, 1381,1365,1325,1294,1270,1222,1195,1178,1154,1100,1096, 1087,1011,988,781,748,727,708,688,590 cm~
NMR(90MHz CDCl3 ) ~ 7.57(lH,s),7.30-6.81(8H,m),4.87(2H,s), 4.65(2H,d,J=5.7Hz),4.55(2H,s),3.81(3H,s) EI-MS m/e 369(M+) Example 2 (3-((phenoxyacetylamino)methyl)benzofuran-7-yloxy)acetic acid ~ OPh COOH
Methyl (3-((phenoxyacetylamino)methyl)benzofuran-7-yloxy)acetate (126 mg) was dissolved in methanol (5 ml) and lN aqueous sodium hydroxide solution (0.5 ml) was added to the obtained solution, followed by stirring the resulting solution at room temperature for 1 hour. To the reaction solution, lN hydrochloric acid (1 ml) was added and the solution was poured into water layer (30 ml), followed by extracting the resultant twice with ethyl acetate (20 ml~. The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was recrystallized from cyclohexane/ethyl acetate to obtain the desired compound (108 mg, yield: 89%).
m.p.: 156-157C
IR (KBr method) 3412,3386,2918,2760,2546,1758,1742,1626,1595,1551,1493, 1460,1439,1373,1350,1278,1226,1191,1151,1106,1089,1058, 1017,953,793,783,760,725,706,690,634,605,590cm~
NMR(500MHz CDC13 ) ~ 7.58(lH,s),7.30-7.24(4H,m),7.16(1H,t,J=7.9Hz), 7.01(1H,d,J=7.3Hz),6.88(1H,d,J=7.9Hz),6.84(1H,d,J=7.9Hz), 4.91(2H,s),4.65(2H,d,J=6.1Hz),4.56(2H,s),2.01(3H,s) EI-MS m/e 355(M+) HR-EI-Ms Calcd. 355.1056 (Cl9Hl7NO6 ) Found 355.1053 (Cl9Hl7NO6 ) Elementary Analysis Calcd. C:64.23% H:4.82% N:3.94%
Found C:63.99% H:4.90% N:4.00%
Example 3 Methyl (3-(((2-phenoxyethyl)sulfonylamino)methyl)benzofuran-7-yloxy)acetate NHSO~ ~

~ COOMe Methyl (3-((acetylamino)methyl)benzofuran-7-yloxy)acetate (224 mg) was dissolved in methanol (4 ml) and hydrogen chloride (2.94N solution in methanol, 0.8 ml) was added thereto, followed by refluxing the resulting solution for 18.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl alcohol (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (5 ml). To this solution, triethylamine (0.23 ml) and 2-phenoxyethylsulfonyl chloride (193 mg) ~.
were added and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with lN hydrochloric acid and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:

chloroform/methanol=95/5) using silica gel to obtain the desired compound (85 mg, yield: 25%).
m.p.: 83-84C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3296,1736,1601,1499,1435,1394,1352,1317,1296,1282,1245, 1187,1137,1110,1081,1040,1000,857,785,752,731,694,567cm~
NMR(90MHz CDCl3 ) ~ 7.57(lH,s),7.30-6.81(8H,m),4.87(2H,s), 4.65(2H,d,J=5.7Hz),4.55(2H,s),3.81(3H,s) -EI-MS m/e 419(M+) Example 4 3-(((2-phenoxyethyl)sulfonylamino)methyl)benzofuran-7-yloxy)acetic acid S~ NHSO2~

o - COOH

Methyl 3-(((2-phenoxyethyl)sulfonylamino)methyl)benzofuran-7-yloxy)acetate (84 mg) was dissolved in methanol (2.5 ml) and 2N aqueous sodium hydroxide solution (0.2 ml) was added to the obtained solution, followed by stirring the solution at room temperature for 2 hours. To the reaction solution, lN hydrochloric acid (0.5 ml) was added and the resulting solution was poured into water layer (30 ml), followed by extracting the resultant twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was recrystallized from cyclohexane/ethyl acetate to obtain the desired compound (72 mg, yield: 89%).
m.p.: 135-136C
IR (KBr method) 3276,2926,1736,1711,1630,1601,1589,1495,1475,1460,1429, 1398,1354,1317,1267,1245,1191,1156,1131,1106,1062,959, 783,752,729,690,542,505cm~
NMR(500MHz DMSO-d6 ) ~ 7.93(1H,s),7.76(1H,t,J=6.4Hz),7.35-7.28(3H,m), 7.15(lH,t,J=7.8Hz),6.96(lH,t,J=7.3Hz),6.92(2H,d,J=7.8Hz), 6.85(lH,d,J=7.8Hz),4.85(2H,s),4.32-4.27(4H,m), 3.54(2H,t,J=6.3Hz) EI-MS m/e 405(M+) HR-EI-Ms Calcd. 405.0882 (C1gH17NO7S) Found 405.0909 (C1gH17NO7S) Example 5 Methyl (3-((phenylsulfonylamino)methyl)benzofuran-7-yloxy)acetate lgo 21 88374 0~ NHSO~Ph ~ COOMe By the method similar to Example 3, the desired compound (119 mg, yield: 52%) was obtained from methyl (3-((phenoxyacetylamino)methyl)benzofuran-7-yloxy)acetate (224 mg).
m.p.: 154-155C (recrystallized from cyclohexane/ethyl acetate) IR (KBr method) 3264,3116,1763,1630,1586,1493,1448,1433,1394,1363,1323, 101294,1272,1226,1189,1158,1096,1067,951,748,717,683,632, 580,559,518 cm~1NMR(9OMHz CDCl3 ) ~ 7.92-6.72(9H,m),4.85(2H,s),4.27(2H,brm),3.80(3H,s) EI-MS m/e 375(M+) Example 6 15(3-((phenylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid C~NHSOzPh --COOH
By the method similar to Example 4, the desired compound (73 mg, yield: 83%) was obtained from methyl (3-19l ~1 88374 ((phenylsulfonylamino)methyl)benzofuran-7-yloxy)acetate (91 mg).
m.p.: 229-231C (recrystallized from ethanol) IR (KBr method) 3296,3266,3116,2926,1742,1709,1589,1493,1448,1425,1361, 1321,1294,1253,1199,1154,1094,1052,957,855,785,746,721, 683,667,632,580 cm~l NMR(400MHz DMSO-d6 ) ~ 13.06(1H,brm),8.12(lH,t,J=5.9Hz),7.83-7.54(6H,m), 7.19(1H,d,J=7.4Hz),7.11(1H,t,J=7.8Hz),6.83(1H,d,J=7.8Hz), 4.83(2H,s),4.09(2H,d,J=7.3Hz) EI-MS m/e 361(M+) HR-EI-Ms Calcd. 361.0620 (Cl7Hl5NO6s) Found 361.0640 (Cl7Hl5NO6s) Elementary Analysis Calcd. C:56.52% H:4.18% N:3.88% S:8.85%
Found C:56.48% H:4.30% N:3.97% S:8.80%
Example 7 (3-((benzylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid --NHSO2/~Ph - COOH
To lN hydrochloric acid (10 ml), methyl (3-acetylaminomethylbenzofuran-7-yloxy)acetate (145 mg) was added and the obtained mixture was heated to reflux for 5 .

hours. To the reaction mixture, 2N aqueous sodium hydroxide solution (5 ml) was added to neutralize the mixture, and potassium carbonate (1.46 g) and benzylsulfonyl chloride (1.48 g) were added to the mixture, followed by stirring the resultant at 80C for one day and night. To the resulting mixture, lN
hydrochloric acid was added to neutralize the mixture and the resultant was extracted with ethyl acetate (3 x 20 ml). The organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained s`olids were purified by recrystallization (ethyl acetate/n-hexane) to obtain the desired compound (85 mg, yield: 43%).

m.p.: 191-192C

IR (KBr method) 3248,1736,1495,1429,1309,1267,1125,1060,780,696 cm~

NMR(400MHz CDCl3 ) ~(ppm) 13.06(1H,brs).8.31(1H,s).7.65(1H,t,J=6.1Hz), 7.35(5H,s),7.32(1H,d,J=7.8Hz),7.16(1H,t,J=7.8Hz), 6.86(1H,d,J=7.8Hz),4.86(2H,s),4.36(2H,s), 4.20(2H,d,J=5.4Hz) Mass(m/e) 375(M+) Example 8 (3-(((2-phenylethyl)sulfonylamino)methyl)benzofuran-7-yloxy)acetic acid ~ 1 g8374 S~\NHSO2~

- COOH
By the method similar to Example 4, the desired compound (73 mg, yield: 83%) was obtained from methyl (3-(((2-phenylethyl)sulfonylamino)methyl)benzofuran-7-yloxy)acetate (91 mg) which can be obtained by the method similar to Example 3.
m.p.: 159-160C (recrystallized from hexane/ethyl acetate/methanol) IR (KBr method) 3286,3112,2918,1740,1705,1626,1586,1493,1458,1431,1361, 1315,1294,1249,1191,1156,1133,1110,1094,1056,955,903,870, 785,764,739,725,690,598 cm~
NMR(400MHz CDCl3 ) ~ 7.65(1H,s),7.39(1H,d,J=7.8Hz),7.25-7.16(1H,m), 7.08(lH,brt,J=5.4Hz),6.93(2H,d,J=7.3Hz), 6.83(lH,d,J=7.8Hz),4.82(2H,s),4.36(2H,d,J=5.4Hz), 3.14-3.10(2H,m),3.00-2.96(2H,m) EI-MS m/e 389(M+) Elementary Analysis Calcd. C:58.62% H:4.92% N:3.94% S:8.21%
Found C:58.50% H:5.21% N:3.60% S:8.19%
Example 9 (3-((3-phenylpropylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid NHSO2 ~ Ph - COOH
The same procedure as in Example 7 was repeated except that 3-phenylpropanesulfonyl chloride was used in place of benzylsulfonyl chloride to obtain the desired -compound (341 mg, yield: 58~) from methyl (3-((acetylamino)methyl)benzofuran-7-yloxy)acetate (401 mg).
m.p.: 135-138C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3284,1746,1628,1593,1495,1429,1313,1265,1129,1060,702 cm~l NMR(400MHz CDCl3 ) ~(ppm) 13.08(lH,brs),7.90(lH,s),7.63(lH,t,J=6.lHz), -7.40-7.00(6H,m).6.87(lH,d,J=7.8Hz),4.86(2H,s), 4.23(lH,d,J=5.8Hz),3.00-2.90(2H,m),2.56(2H,t,J=7.8Hz), 1.90-1.80(2H,m) Mass(m/e) 403(M+) Example 10 (3-((4-phenylbutylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid ~1 8837~

NHSO2 ~ Ph ~ COOH
The same procedure as in Example 7 was repeated except that 4-phenylbutanesulfonyl chloride was used in place of benzylsulfonyl chloride to obtain the desired compound (425 mg, yield: 71%) from methyl (3-acetylaminomethylbenzofuran-7-yloxy)acetate (396 mg).
m.p.: 153-154C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3274,1736,1497,1429,1315,1267,1139,1058,727,698 cm~
NMR (400MHz CDCl3 ) ~(ppm) 13.07(lH,brs),7.90(lH,s),7.60(lH,t,J=5.9Hz), 7.40-7.10(6H,m),6.87(lH,d,J=7.8Hz),4.84(2H,s), 4.24(2H,d,J=5.9Hz),3.00-2.90(2H,m),2.50-2.40(2H,m), 1.70-1.50(4H,m) Mass(m/e) 417(M+) Example 11 Methyl (3-((5-phenylpentylsulfonylamino)methyl)benzofuran-7-yloxy)acetate 196 2t ~8374 NHSO2/'`----Ph ~ COOMe To methyl (3-((acetylamino)methyl)benzofuran-7-yloxy)acetate (298 mg) in methanol (15 ml), trifluoromethanesulfonic acid (0.20 ml) was added and the obtained mixture was heated to reflux overnight. After removing the solvent under reduced pressure, water (10 ml) and lN aqueous sodium hydroxide solution were added to adjust the pH to 9, and the resultant was extracted with ethyl acetate (3 x 20 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. Solids were removed by filtration and the solvent was removed under reduced pressure. The obtained oil was transferred to a reaction vessel in which the atmosphere had been replaced with argon, and methylene chloride (10 ml) was added, followed by stirring the resulting mixture at room temperature. To the resultant, triethylamine (0.40 ml) and 5-phenylpentanesulfonyl chloride (607 mg) were added and the resultant was stirred at room temperature for 5 hours.
Water (10 ml) was added to stop the reaction, and the resultant was extracted with ethyl acetate (3 x 10 ml).
The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing 2 1 8837~

solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by silica gel column chromatography to obtain solids (340 mg). The obtained solids were purified by recrystallization to obtain the desired compound (301 mg, yield: 63%).
m.p.: 84.5-85.5C (recrystallized from ethyl acetate/hexane) IR (KBr method) 3254,1767,1742,1495,1437,1319,1284,1183,1154,1135,1040, 785,731cm~1 NMR (400MHz CDC13 ) ~(ppm)7.63(lH,s),7.40-7.02(8H m),6.90-6.70(lH,m), 4.85(2H,s),4.42(2H,s).3.81(3H,s),3.05-2.82(2H,m), 2.70-2.45(2H,m),2.00-1.10(6H,m) Mass(m/e) 445(M+) Example 12 (3-((5-phenylpentylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid ~ NHSO2 ~ Ph - COOH
By the method similar to Example 4, the desired compound (168 mg, yield: 87%) was obtained from methyl (3-((5-phenylpentylsulfonylamino)methyl)benzofuran-7-` 198 2 1 8837~

yloxy)acetate (199 mg).
m.p.: 134-135C (recrystallized from ethyl acetate/hexane) IR (KBr method) 3280,2924,1713,1495,1429,1301,1267,1135,1056,727,696cm~
NMR(40OMHz CDCl3 ) ~(ppm) 13.07(lH,brs),7.91(lH,s),7.57(lH,t,J=6.lHz), 7.40-7.10(7H,m),6.86(lH,d,J=7.8Hz),4.84(2H,s), 4.24(2H,d,J=5.9Hz),3.00-2.90(2H,m),1.70-1.40(4H,m), 1.30-1.20(2H,m) Mass(m/e) 431(M+) Example 13 (3-(2-methylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid ~ NHSO~

- COOH
By the method similar to Example 4, the desired compound (143 mg, yield: 82~) was obtained from methyl (3-((2-naphthylsulfonylamino)methyl)benzofuran-7-yloxy)acetate (180 mg) which can be obtained by using 2-naphthalenesulfonyl chloride in place of phenoxyethylsulfonyl chloride in the method of Example 3.
m.p.: 204-206C (recrystallized from hexane/chloroform/methanol) IR (KBr method) 3262,3114,1742,1707,1628,1589,1493,1435,1363,1319,1253, 1189,1154,1131,1102,1077,1056,957,866,785,743,727,661, 547cm~l NMR (500MHz DMSO-d6) ~ 8.45(1H,s),8.21(1H,t,J=5.8Hz),8.13-8.02(3H,m), 7.83(lH,dd,J=8.3,1.5Hz),7.78(lH,m),7.72-7.64(2H,m), 7.19(1H,d,J=7.8Hz),7.07(1H,t,J=7.8Hz),6.78(1H,d,J=7.8Hz), 4.78(2H,s),4.13(2H,d,J=5.9Hz) EI-MS m/e 411(M+) HR-EI-Ms Calcd. 411.0777 (C21H17NO6S) Found 411.0795 (C21H17NO6S) Elementary Analysis Calcd. C:61.32% H:4.17% N:3.40% S:7.77%
Found C:61.24% H:4.23% N:3.40% S:7.75%
Example 14 (3-((benzylsulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetate NHSO2 ~ Ph ~ COOMe By the method similar to Example 3, the desired compound (196 mg, yield: 27%) was obtained from methyl (3-((acetylamino)methyl)-2-methylbenzofuran-7-yloxy)acetate (488 mg) and benzylsulfonyl chloride.

- 21~38374 m.p.: 96-98C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3290,1717,1630,1495,1450,1435,1317,1272,1205,1133,1104,-1056,1007,961,853,781,745,729,696,607,592,542,524cm~
NMR(90MHz CDCl3 ) ~ 7.37-6.72(8H,m),4.86(2H,s),4.22-4.17(4H,m), 3.80(3H,s),2.43(3H,s) EI-MS m/e 403(M+) Example 15 Methyl (3-((benzylsulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetic acid NHSO2 ~ Ph - COOH
By the method similar to Example 4, the desired compound (175 mg, yield: 93%) was obtained from methyl (3-((benzylsulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetate (195 mg).
m.p.: 181-183C (recrystallized from cyclohexane/ethyl acetate) IR (KBr method) 3250,2928,1738,1715,1638,1630,1593,1495,1433,1367,1342, 1319,1267,1209,1162,1129,1112,1050,965,936,781,733,698, 600,547 c m~1 NMR(400MHz CDCl3 ) ~ 7.55-7.26(4H,m),7.23(1H,dd,J=7.3,1.5Hz), 7.18(1H,dd,J=7.8,0.9 Hz),7.11(1H,t,J=7.8Hz), - 6.74(lH,d,J=7.3Hz),-5.51(lH,t,J=S.3Hz),4.81(2H,s), 4.17(2H,d,J=5.4Hz),4.13(2H,s),2.43(3H,s) EI-MS m/e 389(M+) Elementary Analysis Calcd. C:58.62% H:4.92% N:3.60% S:8.21%
Found C:58.45% H:4.82% N:3.63% S:8.22%
Example 16 -(3-(((2-phenylethyl)sulfonylamiono)methyl)-2-methylbenzofuran-7-yloxy)acetic acid NHSO~ ~

- COOH
By the method similar to Example 4, the desired compound (121 mg, yield: 91%) was obtained from methyl (3-(((2-phenylethyl)sulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetate (137 mg) which can be obtained by using 2-phenylethanesulfonyl chloride in place of phenoxyethylsulfonyl chloride in the method of Example 3.
m.p.: 149-150C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3246,3064,2926,1752,1711,1630,1589,1493,1435,1367,1342, 202 2 1 ~8374 1311,1288,1251,1212,1180,1127,1108!1044,967,926,783,731, 698,596,520cm~l NMR(400MHz CDC13 ) ~ 7.28-7.19~4H,m),7.15(lH,t,J=7.8Hz), 6.94(2H,d,J=6.4Hz),6.77(lH,d,J=7.8Hz),4.90(2H,s), 4.32(lH,m),4.28(2H,d,J=5.3Hz),3.15, 2.97(eachlH,ABq,J=8.8Hz),3.13,3.00(eachlH,ABq,J=4.9Hz), 2.44(3H,s) EI-MS m/e 403(M+) 10HR-EI-Ms Calcd. 403.1090 (C20H21NO6s) Found 403.1086 (C20H21NO6s) Elementary Analysis Calcd. C:59.56% H:5.25% N:3.47% S:7.93%
Found C:59.38% H:5.47% N:3.47% S:7.87%
Example 17 (3-(((3-phenylpropyl)sulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetic acid NHSO~ ~ Ph ~ COOH
By the method similar to Example 4, the desired compound (176 mg, yield: 92%) was obtained from methyl (3-(((3-phenylpropyl)sulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetate (197 mg) which can be obtained by using 3-phenylpropylsulfonyl chloride in place of phenoxyethylsulfonyl chloride in the method of Example 3.
m.p.: 121-122C (recrystallized from cyclohexane/chloroform) IR (KBr method) 3268,2924,1750,1630,1493,1460,1427,1344,1317,1288,1259, 1241,1212,1135,1110,1054,735,702 cm~
NMR(400MHz CDCl3 ) ~ 7.29-7.11(5H,m),7.04(2H,d,J=6.8Hz), 6.75(1H,d,J=7.3Hz),4.88(2H,s),4.54-4.52(1H,m), 4.28(2H,d,J=5.4Hz),2.87-2.83(2H,m),2.57(2H,t,J=7.8Hz), 2.42(3H,s),2.17-1.98(2H,m) EI-MS m/e 417(M+) Elementary Analysis Calcd. C:60.44% H:5.55% N:3.36% S:7.66%
Found C:60.10% H:5.63% N:3.39% S:7.67%
Example 18 Methyl (3-(((2-phenylethyl)sulfonylamino)methyl)-2--isopropylbenzofuran-7-yloxy)acetate NHSO2 ~ Ph C~

~ COOMe By the method similar to Example 3, the desired compound (217 mg, yield: 60%) was obtained from (3-((acetylamino)methyl)-2-isopropylbenzofuran-7-2 ~ 88374 yloxy)acetic acid (260 mg).
m.p.: 103-104C (recrystallized from hexane/ethyl acetatej IR (KBr method) 3250,2974,1725,1626,1510,1493,1475,1458,1431,1375,1342, 1313,1282,1212,1141,1129,1093,1048,1017,975,777,743,727, 700,600,518cm~1 NMR(400MHz CDCl3 ) ~ 7.28-6.73(8H,m),4.80(2H,s),4.29(3H,m), 3.80(3H,s),3.32-2.93(4H,m),1.33(6H,d,J=6.8Hz) EI-MS m/e 445(M+) Example 19 (3-(((2-phenylethyl)sulfonylamino)methyl)-2-isopropylbenzofuran-7-yloxy)acetic acid ~SO2~

- COOH
By the method similar to Example 4, the desired compound (171 mg, yield: 83%) was obtained from methyl (3-(((2-phenylethyl)sulfonylamino)methyl)-2-isopropylbenzofuran-7-yloxy)acetate (214 mg).
m.p.: 133-135C (recrystallized from hexane/chloroform) IR (KBr method) 3274,2978,2936,1756,1626,1493,1468,1458,1429,1342,1311, 1292,1259,1216,1154,1137,1100,1050,971,928,777,729,700, 600,522 cm~l NMR(40OMHz CD3 OD) ~ 7.34(IH,dd,J=7.8,1.0Hz),7.20-7.10(4H,m), 6.83(1H,dd,J=7.8,1.0Hz),6.75-6.73(2H,dd,J=8.3,1.3Hz), 4.87(2H,s),4.33(2H,s),3.38-3.33(lH,m), 2.98-2.93(2H,m),2.89-2.80(2H,m),1.34(6H,d,J=6.8Hz) EI-MS m/e 431(M+) HR-EI-Ms Calcd. 431.1403 (C22H25NO6s) Found 431.1387 (C22H25NO6s) Elementary Analysis Calcd. C:61.26% H:5.84% N:3.25% S:7.41%
Found C:61.15% H:5.79% N:3.37% S:7.27%
Example 20 Methyl (3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetate NHSO~ " Ph ~ COOMe Methyl (3-(2-azidoethyl)benzofuran-7-yloxy)acetate (638 mg) was dissolved in THF-methanol (1:4, 10 ml) and 5% Pd/C (95 mg) was added to the obtained solution, followed by stirring the resulting mixture under hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through Celite and the filtrate was concentrated. The obtained residue was dissolved in THF

2l883~

(8 ml), and triethylamine (2.61 ml) and benzylsulfonyl chloride (885 mg) were added, followed by stirring the resulting mixture at room temperature for 1.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with lN
hydrochloric acid and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/2) using silica gel to obtain the desired compound (320 mg, yield:
34%)-IR (liquid film method) 3302,3036,2956,1750,1628,1589,1493,1458,1437,1377,1359, 1328,1205,1152,1129,1083,1048,924,785,733,700,605cm~
NMR(9OMHz CDCl3 ) ~ 7.42(1H,s),7.30-7.12(7H,m),6.79(1H,dd,J=5.1,3.8Hz), 4.87(2H,s),4.21(2H,s),3.80(3H,s),3.18(2H,m),2.84(2H,m) EI-MS m/e 403(M+) Example 21 ~ 3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid 207 i) 1 88374 ~NHSO2 Ph ~/-0 - COOH
By the method similar to Example 4, the desired compound (110 mg, yield: 74%) was obtained from methyl (3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetate (153 mg).
m.p.: 132-134C (recrystallized from ethanol) IR (KBr method) 3256,1738,1719,1628,1589,1493,1458,1431,1359,1319,1265, 1205,1154,1125,1081,785,733,698,605,545cm~
NMR(400MHz CDCl3 ) ~ 7.43(1H,brs),7.31(5H,brs),7.11(2H,m),6.78(1H,brm), 5.48(lH,brm),4.79(2H,brs),4.20(2H,s), 3.21(2H,dd,J=12.7,6.4Hz),2.82(2H,brt,J=6.8Hz) EI-MS m/e 389(M 4) HR-EI-Ms Calcd. 389.0933 (C1gH1gNO6S) Found 389.0914 (C1gH1gNO6S) Example 22 Methyl (3-(2-(benzylsulfonyl-N-benzyl-amino)ethyl)benzofuran-7-yloxy)acetate - Ph ~NSO2~Ph ~ COOMe Methyl (3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetate (143 mg) was dissolved in DMF (3 ml), and potassium carbonate (49 mg) and benzyl bromide (0.13 ml) were added to the obtained solution, followed by stirring the resulting mixture at room temperature for 27 hours and then at 50C for 14.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with lN hydrochloric acid and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=2/1-1/1) using silica gel to obtain the desired compound (100 mg, yield: 57%).
IR (liquid film method) 3034,2932,1763,1736,1628,1589,1508,1495,1458,1437,1363, 1340,1296,1220,1183,1151,1127,1093,940,785,735,700 cm~
NMR(90MHz CDCl3 ) ~ 7.42-6.68(14H,m),4.84(2H,s),4.25(2H,s),4.19(2H,s), 3.79(3H,s),3.32-3.15(2H,m),2.70-2.52(2H,m) 2 1 88~74 Example 23 (3-(2-(benzylsulfonyl-N-benzyl-amino)ethyl)benzofuran-7-yloxy)acetic acid NSO2~" Ph - COOH
By the method similar to Example 4, the desired compound (103 mg, yield: 82%) was obtained from methyl (3-(2-(benzylsulfonyl-N-benzyl-amino)ethyl)benzofuran-7-yloxy)acetate (130 mg).
m.p.: 155-157C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3130,3064,3034,2954,2924,2868,2788,1740,1707,1628,1584, 1493,1456,1435,1425,1408,1357,1330,1296,1257,1230,1197, 1147,1135,1122,1093,1065,996,957,940,920,882,806785,737, 702,603,542 cm~1 NMR(400MHz CDCl3 ) ~ 7.37-7.30(lOH,m),7.06(lH,t,J=7.8Hz), 6.87(lH,d,J=7.8Hz),6.74(lH,d,J=8.4Hz),4.77(2H,s), 4.25(2H,s),4.18(2H,s),3.23(2H,m),2.60(2H,m) EI-MS m/e 479(M+) HR-EI-Ms Calcd. 479.1403 (C26H25NO6 ) Found 479.1425 (C26H25NO6 ) Elementary Analysis Calcd. C:65.14% H:5.26% N:2.92% S:6.67%
Found C:64.85% H:5.31% N:3.11% S:6.73%
Example 24 (3-(2-(benzylsulfonylamino)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid NHSO2 ~ Ph - COOH
By the method similar to Example 4, the desired compound (104 mg, yield: 86%) was obtained from methyl (3-(2-(benzylsulfonylamino)ethyl)-2-methylbenzofuran-7-yloxy)acetate (125 mg) which is obtained by the method similar to Example 20 from methyl (3-(2-azidoethyl)-2-methylbenzofuran-7-yloxy)acetate.
m.p.: 130-132C (recrystallized from chloroform) IR (KBr method) 3244,3034,2980,2042,1723,1638,1628,1495,1448,1323,1272, 1199,1172,1154,1131,1112,1075,791,739,729,69645cm~
NMR(400MHz CD3 OD) ~ 7.34-7.31(5H,m),7.10-7.04(2H,m), 6.75(1H,dd,J=6.8,3.4Hz),4.84(2H,s),4.25(2H,s), 3.09(2H,t,J=6.8Hz),2.76(2H,t,J=7.3Hz),2.38(3H,s) EI-MS m/e 403(M+) HR-EI-Ms Calcd. 403.1090 (C20H21NO6 ) Found 403.1096 (C20H21NO6 ) Elementary Analysis - Calcd. C:59.57% H:5.25% N:3.47% S:7.93%
Found - C:59.21% H:5.26% N:3.57% S:7.61%
Example 25 (3-(2-(2-phenylethylsulfonylamino)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid ~C>` 2 Ph - COOH

By the method similar to Example 4, the desired compound (130 mg, yield: 86%) was obtained from methyl (3-(2-(2-phenylsulfonylamino)ethyl)-2-methylbenzofuran-7-yloxy)acetate (156 mg) which is obtained by the method similar to Example 20 from methyl (3-(2-azidoethyl)-2-methylbenzofuran-7-yloxy)acetate.

-m.p.: 88-90C (recrystallized from cyclohexane/chloroform) IR (KBr method) 3570,3286,2926,1744,1709,1638,1626,1591,1493,1433,1315, 1263,1205,1152,1131,1114,1075,779,733,700cm~
NMR(400MHz CDC13 ) ~ 7.24-7.05(7H,m),6.72(lH,d,J=7.8Hz),4.86(2H,s), 4.13(1Hrm),3.27-3.19(4H,m),3.02(2H,m), 2.80(2H,t,J=6.9Hz),2.41(3H,s) - 212 2l883 74 EI-MS m/e 417(M+) HR-EI-Ms Calcd. 417.1246 (C2lH23NO6 ?
Found 417.1227 (C2lH23NO6 ) Example 26 (3-(2-((2,2-diphenylethyl)sulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid Ph NHS02 ~ Ph - COOH

By the method similar to Example 4, the desired compound (153 mg, yield: 70%) was obtained from methyl (3-(2-((2,2-diphenylethyl)sulfonylamino)ethyl)benzofuran-7-yloxy)acetate (225 mg) which is obtained by the method similar to Example 20 from methyl (3-(2-azidoethyl)benzofuran-7-yloxy)acetate.
m.p.: 134-136C (recrystallized from hexane/chloroform) IR (KBr method) 3328,3030,2924,1742,1628,1586,1493,1454,1423,1357,1323, 1267,1187,1137,1094,785,737,706cm~
NMR(300MHz CDCl3 ) ~7.32(lH,s),7.23-7.06(12H,m),6.83)lH,dd,J=7.8,0.8Hz), 4.93(2H,s),4.55(1H,t,J=7.4Hz),3.74(2H,d,J=7.4Hz), 3.37(lH,t,J=6.5Hz),2.94(2H,q,J=6.6Hz),2.61(2H,t,J=6.6Hz) 21~8374 EI-MS m/e 479(M+) Elementary Analysis Calcd. C:65.12% H:5.26% N:2.92% S:6.69~
Found C:64.55% H:5.26% N:3.21% S:6.55%
Example 27 (3-(2-((3,3-diphenylpropyl)sulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid NHSC~

- COOH
By the method similar to Example 4, the desired compound (172 mg, yield: 84%) was obtained from methyl (3-(2-((3,3-diphenylpropyl)sulfonylamino)ethyl)benzofuran-7-yloxy)acetate (210 mg) which is obtained by the method , similar to Example 20 from methyl (3-(2-azidoethyl)benzofuran-7-yloxy)acetate.

m.p.: 95-97C (recrystallized from hexane/chloroform) IR (KBr method) 3280,3062,3030,2930,1738,1628,1586,1493,1454,1425,1359, 1319,1263,1207,1185,1149,1091,785,748,704, 542 cm~
NMR(300MHz CDCl3 ) ~7.38(lH,s),7.32-7.12(12H,m),6.80(lH,dd,J=6.8,2.3Hz), 4.88(2H,s),4.41(1H,t,J=6.6Hz),3.93(1H,t,J=8.0Hz), - 21 8837~

- 3.34(2H,q,J=6.5Hz),2.94-2.86(4H,m),2.51-2.43(2H,m) -EI-MS m/e 493(M+) - Elementary Analysis Calcd. C:65.70% H:5.51% N:2.84% S:6.50%
Found C:65.56% H:5.53% N:2.70% S:6.50%
Example 28 Methyl (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetate S~,,S
~ COOMe 2-phenylethanethiol (0.42 ml) was dissolved in DMF
(5 ml) and sodium hydride (60%, 132 mg) was added to the obtained solution, followed by stirring the resulting mixture at room temperature for 40 minutes. To this reaction solution, a solution of methyl 3-(2-bromoethyl)-2-methyl-benzofuran-7-yloxyacetate (900 mg) in DMF (8 ml) was added dropwise and the resulting solution was stirred for 30 minutes. Acetic acid (0.5 ml) was added to the reaction solution and the solution was poured into water layer (100 ml), followed by extraction of the resultant twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: cyclohexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (1.03 g, yield: 98%).
IR (liquid film method) 3030,2954,2922,1763,1742,1626,1591,1508,1491437,1290, 1203,1100,731,698cm~
NMR(90MHz CDCl3 ) ~ 7.28-7.05(7H,m),6.69(lH,dd,J=5.3,3.8Hz),4.87(2H,s), 3.80(3H,s),3.02-2.77(6H,m),2.41(3H,s) EI-MS m/e 384(M+) Example 29 Methyl (3-(2-(2-phenylethylsulfinyl)ethyl)-2-methylbenzofuran-7-yloxy)acetate ~ COOMe Methyl (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetate (340 mg) was dissolved in methanol (15 ml) and the obtained solution was cooled to -10C. To this solution, NBS (190 mg) was added for 5 minutes and the resulting mixture was stirred at -10C
for 30 minutes. This reaction solution was poured into water layer (100 ml) and the resultant was extracted twice with ethyl acetate (30 ml). The organic layers ~ 1 88374 were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: dichloromethane/ethyl acetate=2/1) using silica gel to obtain the desired compound (225 mg, yield: 64%).
m.p.: 77-78C (recrystallized from cyclohexane/ethyl acetate) IR (KBr method) 2922,1734,1632,1589,1495,1450,1437,1383,1371,1303,1267, 1214,1180,1156,1093,1065,1044,1025,1009,971,864,791,766, 725,706,694cm~1 NMR(90MHz CDCl3 ) ~ 7.45-6.64(8H,m),4.87(2H,s),3.81(3H,s), 3.24-2.79(8H,m),2.45(3H,s) CI-MS m/e 401(M+H)+

Example 30 Methyl (3-(2-(2-phenylethylsulfonyl)ethyl)-2-methylbenzofuran-7-yloxy)acetate ~Ph ~ COOMe Methyl (3-(2-(2-phenylethylthio)ethyl-2-methylbenzofuran-7-yloxy)acetate (248 mg) was dissolved 2 1 8~374 in dichloromethane (7 ml) and the obtained solution was cooled to 0C. To this solution, m-chloroperbenzoic acid (350 mg) was added and the resulting solution was stirred at 0C for 30 minutes. To this reaction solution, saturated aqueous sodium thiosulfate solution was added and the resulting solution was poured into water layer (50 ml), followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=3/2) using silica gel to obtain the desired compound (248 mg, yield: 88~).

m.p.: 91-92C (recrystallized from hexane/ethyl acetate) IR (KBr method) 1750,1719,1702,1630,1591,1510,1493,1450,1315,1292,1276, 1253,1226,1210,1125,1100,779,725,694,613,528,511 cm~1 -NMR(9OMHz CDCl3 ) ~ 7.31-6.63(8H,m),4.86(2H,s),3.81(3H,s), 3.15-3.11(8H,m)2.42(3H,s) EI-MS m/e 416(M+) Example 31 (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid ~S--Ph y O
o - COOH
By the method similar to Example 4, the desired compound (141 mg, yield: 88%) was obtained from methyl (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetate (166 mg).
m.p.: 97-98C (recrystallized from cyclohexane/ethyl acetate) IR (KBr method) 3030,2930,1719,1707,1636,1624,1589,1288,1265,1234,1201, 1174,1110,777,729,696cm~
NMR(500MHz CDCl3 ) ~ 7.31-7.08(7H,m),6.75-6.70(lH,m),4.92(2H,s), 2.88-2.75(8H,m),2.40(3H,s) EI-MS m/e 370(M+) HR-EI-Ms Calcd. 370.1239 (C21H22O4S) Found 370.1220 (C21H22O4S) Elementary Analysis Calcd. C:68.11% H:5.99% S:8.63%
Found C:67.68% H:5.92% S:8.65%
Example 32 (3-(2-(2-phenylethylsulfinyl)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid ¢~-- COOH

By the method similar to Example 4, the desired compound (188 mg, yield: 89%) was obtained from methyl (3-(2-(2-phenylethylsulfinyl)ethyl)-2-methylbenzofuran-7-yloxy)acetate (220 mg).
m.p.: 139-141C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3054,2922,2856,2498,1734,1628,1591,1495,1446,1288,1261, 1197,1093,996,963,934,874,777,727,706cm-NMR(400MHz CDCl3 ) ~ 7.31-7.17(5H,m),7.04-7.00(2H,m),6.74-6.70(lH,m), 4.88(2H,s),3.15-3.01(6H,m),2.92-2.84(2H,m),2.36(3H,s) FAB-MS m/e 387(M+H)+
HR-FAB-Ms Calcd. 387.1308 (C21H23OsS) Found 387.1287 (C21H23OsS) Elementary Analysis Calcd. C:65.29% H:5.74% S:8.28%
Found C:65.12% H:5.74% S:8.27%
Example 33 (3-(2-(2-phenylethylsulfonyl)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid S Ph - COOH
By the method similar to Example 4, the desired compound (204 mg, yield: 81%) was obtained from methyl (3-(2-(2-phenylethylsulfonyl)ethyl)-2-methylbenzofuran-7-yloxy)acetate (260 mg).
m.p.: 155-156C (recrystallized from isopropanol) IR (KBr method) 3270,1760,1731,1628,1593,1493,1452,1431,1417,1336,1313, 1284,1272,1251,1212,1172,1137,1116,1096,777,729,694,615, 528,511,485cm~1 NMR(500MHz DMSO-d6 ) ~ 7.31-7.09(7H,m),~.7~(lH,dd,J=~.9, 2 . 4Hz), 4.82(2H,s),32-3.34(4H,m),3.06-2.96(4H,m),2.41(3H,s) EI-MS m/e 402(M+) HR-EI-Ms Calcd. 402.1137 (C21H22O6S) Found 402.1141 (C2lH22O6s) Elementary Analysis Calcd. C:62.69% H:5.51% S:7.95%
Found C:62.34% H:5.49% S:7.99%
Example 34 Methyl (3-(2-(diphenylmethyleneaminoxy)ethyl)-2-methylbenzofuran-7-yloxy)acetate 221 2 1 ~8374 S~/ N=~Ph ~ COOMe Sodium hydride (60%, 30 mg) was suspended in DMF (1 ml) and a solution of benzophenoneoxime (157 mg) in DMF
(2 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. To this solution, a solution of methyl (3-(2-bromoethyl)-2-methylbenzofuran-7-yloxy)acetate (201 mg) in DMF (3 ml) was added dropwise and the solution was stirred at room temperature for 30 minutes. Acetic acid was added to this reaction solution and the resulting solution was added to water layer (50 ml) followed by extraction of the resultant twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (177 mg, yield: 65%).
IR (liquid film method) 2956,2926,2876,1756,1622,1589,1493,1446,1398,1379,1350, 1336,1290,1274,1228,1203,1170,1118,1091,1071,1052,1029, 980,955,915,899,791,774,748,733,696,663,652,600 cm~1 -~ 222 ~t~8374 - NMR(90MHz CDC13 ) ~ 7.50-7.02(11H,m),6.67(lH,dd,J=5.3,3.7Hz),4.87(2H,m), 47(2H,t,J=6.8Hz),8.80(3H,s),2.99(2H,t,J=6.8Hz),2.28(3H,s) EI-MS m/e 443(M+) Example 35 (3-(2-(diphenylmethyleneaminoxy)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid N

- COOH
By the method similar to Example 4, the desired compound (159 mg, yield: 82%) was obtained from methyl (3-(2-(diphenylmethyleneaminoxy)ethyl)-2-methylbenzofuran-7-yloxy)acetate (200 mg).
m.p.: 151-152C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3060,2954,2936,2886,1736,1711,1622,1589,1493,1448,1431, 1365,1330,1284,1245,1205,1178,1116,1065,984,953,938,917, 779,729,700,692,650cm~
NMR(400MHz CDCl3 ) ~ 7.45-7.24(lOH,m),7.08(lH,dd,J=8.2,1.5Hz), 7.04(lH,t,J=7.8Hz),6.70(1H,dd,J=7.8,1.0Hz),4.89(2H,s), 4.36(2H,t,J=6.3Hz),2.99(1H,t,J=6.3Hz) EI-MS m/e 429(M+) HR-EI-Ms Calcd. 429.1576 (C26H23NO5) Found 429.1590 (C26H23NOs) Elementary Analysis Calcd. - C:72.72% H:5.40% N:3.26%
Found C:72.60% H:5.41% N:3.38%
Example 36 Methyl (3-((4-phenyloxazole-2-yl)methyl)benzofuran-7-yloxy)acetate S~
o "~--COOMe By the method similar to Reference Example 17, the desired compound (250 mg, yield: 83%) was obtained from 7-hydroxy-3-((4-phenyloxazole-2-yl)methyl)benzofuran (242 mg).
m.p.: 95-96C (recrystallized from hexane/ethyl acetate) IR (KBr method) 1729,1626,1586,1562,1491,1450,1435,1404,1379,1309,1282, 1257,1195,1162,1137,1114,1081,1067,1011,959,942,864,818, 777,770,731,704cm~
NMR(90MHz CDCl3 ) ~ 7.83(lH,s),7.78-6.64(9H,m),4.88(2H,s), 4.22(2H,d,J=l.OHz),3.80(3H,s) EI-MS m/e 363(M+) Example 37 (3-((4-phenyloxazole-2-yl)methyl)benzofuran-7-yloxy)acetic acid Ph ~ COOH
By the method similar to Example 4, the desired compound (209 mg, yield: 90%) was obtained from methyl (3-((4-phenyloxazole-2-yl)methyl)benzofuran-7-yloxy)acetate (243 mg).
m.p.: 165-167C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3118,2968,2932,1765,1734,1626,1591,1557,1493,1450,1435, 1377,1365,1292,1214,1195,1181,1149,1118,1087,1077,953, 797,772,745,731,694,613cm~
NMR(400MHz CDCl3 ) ~ 7.84(1H,s),7.71(2H,dd,J=8.3,1.0Hz),7.67(1H,s), 7.40(2H,t,J=7.3Hz),7.31(1H,d,J=7.3Hz),7.22(1H,d,J=7.8Hz), 7.14(1H,J=7.8Hz),6.80(1H,d,J=1.8Hz),4.83(2H,s),4.23(2H,s) EI-MS m/e 349(M+) HR-EI-Ms Calcd. 349.0950 (C20HlsNOs) Found 349.0968 (C20HlsNOs) Elementary Analysis Calcd. C:68.77% H:4.33% N:4.01%
Found C:68.69% H:4.53% N:4.09%

~ 22s 2188374 Example 38 (3-((4-(2-phenylethyl)oxazole-2-yl)methyl)benzofuran-7-yloxy)acetic acid Ph o "~--COOMe By the method similar to Example 4, the desired compound (56 mg, yield: 68%) was obtained using methyl (3-((4-(2-phenylethyl)oxazole-2-yl)methyl)benzofuran-7-yloxy)acetate (86 mg) which is obtained from 7-methoxy-3-((4-(2-phenylethyl)oxazole-2-yl)methylbenzofuran according to the method similar to Reference Examples 12 and 17.
m.p.: 124-125C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3116,2936,2920,1746,1601,1562,1504,1437,1425,1377,1363, 1278,1209,1193,1180,1154,1100,787,754,733,72302,642cm~
NMR(40OMHz CDCl3 ) ~ 7.55(1H,s),7.27-7.10(8H,m),6.82(1H,dd,J=7.3,1.0Hz), 4.88(2H,s),4.14(2H,s),2.94-2.90(2H,m),2.83-2.79(2H,m) EI-MS m/e 377(M+) Elementary Analysis Calcd. C:70.02% H:5.07% N:3.71%
Found C:69.76% H:5.11% N:3.77%

Example 39 - Methyl (3-(2-(3-phenylpropyloxy)ethyl)benzofuran-7-yloxy)acetate O ~ Ph ~ COOMe By the method similar to Reference Example 17, the desired compound (123 mg, yield: 93~) was obtained from 3-(2-(3-phenylpropyloxy)ethyl-7-hydroxybenzofuran (106 mg)-IR (liquid film method) 3064,3030,2950,2864,2802,1763,1628,1591,1495,1437,1361, 1294,1181,1151,1093,926,845,785,733,700cm~
NMR(90MHz CDCl3 ) ~ 7.50(1H,s),7.27-7.03(7H,m),6.77(1H,dd,J=7.0,2.0Hz), 4.87(2H,s),3.79(3H,s),3.69(2H,t,J=6.4Hz), 3.46(2H,t,J=6.4Hz),2.92(2H,t,J=6.8Hz), 2.76-2.59(2H,m),1.98-1.81(2H,m) EI-MS m/e 368(M+) Example 40 (3-(2-(3-phenylpropyloxy)ethyl)benzofuran-7-yloxy)acetic acid ~ 227 21 88374 O Ph - COOH

By the method similar to Example 4, the desired compound (95 mg, yield: 81%) was obtained from methyl (3-(2-(3-phenylpropyloxy~ethyl)benzofuran-7-yloxy)acetate (122 mg).
m.p.: 70-71C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3030,2944,2876,2804,1740,1715,1626,1582,1493,1456,1423, 1363,1319,1288,1261,1214,1187,1151,1120,1098,1062,938, 911,787,743,716,692cm~
NMR(400MHz CDCl3 ) ~ 7.63(1H,s),7.41-7.26(7H,m),6.93(1H,d,J=7.8Hz), 5.04(2H),3.83(2H,t,J=6.8Hz),3.60(2H,t,J=6.3Hz), 3.07(2H,t,J=6.8Hz).80(2H,t,J=7.3Hz),2.07-2.00(2H,m) EI-MS m/e 354(M+) HR-EI-Ms Calcd. 354.1467 (C21H22O5) Found 354.1479 (C21H22O5) Elementary Analysis Calcd. C:71.17% H:6.26%
Found C:70.95% H:6.18%
Example 41 Methyl (3-(2-benzyloxyethyl)benzofuran-7-yloxy)acetate -o___~Ph ~ COOMe By the method similar to Reference Example 17, the desired compound (176 mg, yield: 96%) was obtained from 3-(2-benzyloxyethyl)-7-hydroxybenzofuran (145 mg) which - 5 is obtained by the method similar to Reference Example 90 except that benzyl bromide is used in place of 1-bromo-3-phenyl-propane.
IR (liquid film method) 2862,1763,1589,1493,1437,1363,1294,1214,1151,1093,733,698 10 cm~l NMR(90MHz CDCl3 ) ~ 7.49(lH,s),7.32-7.11(7H,m),6.77(lH,dd,J=6.6,2.4Hz), 4.88(2H,s),4.55(2H,s),3.82-3.70(2H,m),3.80(3H,s), - 2.97(2H,dd,J=7.0,5.9Hz) EI-MS m/e 340(M+) Example 42 (3-(2-benzyloxyethyl)benzofuran-7-yloxy)acetic acid S ~.~o--Ph ~ COOH
By the method similar to Example 4, the desired ~ ~ 229 21 88374 compound (128 mg, yield: 76%) was obtained from methyl (3-(2-benzyloxyethyl)benzofuran-7-yloxy)acetate (175 mg).
m.p.: 91-92C (recrystallized from hexane/ethyl acetate) IR (KBr method) 1742,1711,1584,1491,1423,1363,1315,1267,1193,1149,1120, 1093,1067,938,737cm~
NMR(400MHz CDC13 ) ~ 7.49(lH,s),7.36-7.27(5H,m),7.21(lH,dd,J=7.8,1.0Hz), _ 7.13(1H,t,J=7.8Hz),6.79(1H,d,J=7.3Hz),4.90(2H,s), 4.55(2H,s),3.77(2H,t,J=6.9Hz),2.97(2H,t,J=6.9Hz) EI-MS m/e 326(M+) HR-EI-Ms Calcd. 326.1154 (Cl9H18O5) Found 326.1123 (Cl9Hl85) Elementary Analysis Calcd. C:69.93% H:5.56%
Found C:69.82% H:5.54%
Example 43 -- (3-(2-(diphenylmethoxy)ethyl)benzofuran-7-yloxy)acetate ~ O y Ph o ~ COOH
By the method similar to Example 4, the desired compound (104 mg, yield: 74%) was obtained from methyl (3-(2-(diphenylmethoxy)ethyl)benzofuran-7-yloxy)acetate (145 mg) which is obtained by the method similar to Reference Examples 90 and 17 from 3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran.
m.p.: 121-122C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3062,2926,2876,1740,1717,1591,1493,1458,1437,1367,1296, 1251,1220,1197,1187,1151,1096,1062,944,783,758,739,706 - cm~l NMR(400MHz CDCl3 ) ~ 7.49(1H,s),7.32-7.20(10H,m),7.16(1H,dd,J=7.7,0.8Hz), 7.10(1H,t,J=7.7Hz),6.79(1H,dd,J=7.7,0.7Hz), 5.38(lH,s),4.91(2H,s),3.75(2H,t,J=6.6Hz), 3.00(2H,t,J=6.6Hz) EI-MS m/e 402(M+) Elementary Analysis Calcd. C:74.61% H:5.51%
- Found C:74.55% H:5.48%
Example 44 (3-(2-(3,3-diphenylpropyloxy)ethyl)benzofuran-7-yloxy)acetic acid O ~ Ph - COOH
By the method similar to Example 4, the desired compound (71 mg, yield: 60%) was obtained from methyl (3-(2-(3,3-diphenylpropyloxy)ethyl)benzofuran-7-yloxy)acetate (122 mg) which is obtained by the method similar to Reference Examples 90 and 17 from 3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran.
m.p.: 74-76C (recrystallized from cyclohexane/ethyl acetate) IR (KBr method) _ 3024,2940,2922,2868,1742,1713,1580,1493,1288,1261,1207, 1187,1152,1120,1096,1064,938,789,750,741,698,559 cm~
NMR(400MHz CDCl3 ) ~ 7.46(1H,s),7.26-7.12(12H,m),6.79(1H,d,J=8.1Hz), 4.90(2H,s),4.06(lH,t,J=7.7Hz),3.62(2H,t,J=6.6Hz), 3.37(2H,t,J=6.6Hz),2.89(2H,t,J=7.0Hz),2.30(2H,q,J=7.7Hz) EI-MS m/e 430(M+) Elementary Analysis Calcd. C:75.33% H:6.09%
_ Found C:75.28% H:6.05%
Example 45 Methyl (3-(2-(4-phenylbenzyloxy)ethyl)benzofuran-7-yloxy)acetate S~--~' ~ COOMe By the method similar to Reference Example 45, the desired compound (519 mg, yield: 95%) was obtained from 3-(2-(4-phenylbenzyloxy)ethyl)-7-methoxybenzofuran (455 mg)-IR (liquid film method) 3032,2956,2862,1767,1628,1591,1491,1437,1363,1294,1218, 1183,1151,1096,1009,845,826,783,766,737,700cm~
NMR( 90MHz CDCl3 ) ~ 7.67-6.72(13H,m),4.87(2H,s),4.58(2H,s),3.80(3H,S), - 3.97(2H,m),2.98(2H,t,J=6.8Hz) EI-MS m/e 416(M+) Example 46 (3-(2-(4-phenylbenzyloxy)ethyl)benzofuran-7-yloxy)acetic acid ~,0~ 0 _ - COOH
By the method similar to Example 4, the desired compound (435 mg, yield: 89%) was obtained from methyl (3-(2-(4-phenylbenzyloxy)ethyl)benzofuran-7-yloxy)acetate (505 mg)-m.p.: 114-116C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2912,2864,1742,1711,1686,1626,1584,1562,1510,1491,1460, 1423,1363,1315,1288,1265,1191,1149,1120,1106,1093,1067, ` 2188374 938,824,787,758,737,696,538 cm~
NMR(40OMHz CDCl3 ) ~ 7.59-7.32(10H,m),7.21(1H,dd,J=7.8,1.0Hz), 7.13(1H,t,J=7.8Hz),6.79(1H,d,J=7.4Hz),4.90(2H,s), 4.59(2H,s),3.80(2H,t,J=6.9Hz),2.98(2H,t,J=6.9Hz) EI-MS m/e 402(M+) HR-EI-Ms Calcd. 402.1467 (C25H22O5) Found 402.1476 (C25H22O5) _ Elementary Analysis Calcd. C:74.61% H:5.51%
Found C:74.63% H:5.52%
Example 47 (3-(2-(2-oxo-2-phenylethoxy)ethyl)benzofuran-7-yloxy)acetic acid ~ ~ Ph o o - COOH
By the method similar to Example 4, the desired compound (100 mg, yield: 80%) was obtained from methyl (3-(2-(2-oxo-2-phenylethoxy)ethyl)benzofuran-7-yloxy)acetate (130 mg) which is obtained by the method similar to Reference Example 17 from 3-(2-(2-oxo-2-phenylethoxy)ethyl)-7-hydroxybenzofuran.
m.p.: 124-126C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2918,1886,1742,1698,1628,1582,1491,1454,1425,1315,1292, 1267,il95,1145,1093,1050,980,787,752,739,687,576 cm~
NMR(400MHz CDC13 ) ~ 7.89(2H,d,J=7.3Hz),7.58(lH,d,J=7.8Hz),7.56(1H,s), 7.44(2H,t,J=7.8Hz),7.23(1H,d,J=7.8Hz),7.13(1H,t,J=7.8Hz), 6.80(1H,d,J=7.8Hz),4.91(2H,s),4.77(2H,s), 3.88(2H,t.J=6.8Hz), 3.03(lH,t,J=6.8Hz) - EI-MS m/e 354(M+) HR-EI-Ms Calcd. 354.1103 (C20Hl8O6) Found 354.1097 (C20Hl8O6) Elementary Analysis Calcd. C:67.79% H:5.12%
Found C:67.64% H:5.11%

, - 235 2~88374 Example 48 (3-((3,3-diphenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid O ~ Ph ~ COOH
- 5 By the method similar to Example 4, the desired compound (465 mg, yield: 89%) was obtained from methyl (3-((3,3-diphenylpropyloxy)methyl)-benzofuran-7-yloxy)acetate (537 mg) which is obtained by the method similar to Reference Example 45 from 3-((3,3-diphenylpropyloxy)methyl)-7-methoxybenzofuran.
m.p.: 147-149C (recrystallized from hexane/ethyl acetate) IR (KBr method) - 3028,2942,2878,1748,1717,1628,1593,1493,1450,1431,1359, 1294,1257,1236,1203,1156,1096,1073,957,785,774,748,731 cm~l NMR(400MHz CDC13 ) ~ 7.51(1H,s),7.31-7.13(12H,m),6.82(1H,d,J=7.3Hz), 4.91(2H,s),4.55(2H,s),4.10(1H,t,J=7.8Hz), 3.43(2H,t.J=6.4Hz),2.33(2H,dt,J=7.8,6.4Hz) EI-MS m/e 416(M+) HR-EI-Ms Calcd. 416.1624 (C26H24O5) Found 416.1647 (C26H24O5 ) `~ 236 2 ~ 88374 Elementary Analysis Calcd. C:74.98% H:5.81%
- Found C:74.89% H:5.83%
Example 49 (3-((2,2-diphenylethoxy)methyl)benzofuran-7-yloxy)acetic acid p~

~ COOH

By the method similar to Example 4, the desired compound (118 mg, yield: 80%) was obtained from methyl (3-((2,2-diphenylethoxy)methyl)benzofuran-7-yloxy)acetate (153 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that 2,2-diphenylethanol is used in place of 3,3-diphenylpropanol - in Reference Example 68.
m.p.: 160-162C (recrystallized from hexane/ethyl -- acetate) IR (KBr method) 3118,3058,3032,2898,2868,2796,1742,1719,1630,1599,1493, 1452,1435,1357,1290,1259,1238,1203,1185,1151,1120,1098, 1081,1019,955,905,847,832,783,766,754,739,700,592 cm~
NMR(400MHz CDCl3 ) ~ 7.47(lH,s),7.28-7.18(lOH,m),7.09-7.01(2H,m), 6.78(1H,dd,J=7.3,1.0Hz),4.88(2H,s),4.65(2H,s), 21 8837~

4.31(1H,t,J=7.3Hz),4.01(2H,d,J=7.3Hz), 2.33(2H,dt,J=7.8,6.4Hz) EI-MS m/e 402(M+) HR-EI-Ms Calcd. 402.1467 (C25H22O5) Found 402.1441 (C25H22O5) Elementary Analysis Calcd. C:74.61% H:5.51%
Found C:74.41% H:5.53%
_ Example 50 (3-((diphenylmethoxy)methyl)benzofuran-7-yloxy)acetic acid Ph O l Ph ~0 o - COOH
By the method similar to Example 4, the desired - compound (216 mg, yield: 83%) was obtained from methyl (3-((diphenylmethoxy)methyl)benzofuran-7-yloxy)acetate (270 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that diphenylmethanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
m.p.: 153-155C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3062,3032,2920,2872,1746,1628,1589,1493,1454,1433,1354, 21 8837~

1332,1284,1255,1197,1151,1091,1075,1031,1006,901,801,777, 743,731,702,652 cm~

NMR(400MHz CDCl3 ) ~ 7.57(lH,s),7.37-7.24(llH,m),7.15(lH,t,J=7.8Hz), 6.82(1H,d,J=7.8Hz),5.48(1H,s),4.91(2H,s),4.65(2H,s) EI-MS m/e 388(M+) HR-EI-Ms Calcd. 388.1311 (C24H20O5) Found 388.1300 (C24H20O5) _ Elementary Analysis Calcd. C:74.21% H:5.19%

Found C:74.03% H:5.19%

Example 51 (R)-(3-((2-phenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid ~ Ph ~0 O
- COOH

By the method similar to Example 4, the desired compound (275 mg, yield: 87%) was obtained from methyl (R)-(3-((2-phenylpropyloxy)methyl)benzofuran-7-yloxy)acetate (330 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that (R)-2-phenylpropanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
- [a] D: -8.82 (c=1.065, CHCl3) 21 8&37~

m.p.: 125-127C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3124,3066,3032,2968,2902,2872,2798,2688,2586,1744,1717, 1628,1589,1493,1454,1431,1361,1294,1255,1201,1187,1152, 1085,1004,957,897,830,785,766,739,702,565 cm-NMR(400MHz CDCl3 ) ~ 7.52(1H,s),7.31-7.09(7H,m),6.80(1H,dd,J=7.8,1.0Hz), - 4.91(2H,s),4.61(2H,s),3.62(lH,dd,J=9.3,6.8Hz), 3.54(lH,dd,J=9Hz),3.05(1H,m),1.28(3H,d,J=6.8Hz) EI-MS m/e 340(M+) HR-EI-Ms Calcd. 340.1311 (C20H20O5) Found 340.1292 (C20H20O5) Elementary Analysis Calcd. C:70.57% H:5.92%
Found C:70.43% H:5.95%
Example 52 - (S)-(3-((2-phenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid S~ ' - COOH
By the method similar to Example 4, the desired compound (280 mg, yield: 92%) was obtained from methyl (S)-(3-((2-phenylpropyloxy)methyl)benzofuran-7-yloxy)acetate (317 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that (S)-2-phenylpropanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
[a] D: +8.36 (c=1.080, CHCl3) m.p.: 124-126C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3032,2968,2902,1746,1719,1628,1589,1493,1454,1431,1361, 1294,1255,1203,1187,1154,1083,785,766,739,70465cm~
NMR(400MHz CDCl3 ) ~ 7.52(1H,s),7.31-7.09(7H,m),6.80(1H,dd,J=7.8,1.0Hz), 4.91(2H,s),4.61(2H,s),3.62(lH,dd,J=9.3,6.8Hz), 3.54(lH,dd,J=9Hz),3.05(lH,m),1.28(3H,d,J=6.8Hz) EI-MS m/e 340(M+) HR-EI-Ms Calcd. 340.1311 (C20H20O5) Found 340.1326 (C20H20O5) - Elementary Analysis Calcd. C:70.57% H:5.92%
Found C:70.37% H:5.90%
Example 53 (3-((1-benzyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid Ph S~{

- COOH
By the method similar to Example 4, the desired compound (247 mg, yield: 89%) was obtained from methyl (3~ benzyl-2-phenylethoxy)methyl)benzofuran-7-_ 5 yloxy)acetate (288 mg) which is obtained by the methodsimilar to Reference Examples 68 and 45 except that 1,3-diphenyl-2-propanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
m.p.: 107-109C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3110,3062,3028,2914,2856,2792,2576,1740,1715,1630,1599, 1495,1454,1435,1363,1348,1321,1292,1263,1238,1222,1203, 1187,1151,1102,1079,1056,1031,1013,961,878,853,835,783, 754,735,702,501cm-NMR(400MHz CDCl3 ) ~ 7.29-7.18(llH,m),7.02(lH,t,J=7.8Hz), 6.81(1H,d,J=7.8Hz),6.76(1H,d,J=7.8Hz),4.89(2H,s), 4.38(2H,s),3.89(1H,quint,J=6Hz),2.85-2.84(4H,m) EI-MS m/e 416(M+) HR-EI-Ms Calcd. 416.1624 (C26H24O5) Found 416.1629 (C26H24O5) Elementary Analysis Calcd.C:74.98% H:5.81%
FoundC:74.71% H:5.79%
Example 54 (S)-(3-((1-methyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid ~0 - COOH
By the method similar to Example 4, the desired compound (83 mg, yield: 77%) was obtained from methyl (S)-(3-((1-methyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetate (112 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that (S)-3-phenyl-2-propanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
- [a] D: +31.92 (c=0.570, CHCl3) m.p.: 92-93C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3030,2974,2926,2868,2802,1740,1713,1628,1586,1493,1456, 1423,1375,1359,1323,1290,1265,1189,1154,1131,1087,1058, 957,922,785,733,700 cm~
NMR(400MHz CDCl3 ) ~ 7.47(1H,s),7.29-7.07(7H,m),6.80(1H,dd,J=5.3,2.7Hz), 4.91(2H,s),4.68(1H,dd,J=13.7,5.9Hz),4.54(1H,dd,J=13.7,1.0 Hz),3.84-3.76(1H,m),2.92(lH,dd,J=13.7,6.8Hz), 21 8~374 _ 243 2.71(1H,dd,J=13.7,5.9Hz),1.28(3H,d,J=6.4Hz) EI-MS m/e 340(M+) HR-EI-Ms Calcd. 340.1311 (C20H20O5) Found 340.1312 (C20H20O5) Elementary Analysis Calcd. C:70.57% H:5.92%

Found C:70.43% H:5.95%

Example 55 (3-((1-methyl-2-methoxy-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid ¢~

- COOH
By the method similar to Example 4, the desired compound (78 mg, yield: 62%) was obtained from methyl (3-((1-methyl-2-methoxy-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetate (130 mg) which is obtained by the methodsimilar to Reference Examples 68 and 45 except that (S)-1-phenyl-1-methoxy-2-propanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
m.p.: 104-106C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2986,2930,2878,1740,1715,1630,1586,1493,1456,1427,1377, 1359,1288,1263,1199,1187,1152,1091,953,787,731,702 cm~

21 8837~

NMR(400MHz CDCl3 ) ~ 7.40(lH,s),7.35-7.25(5H,m),7.07(lH,t,J=7.8Hz), 6.98(lHd,J=7.8,1.OHz),6.78(lH,dd,J=7.8,1.OHz),4.89(2H,s), 4.59,4.42(eachlH,ABq,J=12.2Hz),4.09(lH,d,J=5.8Hz), 3.70-3.64(lH,m),3.26(3H,s),1.24(3H,d,J=6.3Hz) EI-MS m/e 370(M+) HR-EI-Ms Calcd. 370.1416 (C2lH2306) Found 370.1421 (C21H2306) _ Elementary Analysis Calcd. C:68.10% H:5.99%
Found C:67.97% H:5.96%
Example 56 (R)-(3-((2-phenylbutoxy)methyl)benzofuran-7-yloxy)acetic acid ~ Ph COOH
By the method similar to Example 4, the desired compound (275 mg, yield: 89%) was obtained from methyl (R)-(3-((2-phenylbutoxy)methyl)benzofuran-7-yloxy)acetate (320 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that (R)-2-phenyl-1-butanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
[a] D: -16.63 (c=1.190, CHCl3) ` 245 Zl 88374 m.p.: 133-135C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3126,3030,2962,2904,1746,1719,1628,1589,1510,1493,1454, 1431,1359,1292,1255,1203,1187,1154,1083,78533,700cm-NMR(400MHz CDC13 ) ~ 7.50(1H,s),7.30-7.10(7H,m),6.80(1H,dd,J=5.8,3.4Hz), 4.91(2H,s),4.59(2H,brs),3.63(1H,dd,J=6.8,1.0Hz), 2.81-2.74(lH),1.88-1.79(lH,m), 1.61-1.52(lH,m),0.79(3H,t,J=7.3Hz) EI-MS m/e 354(M+) HR-EI-Ms Calcd. 354.1467 (C21H22O5) Found 354.1489 (C21H22O5) Elementary Analysis Calcd. C:71.17% H:6.26%
Found C:70.86% H:6.16%
Example 57 - (R)-(3-((1-methyl-2-(phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid ~ ~ Ph - COOH
By the method similar to Example 4, the desired compound (215 mg, yield: 88%) was obtained from methyl (R)-(3-((1-methyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetate which is obtained by the method similar to Reference Examples 68 and 45 except that (R)-1-phenyl-2-propanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
[a] D: -30-54 (c=1.100, CHCl3) m.p.: 90-92C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3064,3030,2974,2926,2866,2798,2682,2590,1742,1713,1628, - 1586,1493,1456,1423,1377,1361,1323,1288,1265,1234,1189, 1152,1131,1085,1058,957,924,909,787,733,700 cm~
NMR(400MHz CDC13 ) ~ 7.47(lH,s),7.29-7.07(7H,m),6.79(lH,dd,J=5.9,3.4Hz), 4.90(2H,s),4.67(lH,d,J=12.2Hz),4.54(lH,dd,J=12.2,1.OHz), 3.84-3.76(1H,m),2.92(1H,dd,J=13.7,6.8Hz), 2.72(1H,dd,J=13.7,5.9Hz),1.22(3H,d,J=5.9Hz) EI-MS m/e 340(M+) Elementary Analysis - Calcd. C:70.57% H:5.92%
Found C:70.35% H:5.86%
Example 58 (3-((2-phenoxyethoxy)methyl)benzofuran-7-yloxy)acetic acid S~~

- COOH

247 2 1 8837~

By the method similar to Example 4, the desired compound (286 mg, yield: 92%) was obtained from methyl (3-((2-phenoxyethoxy)methyl)benzofuran-7-yloxy)acetate (325 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that 2-phenoxyethanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
m.p.: 129-131C (recrystallized from hexane/ethyl - acetate) IR (KBr method) 2884,1742,1605,1586,1508,1493,1425,1361,1292,1263,1241, 1193,1183,1112,1081,1050,787,752,735 cm~
NMR(400MHz CDCl3 ) ~ 7.62(1H,s),7.35(1H,d,J=7.8Hz),7.29-7.25(2H,m), 7.16(lH=7.8Hz),6.90(lH,t,J=7.3Hz),6.82(lH,d,J=7.8Hz), 4.91(2H,s).77(2H,s),4.15,3.85(eachlH,ABq,J=4.9Hz),4.13, 3.86(eachlH,ABq=3.4Hz) - EI-MS m/e 342(M+) Elementary Analysis Calcd. C:66.66% H:5.30%
Found C:66.35% H:5.29%
Example 59 (3-((2-(diphenylmethoxy)ethoxy)methyl)benzofuran-7-yloxy)acetic acid 21 ~8374 2~8 ~ O ~ Ph ~ COOH
By the method similar to Example 4, the desired compound (282 mg, yield: 82%) was obtained from methyl (3-((2-(diphenylmethoxy)ethoxy)methyl)benzofuran-7-- 5 yloxy)acetate (354 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that 2-(diphenylmethoxy)ethanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
m.p.: 95-97C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3030,2920,2866,1746,1719,1630,1589,1493,1452,1431,1354, 1294,1257,1230,1207,1187,1141,1096,1087,1029,830,783,739, 696,648 cm~1 - NMR(400MHz CDCl3 ) ~ 7.58(lH,s),7.36-7.21(llH,m),7.11(lH,t,J=7.8Hz), 6.80(lH,d,J=7.8Hz),5.41(lH,s),4.90(2H,s),4.71(2H,s),3.73, 3.65(eachlH,ABq,J=6.4Hz),3.73,3.66(eachlH,ABq,J=5.4Hz) EI-MS m/e 432(M+) Elementary Analysis Calcd. C:72.21% H:5.59%
Found C:71.86% H:5.62%
Example 60 (3-((2-methyl-2-phenoxypropyloxy)methyl)benzofuran-7-yloxy)acetic acid - COOH

By the method similar to Example 4, the desired compound (260 mg, yield: 85%) was obtained from methyl - 5 (3-((2-methyl-2-phenoxypropyloxy)methyl)benzofuran-7-yloxy)acetate (317 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that 2-methyl-2-phenoxy-1-propanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
m.p.: 91-92C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2980,2928,2876,2800,1738,1713,1628,1593,1491,1460,1423, 1381,1365,1352,1290,1265,1226,1199,1152,1110,1091,1060, 1025,957,922,891,787,743,731,721,700cm~
NMR(400MHz CDCl3 ) ~ 7.61(1H,s),7.36(1H,dd,J=7.8,1.0Hz),7.26-6.99(6H,m), 6.82(lH,d,J=7.3Hz),4.93(2H,s),4.75(2H,s),3.46(2H,s), 1.29(6H,s).

EI-MS m/e 370(M+) Elementary Analysis Calcd. C:68.10% H:5.99%
Found C:67.91% H:6.00%
Example 61 2s0 (3-(2-(2-(diphenylmethoxy)ethoxy)ethyl)benzofuran-7-yloxy)acetic acid Ph O l Ph ~ COOH
By the method similar to Example 4, the desired _ 5 compound (185 mg, yield 72%) was obtained from methyl (3-(2-(2-(diphenylmethoxy)ethoxy)ethyl)benzofuran-7-yloxy)acetate (265 mg) which is obtained by the method similar to Reference Examples 90 and 17.
m.p.: 76-78C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3102,3086,3064,3028,2936,2910,2868,2784,1756,1715,1626, 1584,1493,1452,1427,1363,1305,1288,1253,1241,1205,1191, 1178,1145,1093,1040,1027,1004,899,779,754,737,702,650,511 - cm~l NMR(400MHz CDCl3 ) ~ 7.51(1H,s)!7.35-7.22(11H,m),7,11(1H,t,J=7.8Hz), 6.80(lH,d,J=7.8Hz),5.40(lH,s),4.90(2H,s), 3.78(2H,t,J=6.8Hz),3.713(eachlH,ABq,J=3.9Hz),3.70, 3.64(eachlH,ABq,J=2.9Hz),2.94(2H,t,J=6.lHz) EI-MS m/e 446(M+) Elementary Analysis Calcd. C:72.63% H:5.87%
Found C:72.35% H:5.86%

~ 25~ 8 3 7 ~

Example 62 (3-((3-~diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid Ph O ~ O l Ph - COOH
_ 5 By the method similar to Example 4, the desired compound (309 mg, yield: 89%) was obtained from methyl (3-((3-diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetate (359 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that 3-(diphenylmethoxy)-1-propanol is used in place of 3,3-diphenylpropanol in Reference Example 68.
m.p.: 140-141C (recrystallized from hexane/ethyl acetate) - IR (KBr method) 3128,3086,3064,3030,2974,2924,2876,1748,1628,1586,1493, 1452,1431,1361,1294,1270,1251,1236,1203,1189,1154,1139, 1100,1089,1075,957,930,835,787,739,700cm~
NMR(400MHz CDCl3 ) ~ 7.57(lH,s),7.30-7.21(llH,m),7.13(lH,t,J=7.8Hz), 6.81(1H,d,J=7.8Hz),5.27(1H,s),4.90(2H,s),4.61(2H,s), 3.66(2H,t,J=6.4Hz),3.54(2H,t,J=6.4Hz), 1.94(2H,quint,J=6.4Hz) EI-MS m/e 446(M+) - 2s2 2l 8 83 7l~

Elementary Analysis Calcd. C:72.63% H:5.87%
- Found C:72.19% H:5.89%
Example 63 Methyl (3-(diphenylmethylthiomethyl)benzofuran-7-yloxy)acetate Ph ~\SlPh ~0 ~ COOMe By the method similar to Reference Example 17, the desired compound (73 mg, yield: 90%) was obtained from 3-(diphenylmethylthiomethyl)-7-hydroxybenzofuran (67 mg).
IR (liquid film method) 2956,1748,1628,1595,1493,1437,1381,1359,1294,1183,1031, 783,733,704cm~1 _ NMR(400MHz CDCl3 ) ~ 7.40-7.12(13H,m),5.00(lH,s),4.88(2H,s),3.82(3H,s), 3.63(2H,d,J=0.6Hz)EI-MS m/e 418(M+) Example 64 (3-(diphenylmethylthiomethyl)benzofuran-7-yloxy)acetic acid Ph S l Ph O
~ COOH
By the method similar to Example 4, the desired compound (70 mg, yield: 99%) was obtained from methyl (3-(diphenylmethylthiomethyl)benzofuran-7-yloxy)acetate (73 _ 5 mg)-m.p.: 135.5-137.0C (recrystallized from hexane/ethyl acetate) IR (KBr method) 1742,1626,1599,1497,1450,1433,1361,1294,1261,1205,1139, 1096,779,729,702 cm-NMR(400MHz CDCl3 ) ~ 7.39-7.14(13H,m),6.83(lH,d,J=5.9Hz),5.00(lH,s), 4.92(2H,s),3.64(2H,d,J=0.8Hz) - EI-MS m/e 404(M+) Elementary Analysis Calcd. C:71.27% H:4.98% S:7.93%
Found C:70.99% H:5.00% S:7.97%
Example 65 (3-(2,2-diphenylethylthiomethyl)benzofuran-7-yloxy)acetic acid - ~1 88374 Ph O
O
- COOH

By the method similar to Example 4, the desired compound (144 mg, yield: 89%) was obtained from methyl (3-(2,2-diphenylethylthio)methylbenzofuran-7-- 5 yloxy)acetate (167 mg) which can be obtained from 3-bromomethyl-7-methoxybenzofuran by the method similar to Reference Examples 11 and 45.
m.p.: 91.0-93.5C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3392,2906,1738,1628,1595,1493,1425,1359,1267,1201,1100, 955,785,737,698cm~
NMR(400MHz CDCl3 ) - ~ 7.47(lH,s),7.31-7.13(12H,m),6.83(lH,d,J=7.8Hz), 4.92(2H,s),4.11(lH,t,J=7.8Hz),3.65(2H,s), 3.13(2H,d,J=7.8Hz) EI-MS m/e 418(M+) Example 66 (3-(3,3-diphenylpropylthiomethyl)benzofuran-7-yloxy)acetic acid S ~ Ph - COOH
By the method similar to Example 4, the desired compound (140 mg, yield: 96%) was obtained from methyl (3-(3,3-diphenylpropylthiomethyl)benzofuran-7-yloxy)acetate (150 mg) which can be obtained from 3-bromomethyl-7-methoxybenzofuran by the method similar to Reference Examples 11 and 45.
m.p.: 154.5-155C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3028,2922,1748,1626,1593,1493,1433,1359,1259,1201,1125, 1093,957,781,731,700 cm~
NMR(400MHz DMSO-d6) -- ~ 13.14-13.02(lH,br s),7.70(lH,s),7.30-7.10(12H,m), 6.84(lH,d,J=7.8Hz),4.85(2H,s),4.02(lH,t,J=6.3Hz), 3.82(2H,s),2.35-2.15(4H,m) EI-MS m/e 432(M+) Example 67 Methyl (3-(2-(diphenylmethylthio)ethyl)benzofuran-7-yloxy)acetate 21 8837~

~ COOMe Diphenylmethanethiol (297 mg) was dissolved in DMF
(2 ml) and potassium t-butoxide (166 mg) was added to the obtained solution, followed by stirring the resulting _ 5 solution at room temperature for 5 minutes. To this reaction solution, a solution of 3-(2-bromoethyl)-7-tetrahydropyranyloxybenzofuran (335 mg) in DMF (2.5 ml) was added dropwise for 5 minutes, and the resulting solution was stirred at room temperature for 15 minutes.
To this reaction solution, lN hydrochloric acid (1.5 ml) was added and the solution was stirred at room temperature for 1 hour. The reaction mixture was poured into water layer (50 ml) and the resultant was extracted - twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in DMF (4 ml). To this solution, potassium carbonate (205 mg) and methyl bromoacetate (0.19 ml) were added and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with 2 ~ 88374 ethyl acetate (20 ml). The organic layers were combined and washed with-saturated saline, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (255 mg, yield:
60%).
_ IR (liquid film method) 3064,3030,2956,2926,1763,1744,1628,1589,1493,1437,1361, 1294,1220,1197,1129,1079,789,704,627 cm~
NMR(90MHz CDCl3 ) ~ 7.45-6.69(14H,m),5.17(lH,s),4.87(2H,s), 3.79(3H,s),3.02-2.59(4H,m) EI-MS m/e 432(M+) Example 68 (3-(2-diphenylmethylthio)ethyl)benzofuran-7-yloxy)acetic acid ~ Ph ~ 0 - COOH

By the method similar to Example 4, the desired compound (209 mg, yield: 86%) was obtained from methyl (3-(2-(diphenylmethylthio)ethyl)benzofuran-7-yloxy)acetate (250 mg).

m.p.: 139-141C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3060,3030,2964,2912,1738,1628,1584,1493,1452,1429,1361, -1292,1255,1199,1164,1133,1096,955,789,746,73702cm~
NMR(400MHz CDC13 ) ~ 7.41-7.21(llH,m),7.09(lH,t,J=7.8Hz), 6.97(1H,dd,J=7.7,0.9Hz),6.78(1H,d,J=7.8Hz),5.17(1H,s), _ 4.90(2H,s),2.88(2H,t,J=7.8Hz),2.57(2H,t,J=7.8Hz) EI-MS m/e 418(M+) Elementary Analysis Calcd. C:71.75% H:5.30% S:7.66%
Found C:71.45% H:5.32% S:7.63%
Example 69 (3-(2-(diphenylmethylsulfonyl)ethyl)benzofuran-7-yloxy)acetic acid ~ Ph - COOH
(3-(2-(diphenylmethyl)thioethyl)benzofuran-7-yloxy)acetic acid (126 mg) was dissolved in dichloromethane (2 ml) and the obtained solution was cooled to 0C. To this solution, m-chloroperbenzoic acid (143 mg) was added and the resulting mixture was stirred for 2 hours. The reaction solution was poured into water _ 259 21 ~374 layer (30 ml) and the resultant was extracted twice-with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium thiosulfate solution and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/2+5%
_ acetic acid) using silica gel to obtain the desired compound (97 mg, yield: 72%).
m.p.: 177-179C (recrystallized from hexane/chloroform) IR (KBr method) 3132,1771,1751,1628,1588,1495,1456,1437,1291,1185,1165, 1131,1110,1097,1082,846,794,784,738cm~
NMR(300MHz CDCl3 ) ~7.62-7.58(4H,m),7.44-7.38(7H,m),7.10(lH,t,J=7.7Hz), 6.89(1H,d,J=7.1Hz),6.79(1H,d,J=7.4Hz),5.28(1H,s), 4.88(2H,s),3.22-3.14(4H,m) EI-MS m/e 450(M+) Example 70 Methyl (3-(2-(bis(4-methoxyphenyl)methylthio)ethyl)benzofuran-7-yloxy)acetate OMe o OMe ~ COOMe _ Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy) acetate (284 mg) and triethylamine (0.242 ml) were dissolved in dichloromethane (4 ml) and the obtained solution was cooled to 0C. To this solution, methanesulfonyl chloride (0.114 ml) was added and the resulting solution was stirred at 0C for 1 hour. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with - saturated brine, followed by drying over sodium sulfate.
The sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The obtained residue was dissolved in DMF (2 ml) and the obtained solution was added to a separately prepared solution of bis(4-methoxyphenyl)methanethiol (286 mg) and potassium t-butoxide (140 mg) in DMF (3 ml), followed by stirring the resulting solution at room temperature for 3 hours.
The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated saline, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (286 mg, yield: 51%).
IR (liquid film method) _ 3004,2956,2840,1765,1742,1609,1584,1512,1464,1439,1361, 1303,1249,1178,1129,1091,1035,816,785,733cm~
NMR(300MHz CDCl3 ) ~7.41(1H,brs),7.32-7.27(4H,m),7.08(lH,t,J=8.0Hz), 6.96(1H,dd,J=7.7,1.1Hz),6.86-6.81(4H,m), 6.75(1H,dd,J=8.0,1.1Hz),5.11(1H,s),4.88(2H,s),3.80(3H,s), 3.78(6H,s),2.91-2.86(2H, brm),2.71-2.66(2H,brm) CI-MS m/e 493(MH+) Example 71 (3-(2-(bis(4-methoxyphenyl)methylthio)ethyl)benzofuran-7-yloxy)acetic acid OMe OM

COOH

2 1 8837¢

By the method similar to Example 4, the desired compound (175 mg, yield: 70%) was obtained from methyl (3-(2-(bis(4-methoxyphenyl)methylthio)ethyl)benzofuran-7-yloxy)acetate (257 mg).
m.p.: 118-120C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3004,2908,2840,1731,1610,1582,1512,1438,1358,1304,1258, _ 1198,1179,1087,1033,953,832,814,791,734cm~
NMR(300MHz CDCl3 ) ~7.41(lH,brs),7.32-7.27(4H,m),7.10(lH,t,,J=7.7Hz), 6.99(1H,dd,J=7.7,0.8Hz),6.86-6.78(5H,m),5.11(1H,s), 4.91(2H,s), 3.78(6H,s),2.91-2.85(2H,brm), 2.72-2.66(2H,brm) EI-MS m/e 478(M+) Elementary Analysis Calcd. C:67.76% H:5.48% S:6.70%
_ Found C:67.66% H:5.47% S:6.64%
Example 72 Methyl (3-(2-(bis(4-hydroxyphenyl)methylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetate 263 21 8~37~ -OH

¢~ ' .

OH
~ COOMe Methyl (3-(2-hydroxyethyl)-2-methylbenzofuran-7-_ yloxy)acetate (203 mg) and triethylamine (0.16 ml) were dissolved in dichloromethane (4 ml) and the obtained solution was cooled to 0C. To this solution, methanesulfonyl chloride (0.071 ml) was added and the solution was stirred at 0C for 20 minutes. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml).
The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate.
_ The sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The obtained residue was dissolved in DMF (2.5 ml) and the obtained solution was added to a separately prepared solution of bis(4-tetrahydropyranyloxyphenyl)methanethiol (369 mg) and potassium t-butoxide (104 mg) in DMF (2 ml), followed by stirring the resulting solution at room temperature for 30 minutes. To this reaction solution, lN
hydrochloric acid (1.5 ml) was added and the solution was stirred for 1 hour. The reaction solution was poured into water layer (50 ml) and the resultant was extracted - twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using silica gel to obtain the desired compound (54 mg, yield:
_ 15%)-m.p.: 178-180C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3378,3352,1754,1611,1595,1514,1491,1435,1357,1294,1241, 1214,1174,1102,839,774,735 cm-NMR(300MHz CDCl3 ) ~7.17-7.13(4H,m),7.00(lH,t,J=7.7Hz), 6.81(1H,dd,J=7.7,0.8Hz),6.71-6.67(4H,m), - 6.64-6.61(1H,brm),5.00(1H,s),4.88(2H,s),3.82(3H,s), 2.81-2.76(2H,brm),2.67-2.62(2H,brm),2.36(3H,s) EI-MS m/e 478(M+) Example 73 (3-(2-bis(4-hydroxyphenyl)methylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid 2 1 8~374 ~ OH
~,~S~

OH
- COOH

By the method similar to Example 4, the desired compound (175 mg, yield: 60%) was obtained from methyl (3-(2-(bis(4-hydroxyphenyl)methyl)ethyl)-2-methylbenzofuran-7-yloxy)acetate (210 mg).
Decomposition Point: 213-215C (recrystallized from methanol/chloroform/hexane) IR (KBr method) 3494,3446,2922,1727,1612,1592,1513,1438,1359,1277,1256, 1215,1171,1104,966,829,785,732 cm~
NMR(300MHz CD3 OD) ~7.16(4H,m),7.01(1H,t,J=7.7Hz),6.82(1H,dd,J=7.7,0.8Hz), 6.74(1H,dd,J=8.0,0.8Hz),6.71-6.66(4H,m),5.00(1H,s), 4.84(2H,s),2.85-2.79(2H,brm),2.59-2.54(2H,brm),2.32(3H,s) EI-MS m/e 464(M+) Example 74 Methyl (3-(2-(bis(4-chlorophenyl)methylthio)ethyl)benzofuran-7-yloxy)acetate `~ 266 21 8~374 ~",s~

Cl ~ COOMe _ Methyl (3-(2-methanesulfonyloxyethyl)benzofuran-7-yloxy)acetate (203 mg) and diphenylmethanethiol (250 mg) were dissolved in DMF and potassium carbonate (288 mg) was added to this solution, followed by stirring the resulting solution at room temperature for 21 hours and then at 30C for 3.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, - followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (118 mg, yield: 38%).
m.p.: 68-69C`(recrystallized from hexane/ethyl acetate) IR (KBr method) 1763,1628,1586,1491,1437,1426,1361,1299,1263,1220,1203, 1185,1164,1135,1093,1013,948,801,787,737cm-1 NMR(300MHz CDCl3 ) ~7.43~lH,s),7.32-7.26(8H,m),7.11(lH,t,J=7.7Hz), - 6.95(lH,dd,J=7.7,0.8Hz),6.79-6.76(lH,m),5.05(lH,s), 4.88(2H,s),3-.81(3H,s),2.92-2.87(2H,brm),2.72-2.67(2H,brm) EI-MS m/e 500(M+) Example 75 (3-(2-bis(4-chlorophenyl)methylthio)ethyl)benzofuran-7-yloxy)acetic acid Cl S ~

O Cl COOH

By the method similar to Example 4, the desired _ compound (75 mg, yield: 67%) was obtained from methyl (3-(2-(bis(4-chlorophenyl)methylthio)ethyl)benzofuran-7-yloxy)acetate (115 mg).
m.p.: 130-132C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3094,3034,2920,2854,1736,1626,1591,1491,1437,1406,1359, 1292,1197,1164,1129,1091,1015,953,814,799,733 cm~

NMR(300MHz CDCl3 ) ~7.44tlH,s),7.27(8H,brs),7.12(lH,t,J=8.OHz), 6.98(1H,dd,J=7.7,0.8Hz),6.80(1H,dd,J=8.0,0.8),5.06(1H,s), 4.92(2H,s),2.92-2.86(2H,brm),2.73-2.67(2H,brm) EI-MS m/e 486(M+) Example 76 (3-(2-(bis(4-fluorophenyl)methylthio)ethyl)-benzofuran-7-yloxy)acetic acid F

~S~

O F
~ COOH
By the method similar to Example 4, the desired compound (171 mg, yield: 93%) was obtained from methyl (3-(2-(bis(4-fluorophenyl)methylthio)ethyl)-benzofuran-7-yloxy)acetate (195 mg) which can be obtained by the method similar to Example 74 from methyl (3-(2-methanesulfonyloxyethyl)benzofuran-7-yloxy)acetate.
m.p.: 132-134C (recrystallized from ethyl acetate/n-hexane).
IR (KBr method) 3114,3046,2914,1740,1628,1603,1506,1435,1415,1359,1294, 1257,1224,1201,1156,1133,1093,953,835,789,733cm-NMR(300MHz CDCl3 ) ~ 7.42(1H,brs),7.03-7.28(4H,m),7.11(1H,t,J=8.0Hz),7.03-6.95(5H,m), 6.80(1H,dd,J=8.0,0.8Hz),5.10(1H,s),4.91(2H,s), ~ ~ ~837¢
_ 269 2.92-2.86(2H,m),2.72-2.66(2H,m) EI-MS m/e 454(M+) Example 77 (3-(2-(dicyclohexylmethylthio)ethyl)-benzofuran-7-yloxy)acetic acid O
Sx~ S~>

- COOH
By the method similar to Example 4, the desired compound (131 mg, yield: 96~) was obtained from methyl 3-(2-dichclohexylmethylthioethyl)-benzofuran-7-yloxyacetate (140 mg) which can be obtained by the method similar to Example 74 from methyl (3-(2-methanesulfonyloxyethyl)benzofuran-7-yloxy)acetate.
m.p.: 131.0C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3400,2926,2854,1709,1497,1439,1234,1195,1085,783,725cm~
NMR(300MHz CDCl3 ) ~
7.50(lH,s),7.21(lH,dd,J=1,8Hz),7.16(lH,t,J=8Hz), 6.82(lH,dd,J=1,8Hz),4.92(2H,s),2.90-2.95(2H,m), 2.79-2.85(2H,m),2.11(lH,t,J=6Hz),1.93(2H,m), 1.54-1.76(lOH,m),1.04-1.34(lOH,m) EI-MS m/e 430(M+) Example 78 3-(2-(phenyl(2-thienyl)methylthiojethyl)-benzofuran-- 7-yloxyacetic acid ,~
S ~

~ COOH
By the method similar to Example 4, the desired compound (163 mg, yield: 98%) was obtained from methyl 3-(2-(phenyl(2-thienyl)methylthio)ethyl)-benzofuran-7-yloxy acetate (172 mg) which can be obtained by the method similar to Example 74 from methyl (3-(2-methanesulfonyloxyethyl)benzofuran-7-yloxy)acetate.
- m.p.: 111.0C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 2914,1738,1626,1593,1493,1452,1431,1361,1261,1199,1089, 955,791,733,700cm~1 NMR(300MHz CDCl3 ) ~ 7.45(3H,m),7.22-7.36(4H,m), 7.11~1H,t,J=8Hz),7.03(1H,dd,J=1,8Hz),6.91(2H,m), 6.80(1H,dd,J=1,8Hz),5.36(1H,s),4.91(2H,s),2.90(2H,m), 2.77(2H,m) EI-MS m/e 424(M+) Example 79 Methyl (3-(2-(diphenylmethylthio)ethyl)benzofuran-6-yloxy)acetate S ~ Ph COOMe By the method similar to Example 70, the desired _ compound (191 mg, yield: 81%) was obtained from methyl (3-(2-hydroxyethyl)benzofuran-6-yloxy)acetate (137 mg) which can be obtained by the method similar to Reference Examples 13, 16 and 17 from 6-hydroxy-2,3-dihydrobenzofuran-3-one.
m.p.: 88-89C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2944,1763,1626,1599,1582,1489,1454,1439,1381,1340,1296, 1284,1265,1222,1209,1156,1143,1123,1075,1054,1029,975, - 15 930,820,808,799,775,754,725,708,675cm~
NMR(300MHz CDCl3 ) ~ 7.42-7.20(11H,m),7.16(1H,d,J=8.5Hz), 6.96(1H,d,J=1.8Hz),6.86(1H,dd,J=8.5,2.3Hz),5.17(1H,s), 4.67(2H,s),3.82(3H,s),2.90-2.86(2H,m),2.74-2.67(2H,m) EI-MS m/e 432(M+) Example 80 (3-(2-(diphenylmethylthio)ethyl)benzofuran-6-yloxy)acetic acid ~ 272 2188374 ~ 5 ~ Ph O O

COOH
By the method similar to Example 4, the desired compound (170 mg, yield: 94%) was obtained from methyl (3-(2-(diphenylmethylthio)ethyl)benzofuran-6-yloxy)acetate (188 mg).
- m.p.: 133-135C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3060,3030,2906,2778,2584,1748,1626,1597,1582,1491,1446, 1427,1338,1294,1257,1232,1154,1122,1075,1058,951,926,832, 810,799,754,702cm~
NMR(300MHz CDCl3 ) ~ 7.42-7.20(llH,m),7.18(lH,d,J=8.5Hz), 6.99(1H,d,J=1.9Hz),6.87(1H,dd,J=8.5,2.2Hz),5.17(1H,s), - 15 4.71(2H,s),2.89-2.84( 2H,m),2.73-2.67(2H,m) EI-MS m/e 418(M+) Elementary Analysis Calcd. C:71.75% H:5.30% S:7.66%
Found C:71.46% H:5.28% S:7.58%
Example 81 (3-(2-(diphenylmethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid ~ 273 21 88374 5 ~ Ph - COOH
By the method similar to Example 4, the desired compound (196 mg, yield: 88%) was obtained from methyl (3-(2-(diphenylmethylthio)ethyl)-2-methylbenzofuran-7-_ 5 yloxy)acetate (230 mg) which can be obtained by themethod similar to Reference Example 11 from methyl (3-(2-bromoethyl)-2-methylbenzofuran-7-yloxy)acetate.
m.p.: 146-148C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3064,3030,2924,1742,1713,1630,1589,1493,1452,1431,1361, 1288,1247,1232,1212,1164,1106,1081,965,907,787,768,750, 733,725 cm~1 NMR(300MHz CDCl3 ) ~ 7.40-7.19(lOH,m),7.03(lH,t,J=7.7Hz), 6.84(1H,dd,J=7.7,1.1Hz),6.69(1H,dd,J=8.0,1.1Hz), 5.15(1H,s),4.88(2H,s),2.84-2.78(2H,brm), 2.65-2.59(2H,brm),2.31(3H,s) EI-MS m/e 432(M+) Elementary Analysis Calcd. C:72.20% H:5.59% S:7.41%
Found C:72.01~ H:5.55% S:7.35%
Example 82 `~ 274 21 8837~

Methyl (2-hydroxymethyl-3-(2-(diphenylmethylthlo~ethyl)benzofuran-7-yloxy)acetate S ~ Ph OH

~ COOMe Potassium t-butoxide (465 mg) was dried under - 5 reduced pressure. In DMF (5 ml), n-propanethiol (0.4 ml) was dissolved and the obtained solution was added to the potassium t-butoxide, followed by stirring the resulting mixture at room temperature. 2-hydroxymethyl-3-(2-(diphenylmethylthio)ethyl)-7-methoxybenzofuran (803 mg) was dissolved in DMF (6 ml) and the obtained solution was added to the above-mentioned solution, followed by stirring the resulting solution at 90C for 6 hours. The reaction solution was poured into 5% aqueous citric acid solution and the resultant was extracted with ethyl acetate. The organic layer was washed with water and with saturated brine and dried over magnesium sulfate.
The magnesium sulfate was removed by filtration and the solvent was evaporated off. The obtained residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=1/1) to obtain the phenol compound(406 mg, yield: 52%). This phenol compound (406 mg) was dissolved in ethanol (50 ml) and 4N aqueous potassium hydroxide solution (0.3 ml) was added thereto, followed _ 275 2 1 8837~

by stirring the resulting solution at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure. Dimethylformamide (20 ml) was added to the obtained residue to dissolve the same and methyl bromoacetate (0.20 ml) was added to the obtained solution, followed by stirring the solution at room temperature for 90 minutes. The reaction solution was poured into 5%
aqueous citric acid solution, and the resultant was _ extracted with ethyl acetate. The organic layer was washed with water and with saturated brine, and dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the solvent was evaporated off.
The obtained residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=1/1) to obtain the phenol compound (403 mg, yield: 84%).
IR (thin film method) 3450,1760,1591,1493,1437,1388,1288,1209,1096,1004,785, 752,733,704cm~1 NMR(300MHz CDC13 ) ~ 7.38-7.18(lOH,m),7.08(lH,t,J=8Hz),6.93(lH,dd,J=1,8Hz), 6.77(lH,dd,J=1,8Hz),5.03(1H,s),4.89(2H,s), 4.67(2H,d,J=6Hz),3.80(3H,s),2.92(2H,t,J=7Hz), 2.68(2H,t,J=7Hz),2.18(lH,t,J=6Hz) Example 83 (2-hydroxymethyl-3-(2-(diphenylmethylthio)ethyl)benzofuran-7-yloxy)acetic acid OH
O

~ COOH
By the method similar to Example 4, the desired compound (343 mg, yield: 80%) was obtained from methyl (2-hydroxymethyl-3-(2-_ 5 (diphenylmethylthio)ethyl)benzofuran-7-yloxy)acetate (446 mg).
m.p.: 144.0C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 3400,3026,2924,1736,1657,1628,1591,1493,1452,1439,1286, 1209,1096,748,729,704,692,623cm~
NMR(300MHz CDCl3 ) ~ 7.36-7.19(lOH,m),7.07(lH,t,J=8Hz),6.92(lH,dd,J=1,8Hz), _ 6.77(1H,dd,J=1,8Hz),5.04(1H,s),4.85(2H,s),4.65(2H,s), 2.88(2H,t,J=7Hz),2.66(2H,t,J=7Hz) Elementary Analysis Calcd. C:68.93% H:5.45% S:7.08%
Found C:68.86% H:5.55% S:7.36%
Example 84 Methyl (2-(2-acetoxyethyl)-3-(2-(diphenylmethyl)thioethyl)benzofuran-7-yloxy)acetate - ` 277 218837~

'"`~

~ COOMe By the method similar to Example 70, the desired compound (125 mg, yield: 42~) was obtained from methyl (2-(2-acetoxyethyl)-3-(2-hydroxyethyl)benzofuran-7-_ 5 yloxy)acetate (195 mg).
IR (liquid film method) 3064,3030,2958,1765,1742,1628,1591,1493,1441,1367,1338, 1238,1201,1100,1042,787,762,733,704,629cm~
NMR(300MHz CDCl3 ) ~ 7.41-7.19(lOH,m),7.04(lH,t,J=8.OHz), 6.83(1H,dd,J=7.6,0.8Hz),6.70(1H,dd,J=8.0,1.1Hz), 5.20(1H,s),4.86(2H,s),4.31(2H,t,J=6.6Hz),3.80(3H,s), 2.99(2H,t,J=6.6Hz),2.86-2.81(2H,m),2.66-2.61(2H,m), 1.99(3H,s) EI-MS m/e 518(M+) Example 85 (3-(2-(diphenylmethyl)thioethyl)-2-(2-hydroxyethyl))benzofuran-7-yloxy)acetic acid /

--COOH

21 8837~

By the method similar to Example 4, the desired compound (208 mg, yield: 94%) was obtained from methyl (2-(2-acetoxyethyl)-3-(2-(diphenylmethyl)thioethyl))benzofuran-7-yloxy)acetate (247 mg).
m.p.: 148-150C (recrystallized from hexane/ethyl acetate) IR (KBr method) _ 3340,2904,1742,1711,1628,1589,1493,1450,1303,1274,1232, 1209,1098,1035,1019,748,727,702cm~
NMR(300MHz CD3 OD) ~ 7.38-7.16(lOH,m),7.00(lH,t,J=8.OHz), 6.81(1H,dd,J=7.7,0.8Hz),6.75(1H,dd,J=7.7,0.8Hz), 5.17(lH,s),4.85(2H,s),3.82(2H,t,J=6.6Hz), 2.93-2.85(4H,m),2.66-2.60(2H,m), EI-MS m/e 462(M+) Elementary Analysis _ Calcd. C:70.11% H:5.67% S:6.93%
Found C:69.91% H:5.65% S:6.88%
Example 86 Methyl (2-(3-acetoxypropyl)-3-(2-(diphenylmethyl)thioethyl)benzofuran-7-yloxy)acetate S < Ph Ac ~ COOMe 21 8837~
, .

Methyl (2-(3-acetoxypropyl)-3-(2-- hydroxyethyl)benzofuran-7-yloxy)acetate (78 mg) was dissolved in dichloromethane (l ml) and the obtained solution was cooled to 0C. To this solution, triethylamine (0.02 ml) and methanesulfonyl chloride (0.047 ml) were added and the resulting mixture was stirred for 30 minutes. The reaction solution was poured into water (50 ml) and extracted twice with ethyl acetate _ (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in DMF (2 ml). To this solution, diphenylmethanethiol (89 mg) and potassium carbonate (37 mg) were added and the resultant was stirred at room temperature for 22 hours. The reaction - mixture was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying over sodium sulfate.
After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent:
hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (83 mg, yield: 70%).

2~88374 IR (liquid film method) 3062,3030,2958,1765,1734,1628,-lS91,1493,1448,1369,1243, 1201,1102,1079,1044,779,750,733,704cm~
NMR(300MHz CDC13 ) ~ 7.41-7.19(10H,m),7.02(1H,t,J=8.0Hz), 6.80(1H,dd,J=8.0,1.1Hz),6.68(1H,dd,J=8.0,0.8Hz), 5.16(1H,s),4.86(2H,s),4.05(2H,t,J=6.3Hz),3.80(3H,s), 2.85-2.71(4H,m),2.64-2.59(2H,m),2.05(3H,s), _ 2.06-1.95(2H,m) EI-MS m/e 532(M+) Example 87 (3-(2-(diphenylmethyl)thioethyl)-2-(2-hydroxypropyl)benzofuran-7-yloxy)acetic acid SyPh OH

O
- COOH
lS By the method similar to Example 4, the desired compound (67 mg, yield: 79~) was obtained from methyl (2-(2-acetoxypropyl)-3-(2-(diphenylmethyl)thioethyl)benzofuran-7-yloxy)acetate (9S
mg).
m.p.: 154-156C (recrystallized from hexane/ethyl acetate) IR (KBr method) 281 2~ 8~374 3448,3034,2928,2584,1748,1627,1590,1493,1450,1431,1377, 1356,1285,1240,1208,1158,1098,1059,1005,911,775,749,731, 703cm~1 NMR(300MHz CD30D) ~ 7.39-7.17(lOH,m),7.00(lH,t,J=8.OHz), 6.82(1H,dd,J=7.7,1.1Hz),6.75(1H,dd,J=8.0,0.8Hz), 5.19(1H,s),4.84(2H,s),3.56(2H,t,J=6.3Hz), 2.90-2.85(2H,brt),2.78-2.73(2H,brt),2.64-2.59(2H,brt), _ 1.93-1.84(2H,m) EI-MS m/e 476(M+) Example 88 (3-(2-(2,2-diphenylethylthio)ethyl)benzofuran-7-yloxy)acetic acid ~J, - COOH
By the method similar to Example 4, the desired compound (100 mg, yield: 78%) was obtained from methyl (3-(2-(2,2-diphenylethylthio)ethyl)benzofuran-7-yloxy)acetate (133 mg) which can be obtained by the method similar to Reference Examples 11 and 45 from 3-(2-bromoethyl)-7-methoxybenzofuran.
m.p.: 116.0-118.0C (recrystallized from hexane/ethyl acetate) IR (KBr method) _ 282 21 8~374 2906,1744,1630,1591,1493,1427,1359,1259,1197,1125,1089, 957,748,733,698cm~
NMR(400MHz CDCl3 ) ~ 7.40(1H,s),7.32-7.12tl2H,m),6.82(1H,dd,J=6.6,2.2Hz~, 4.91(2H,s),4.16(1H,t,J=7.8Hz),3.24(2H,d,J=7.8Hz), 2.91-2.87(2H,m),2.79-2.74(2H,m) EI-MS m/e 432(M+) Example 89 _ (3-(2-(3,3-diphenylpropylthio)ethyl)benzofuran-7-yloxy)acetic acid , ~ S ~Ph - COOH
By the method similar to Example 4, the desired compound (61 mg, yield: 97%) was obtained from methyl (3-(2-(3,3-diphenylpropylthio)ethyl)benzofuran-7-yloxy)acetate (65 mg) which can be obtained by the methodsimilar to Reference Examples 11 and 45 from 3-(2-bromoethyl)-7-methoxybenzofuran.
m.p.: 61.0-62.0C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2368,1734,1532,1493,1363,1245,1185,1087,733,700,586,509, 445,426 cm~1 NMR(400MHz CDCl3 ) ~ 7.44(1H,s),7.30-7.11(12H,m),6.82(1H,dd,J=6.8,2.0Hz), ~ 283 2188314 4.91(2H,s),4.07(lH,t,J=7.8Hz),2.89-2.78(4H,m), - 2.49(2H,dd,J=8.8,6.8Hz),2.36-2.29(2H,m) EI-MS m/e 446(M+) Example 90 Methyl (3-(3-diphenylmethylthiopropyl)benzofuran-7-yloxy)acetate S Ph ~ COOMe By the method similar to Reference Example 11, the desired compound (177 mg, yield: 89~) was obtained from methyl (3-(3-bromopropyl)benzofuran-7-yloxy)acetate (145 ml).
IR (liquid film method) 2928,1763,1740,1628,1589,1493,1437,1375,1292,1245,1183, 1091,1046,1031,785,733,702,586cm~
NMR(300MHz CDCl3 ) ~ 7.0-7.5(13H,m),6.77(lH,dd,J=2,6Hz),5.13(lH,s), 4.88(2H,s),3.82(3H,s),2.72(2H,t,J=7Hz),2.46(2H,t,J=7Hz), 1.93(2H,quint,J=7Hz) EI-MS m/e 446(M+) Example 91 (3-(3,3-diphenylmethylthiopropyl)benzofuran-7-yloxy)acetic acid -- 21 ~8374 28~

Ph S Ph - COOH
By the method similar to Example 4, the desired compound (142 mg, yield: 85%) was obtained from methyl (3-(3,3-diphenylmethylthiopropyl)benzofuran-7-- 5 yloxy)acetate (171 mg).
m.p.: 112.0C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 1738,1715,1628,1584,1493,1433,1259,1201,1185,1093,955, 781,739,700cm~1 NMR(300MHz CDCl3 ) ~ 7.10-7.42(13H,m),6.81(1H,d,J=7Hz),5.14(1H,s), 4.91(2H,s),2.72(2H,t,J=7Hz),2.46(2H,t,J=7Hz), - 1.93(2H,sept,J=7Hz) EI-MS m/e 432(M+) Elementary Analysis Calcd. C:71.81% H:5.62% S:7.37 Found C:71.81% H:5.59% S:7.32 Example 92 (3-(3-(2,2-diphenylethylthio)propyl)benzofuran-7-yloxy)acetic acid ¦ Ph - COOH
By the method similar to Example 4, the desired compound (92 mg, yield: 84%) was obtained from methyl (3-(3-(2,2-diphenylethylthio)propyl)benzofuran-7-- 5 yloxy)acetate (114 mg) which can be obtained by the method similar to Reference Example 11 from methyl (3-(3-bromopropyl)benzofuran-7-yloxy)acetate and 2,2-diphenylethanethiol.
m.p.: 94C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 2924,1740,1713,1626,1584,1493,1452,1423,1354,1267,1195, 1094,783,735,702cm~
NMR(300MHz CDC13 ) - ~ 7.10-7.40(13H,m),6.81(lH,d,J=7Hz),4.92(2H,s), 4.17(lH,t,J=8Hz),3.21(2H,d,J=8Hz),2.72(2H,t,J=7Hz), 2.51(2H,t,J=7Hz),1.94(2H,quint,J=7Hz) EI-MS m/e 446(M+) Example 93 (3-(3-(3,3-diphenylpropylthio)propyl)benzofuran-7-yloxy)acetic acid ` 286 2188374 Ph C ~ ~ ~' S ~ Ph ~ COOH
By the method similar to Example 4, the desired compound (54 mg, yield: 85%) was obtained from methyl (3-(3-(3,3-diphenylpropylthio)propyl)benzofuran-7-yloxy)acetate (66 mg) which can be obtained by the methodsimilar to Reference Example 11 from methyl (3-(3-bromopropyl)benzofuran-7-yloxy)acetate and 3,3-diphenylpropanethiol.
m.p.: 94C (recrystallized from ethyl acetate/n-hexane) IR (KBr method) 2930,1738,1582,1493,1423,1263,1023,801,700cm-NMR(300MHz CDCl3 ) ~ 7.10-7.40(13H,m),6.81(1H,d,J=7Hz),4.91(2H,s), - 4.08(lH,t,J=8Hz),2.74(2H,t,J=7Hz),2.54(2H,t,J=7Hz), 2.45(2H,t,J=7Hz),2.32(2H,q,J=7Hz),1.92(2H,quint,J=7Hz) EI-MS m/e 460(M+) Elementary Analysis Calcd. C:73.02% H:6.13% S:6.96 Found C:73.04% H:6.14% S:6.93 Example 94 (3-((3,3-diphenyl-2-propenyloxy)methyl)benzofuran-7-yloxy)acetic acid - 287 2 1 ~8374 Ph Ph O

- COOH
By the method similar to Example 4, the desired compound (286 mg, yield: 94%) was obtained from methyl (3-((3,3-diphenyl-2-propenyloxy)methylbenzofuran-7-_ 5 yloxy)acetate (315 mg) which is obtained by the methodsimilar to Reference Examples 68 and 59 except that 3,3-diphenyl-2-propene-1-ol is used in place of 3,3-diphenylpropanol.
m.p.: 112-115C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3120,3060,3028,2918,2868,1748,1719,1628,1589,1493,1431, 1359,1294,1253,1199,1154,1096,1079,955,828,781,772,764, - 735,702 cm~1 NMR(400MHz CDCl3 ) ~ 7.47(lH,s),7.36-7.12(12H,m),6.82(lH,d,J=7.8Hz), 6.23(lH,t,J=6.8Hz),4.90(2H,s),4.60(2H,s), 4.11(2H,d,J=6.8Hz) EI-MS m/e 414(M+) Example 95 (S)-(3-((2-(diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid 21 8~37~

S~ I

- COOH

By the method similar to Example 4, the desired compound (74 mg, yield: 68%) was obtained from methyl (S)-(3-((2-(diphenylmethoxy)propyloxy)methyl)benzofuran-_ 5 7-yloxy)acetate (112 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that (S)-2-diphenylmethoxy-1-propanol is used in place of 3,3-diphenylpropanol.
[a] D : -8.17 (c=0.881, CHCl3) m.p.: 105-107C
IR (KBr method) 3500,1746,1493,1431,1361,1253,1187,1081,733 cm-NMR(400MHz,CDC13) - ~(ppm) 7.55(1H,s),7.40-7.20(1H,m),7.12(1H,t,J=7.8Hz), 6.82(1H,d,J=7.8Hz),5.60(1H,s),4.92(2H,s),4.65(2H,s), 3.7-3.8(lH,m),3.62(lH,dd,J=10.0,5.8Hz), 3.49(1H,dd,J=10.0,4.4Hz),1.19(3H,d,J=6.4Hz) Mass(m/e) 446(M+) Example 96 (R)-(3-((2-(diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid 21&8374 ~ COOH
By the method similar to Example 4, the desired compound (72 mg, yield: 46%) was obtained from methyl (R)-(3-((2-(diphenylmethoxy)propyloxy)methyl)benzofuran-S 7-yloxy)acetate (160 mg) which is obtained by the method _ similar to Reference Examples 68 and 45 except that (R)-2-diphenylmethoxy-1-propanol is used in place of 3,3-- diphenylpropanol.
[a]D: +8.78 (c=0.957, CHCl3) m.p.: 105-106.5C
IR (KBr method) 3500,1744,1493,1431,1361,1253,1187,1079,739 cm~
NMR(40OMHz CDCl3 ) ~(ppm) 7.55(lH,s),7.20-7.40(llH,m),7.12(lH,t,J=7.8Hz), - 15 6.82(1H,d,J=7.8Hz),S.60(1H,s),4.92(2H,s),4.65(2H,s), 3.7-3.8(lH,m),3.62(1H,dd,J=10.0,5.8Hz), 3.49(1H,dd,J=10.0,5.8Hz),1.19(3H,d,J=6.4Hz) Mass(m/e) 447((M+H)+) Example 97 (R)-(3-((2-(diphenylmethoxy)-1-methylethoxy)methyl)benzofuran-7-yloxy)acetic acid ` 290 21 8837~

-CL~` `~

~ COOH
By the method similar to Example 4, the desired compound (74 mg, yield: 42%) was obtained from methyl (R)-(3-((1-(diphenylmethoxy)-1-_ 5 methylethoxy)methyl)benzofuran-7-yloxy)acetate (180 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that (R)-1-diphenylmethoxy-2-propanol is used in place of 3,3-diphenylpropanol.
[a] D : -11 . 44 (c=0.769, CHCl3) m.p.: 91-92.5C
IR (KBr method) 2868,1746,1717,1628,1591,1543,1495,1454,1431,1363,1292, 1261,1203,1154,1096,1048,998,959,826,783,731 cm~
_ NMR(400MHz CDCl3 ) ~(ppm) 7.56(lH,s),7.20-7.40(llH,m),7.09(lH,t,J=7.8Hz), 6.81(1H,d,J=7.3Hz),5.38(lH,s),4.90(2H,s),4.75(2H,s), 3.90-3.80(1H,m),3.54(1H,dd,J=10.0,6.3Hz), 3.45(1H,dd,J=10.0,4Hz),1.21(3H,d,J=6.4Hz) Mass(m/e) 446(M+) Example 98 (S)-(3-((2-(diphenylmethoxy)-1-methylethoxy)methyl)benzofuran-7-yloxy)acetic acid 'h - COOH
By the method similar to Example 4, the desired compound (40 mg, yield: 30~) was obtained from methyl (R)-(3-((1-(diphenylmethoxy)-1-_ 5 methylethoxy)methyl)benzofuran-7-yloxy)acetate (136 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that (S)-l-diphenylmethoxy-2-propanol is used in place of 3,3-diphenylpropanol.
[a] D : +11- 69 (c=0.872, CHCl3) m.p.: 89.5-92C
IR (KBr method) 2868,1746,1717,1628,1591,1543,1495,1454,1431,1363,1292, 1261,1203,1154,1096,1048,998,959,826,783,731 cm~
NMR(400MHz CDC13 ) ~ 7.56(1H,s),7.20-7.40(11H,m),7.09(1H,t,J=7.3Hz), 6.81(lH,d,J=7.3Hz),5.38(lH,s),4.90(2H,s),4.75(2,s), 3.90-3.80(lH,m),3.54(lH,dd,J=10.0,6.3Hz), 3.45(lH,dd,J=10.0,4Hz),1.21(3H,d,J=6.4Hz) Mass(m/e) 446(M+) Example 99 (3-(((2-(N,N-diphenylamino)ethoxy)methyl)benzofuran-7-yloxy)acetic acid - 2t883-74 Ph ~N` Ph ~ - o - COOH
By the method similar to Example 4, the desired compound (68 mg, yield: 68%) was obtained from methyl (3-(((2-(N,N-diphenylamino~ethoxy)methyl)benzofuran-7-yloxy)acetate (103 mg) which is obtained by the method similar to Reference Examples 68 and 45 except that 2-(N,N-diphenylamino)-1-ethanol is used in place of 3,3-diphenylpropanol.
m.p.: 109-110C (recrystallized from hexane/ethyl acetate) IR (KBr method) 2910,2868,1731,1628,1586,1495,1433,1363,1323,1263,1224, 1195,1154,1094,1077,791,750,733,704cm~
_ NMR(300MHz CDCl3 ) ~ 7.50(lH,lHbrs),7.27-6.80(13H,m),4.91(2H,s), 4.63(2H,d,J=0.8Hz),3.96(2H,t,J=6.3Hz),3.72(2H,t,J=6.3Hz) EI-MS m/e 417(M+) Elementary Analysis Calcd. C:71.93% H:5.55% N:3.36%
Found C:71.63% H:5.56% N:3.69%
Example 100 Methyl (3-(2-hydroxy-5,5-diphenylpentyl)benzofuran-7-yloxy)acetate 21883~

h ~ COOMe 3-(2-acetoxy-5,5-diphenylpentyl)-7-acetoxybenzofuran (184 mg) was dissolved in methanol (5 ml) and the obtained solution was stirred at room temperature. To this solution, lN aqueous sodium hydroxide solution (1 ml) was added and the resulting solution was stirred at room temperature. After confirming vanishment of the materials, the solvent was removed under reduced pressure.
Water (5 ml) was added to the obtained residue and the resultant was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. The sodium sulfate was removed by filtration -- and the solvent was removed under reduced pressure to obtain a crude product. The obtained crude product was dissolved in DMF (3 ml) and the obtained solution was stirred at room temperature. To this solution, potassium carbonate (100 mg) and methyl bromoacetate (0.10 ml) were added and the resultant was stirred at room temperature.
After confirming vanishment of the materlals, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (10 ml). The organic layers were combined ~ 1 88374 and washed wlth saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1-2/1) using silica gel to obtain the desired compound (184 mg, yield: 100%).
IR (liquid film method) _ 2948,1763,1628,1591,1493,1437,1361,1294,1183,1143,1093, 911,845,783,733,702cm-NMR(300MHz CDCl3 ) ~ 7.50-7.10(13H,m),6.78(lH,dd,J=7.2,2.4Hz),4.88(2H,s), 3.90(lH,t,J=7.8Hz),3.81(3H,s),2.86-2.78(lH,m), 2.68(lH,dd,J=14.4,7.5Hz),2.38-2.07(2H,m),1.60-1.40(2H,m) EI-MS m/e 444(M+) Example 101 (3-(2-hydroxy-5,5-diphenylpentyl)benzofuran-7-_ yloxy)acetic acid `Ph ~ COOH

By the method similar to Example 4, the desired compound (116 mg, yield: 78%) was obtained from methyl (3-(2-hydroxy-5,5-diphenylpentyl)benzofuran-7-- 295 21 8837~

yloxy)acetate.
m.p.: 155.0-157.0C (recrystallized from hexane/ethyl acetate) IR (KBr method) 3342,1736,1620,1584,1493,1433,1363,1232,1195,1141,1079, 781,748,729cm~1 NMR(400MHz CDCl3 ) ~ 7.46(lH,s),7.29-7.10(12H,m), _ 6.80(lH,dd,J=7.1,1.7Hz),4.85(2H,s),3.94-3.87(2H,m), 3.42-3.41(lH,m),2.81(lH,dd,J=14.6,4.2Hz), 2.69(lH,dd,J=14.6,8.11Hz),2.33-2.04(3H,m),1.57-1.49(2H,m) EI-MS m/e 430(M+) Elementary Analysis Calcd. C:75.33% H:6.09%
Found C:75.01% H:6.07%
Example 102 Methyl (1-(2-p-toluenesulfonylamino)ethyl)indole-4-_ yloxy)acetate ~NHSO2{}Me ~ COOMe By the method similar to Example 20, the desired compound (200 mg, yield: 46%) was obtained from methyl (1-(2-azideethyl)indole-4-yloxy)acetate (297 mg).
IR (KBr method) ~ l ~8374 ~- 296 3258,1740,1497,1280,1249,1091,741,547 cm~
NMR(90MHz CDCl3 ) ~ 7.70-7.60(2H,m),7.40-7.20(5H,m),7.00-6.90(lH), 6.70-6.40(2H,m),4.78(2H,s),4.30-4.10(2H,m), 3.81(3H,s),3.70-3.40(2H,m),2.41(3H,s) EI-MS 402(M+) Example 103 (1-(2-p-toluenesulfonylamino)ethyl)indole-4-_ yloxy)acetic acid ~ ~ NHso~ O Me - COOH
By the method similar to Example 4, the desired compound (114 mg, yield: 79%) was obtained from methyl (1-(2-(p-toluenesulfonylamino)ethyl)indole-4-_ yloxy)acetate (149 mg).
m.p.: 157-158C
IR (KBr method) 3298,1711,1497,1437,1325,1224,1154,1094,737 cm~
NMR(40OMHz CDC13 ) ~(ppm) 12.97(lH,brs),7.76(lH,t,J=5.9Hz), 7.61(2H,d,J=8.3Hz),7.33(2H,d,J=8.3Hz),7.21(2H,d,J=3.4Hz), 7.00(1H,d,J=2.2Hz),6.99(1H,s),6.43(1H,d,J=3.4Hz), 4.75(2H,s),3.04(2H,q,J=6.4Hz),2.36(3H,s) EI-MS 388(M+) DEMANDES OU BREVE~S VO~UMINEUX

LA PI~ESEI\IT~ PARTIE DE ~ t DEMANDE ~U CE~ BREVEI
COMPP~END PLUS D'UN TOME

CEC~ EST LE. TOME ~ l~E ~ -NO~: .Pour les tomes additionels, veuillez c~ntacter le Bureau canadien des b~evets JUMBO APPLICATIONS/PATENTS

THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME

THlS IS VOLUME /_ OF ~2 -NOTE: ~cr additional volumes please c~ntacI ~he Canadian Patent Cffico

Claims (134)

1. A benzene-condensed heterocyclic derivative of the formula (I):

(I) (wherein R1 is -X-(CH2)nCOOR3 (wherein X is -O-, -S- or -CH2-, R3 is hydrogen, C1-C5 lower alkyl, or an atom or group which gives a pharmaceutically acceptable salt, and n is an integer of 1 to 3);
R is i) -CR4=CR5-O-, ii) -CR5=CR4-O-, or iii) -NR4-CR5R6-CHR7-(wherein R4 is - (CH2) m-Y-R8 (wherein m is an integer of 1 to 4, Y is 1) -O-, 2) -CH2-, 3) -S(O)p- (p is an integer of 0 to 2), 4) -CO-, 5) -CH(OH)-, 6) -NR9SO2-, (wherein R9 is a) hydrogen, b) C1-C5 alkyl, c) phenyl (which may be substituted), d) C1-C5 alkyl substituted with phenyl (which may be substituted) 7) -NR9CO- (wherein R9 represents the same meanings as described above) 8) -CONR9- (wherein R9 represents the same meanings as described above) 9) -NR9- (wherein R9 represents the same meanings as described above) 10) -O-N=CR9- (wherein R9 represents the same meanings as described above), or 11) the group represented by the formula (II):

(IIa) (IIb) R8 is 1) phenyl, thienyl, furyl, naphthyl or C3-C8 cycloalkyl, 2) substituted phenyl, substituted thienyl, substituted furyl or substituted naphthyl, 3) C1-C5 alkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
4) C2-C5 alkenyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
5) C3-C5 alkynyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
6) C2-C8 alkoxyalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
7) C1-C5 hydroxyalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
8) C2-C8 alkylthioalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy;
9) C1-C5 aminoalkyl which is substituted with one or two substituents selected from the group consisting of phenyl (which may be substituted), thienyl (which may be substituted), furyl (which may be substituted), naphthyl (which may be substituted), C3-C8 cycloalkyl and phenoxy; or 10) -CH2-C(O)-R10 (wherein R10 is phenyl (which may be substituted) or C1-C5 alkyl substituted with one or two phenyl groups (which may be substituted);
R5 is 1) hydrogen, 2) C1-C5 alkyl, 3) C1-C5 hydroxyalkyl or acetoxyalkyl, 4) C1-C5 alkyl substituted with one or two phenyl groups (which may be substituted), or 5) C2-C8 alkoxyalkyl substituted with one or two phenyl groups (which may be substituted);
R6 and R7 represent hydrogen or R6 and R7 are covalently bonded to represent a double bond)).

2. The compound according to claim 1, wherein X is -O-.

3. The compound according to claim 1 or 2, wherein R2 is -CR4=CR5-O- or -CR5=CR4-O-

4. The compound according to claim 1 or 2, wherein R2 is -NR4-CR5R6-CHR7-.

5. The compound according to any one of claims 1-4, wherein Y is -O- or -CH2-.

6. The compound according to any one of claims 1-4, wherein Y is -S(O)p-.

7. The compound according to any one of claims 1-4, wherein Y is -NR9SO2- or -NR9CO-.

8. The compound according to any one of claims 1-4, wherein Y is -NR9- or -CONR9-.

9. (3-((Phenoxyacetylamino)methyl)benzofuran-7-yloxy)-acetic acid.

10. (3-((2-Phenoxyethylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid.

11. (3-((Phenylsulfonylamino)methyl)benzofuran-7-yloxy)-acetic acid.

12. (3-((Benzylsulfonylamino)methyl)benzofuran-7-yloxy)-acetic acid.

13. (3-((2-Phenylethylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid.

14. (3-((3-Phenylpropylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid.

15. (3-((4-Phenylbutylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid.

16. (3-((5-Phenylpentylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid.

17. (3-((2-Naphthylsulfonylamino)methyl)benzofuran-7-yloxy)acetic acid.

18. (3-((Benzylsulfonylamino)methyl)-2-methylbenzofuran-7-yloxy)acetic acid.

19. (3-((2-Phenylethylsulfonylamino)methyl)-2-methyl-benzofuran-7-yloxy)acetic acid.

20. (3-((3-Phenylpropylsulfonylamino)methyl)-2-methyl-benzofuran-7-yloxy)acetic acid.

21. (3-((2-Phenylethylsulfonylamino)methyl)-2-isopropyl-benzofuran-7-yloxy)acetic acid.

22. (3-(2-(Benzylsulfonylamino)ethyl)benzofuran-7-yloxy)-acetic acid.

23. (3-(2-(N-Benzylbenzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetic acid.

24. (3-(2-(Benzylsulfonylamino)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid.

25. (3-(2-(2-Phenylethylsulfonylamino)ethyl)-2-methyl-benzofuran-7-yloxy)acetic acid.

26. (3-(2-(2,2-Diphenylethylsulfonylamino)ethyl)benzo-furan-7-yloxy)acetic acid.

27. (3-(2-(3,3-Diphenylpropylsulfonylamino)ethyl)benzo-furan-7-yloxy)acetic acid.

28. (3-(2-(2-Phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid.

29. (3-(2-(2-Phenylethylsulfinyl)ethyl)-2-methylbenzo-furan-7-yloxy)acetic acid.

30. (3-(2-(2-Phenylethylsulfonyl)ethyl)-2-methylbenzo-furan-7-yloxy)acetic acid.

31. (3-(2-(Diphenylmethylideneaminoxy)ethyl)-2-methyl-benzofuran-7-yloxy)acetic acid.

32. (3-((4-Phenyloxazole-2-yl)methyl)benzofuran-7-yloxy)-acetic acid.

33. (3-((4-(2-Phenylethyl)oxazole-2-yl)methyl)benzofuran-7-yloxy)acetic acid.

34. (3-(2-(3-Phenylpropyloxy)ethyl)benzofuran-7-yloxy)-acetic acid.

35. (3-(2-Benzyloxyethyl)benzofuran-7-yloxy)acetic acid.

36. (3-(2-Diphenylmethoxy)ethyl)benzofuran-7-yloxy)acetic acid.

37. (3-(2-(3,3-Diphenylpropyloxy)ethyl)benzofuran-7-yloxy)acetic acid.

38. (3-(2-(4-Phenylbenzyloxy)ethyl)benzofuran-7-yloxy)-acetic acid.

39. (3-(2-(2-Oxo-2-phenylethoxy)ethyl)benzofuran-7-yloxy)acetic acid.

40. (3-((3,3-Diphenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid.

41. (3-((2,2-Diphenylethoxy)methyl)benzofuran-7-yloxy)-acetic acid.

42. (3-(Diphenylmethoxymethyl)benzofuran-7-yloxy)acetic acid.

43. (3-((2-Phenylpropyloxy)methyl)benzofuran-7-yloxy)-acetic acid.

44. (3-((1-Benzyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid.

45. (3-((1-Methyl-2-phenylethoxy)methyl)benzofuran-7-yloxy)acetic acid.

46. (3-((2-Phenyl-2-methoxy-1-methylethoxy)methyl)benzo-furan-7-yloxy)acetic acid.

47. (3-((2-Phenylbutyloxy)methyl)benzofuran-7-yloxy)acetic acid.

48. (3-((2-Phenoxyethoxy)methyl)benzofuran-7-yloxy)acetic acid.

49. (3-((2-Diphenylmethoxy)ethoxy)methyl)benzofuran-7-yloxy)acetic acid.

50. (3-((2-Methyl-2-phenoxypropyloxy)methyl)benzofuran-7-yloxy)acetic acid.

51. (3-(2-(2-(Diphenylmethoxy)ethoxy)ethyl)benzofuran-7-yloxy)acetic acid.

52. (3-((3-Diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid.

53. (3-(-2(Diphenylmethylsulfonyl)ethyl)benzofuran-7-yloxy)acetic acid.

54. (3-(2-(Diphenylmethylthio)ethyl)benzofuran-7-yloxy)-acetic acid.

55. (3-(2-(Bis(4-methoxyphenyl)methylthio)ethyl)benzo-furan-7-yloxy)acetic acid.

56. (3-(2-(Bis(4-hydroxyphenyl)methylthio)ethyl)benzo-furan-7-yloxy)acetic acid.

57. (3-(2-(Bis(4-chlorophenyl)methylthio)ethyl)benzo-furan-7-yloxy)acetic acid.

58. (3-(2-(Bis(4-fluorophenyl)methylthio)ethyl)benzo-furan-7-yloxy)acetic acid.

59. (3-(2-(Diphenylmethylthio)ethyl)benzofuran-6-yloxy)-acetic acid.

60. (3-((3,3-Diphenylpropylthio)methyl)benzofuran-7-yloxy)acetic acid.

61. (3-(3-Diphenylmethylthio)propyl)benzofuran-7-yloxy)-acetic acid.

62. (3-(3-(2,2-Diphenylethylthio)propyl)benzofuran-7-yloxy)acetic acid.

63. (3-(3-(3,3-Diphenylpropylthio)propyl)benzofuran-7-yloxy)acetic acid.

64. (3-((Diphenylmethylthio)methyl)benzofuran-7-yloxy)-acetic acid.

65. (3-((2,2-Diphenylethylthio)methyl)benzofuran-7-yloxy)acetic acid.

66. (3-(2-(2,2-Diphenylethylthio)ethyl)benzofuran-7-yloxy)acetic acid.

67. (3-(2-(3,3-Diphenylpropylthio)ethyl)benzofuran-7-yloxy)acetic acid.

68. (3-(2-(Diphenylmethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetic acid.

69. (3-(2-(Diphenylmethylthio)ethyl-2-hydroxymethylbenzo-furan-7-yloxy)acetic acid.

70. (3-(2-(Diphenylmethylthio)ethyl)-2-(2-hydroxyethyl)-benzofuran-7-yloxy)acetic acid.

71. (3-(2-(Diphenylmethylthio)ethyl)-2-(3-hydroxypropyl)-benzofuran-7-yloxy)acetic acid.

72. (3-((3,3-Diphenyl-2-propenyloxy)methyl)benzofuran-7-yloxy)acetic acid.

73. (3-((2-(Diphenylamino)ethoxy)methyl)benzofuran-7-yloxy)acetic acid.

74. (3-((2-(Diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid.

75. (3-((1-methyl-2-(diphenylmethoxy)ethoxy)methyl)benzo-furan-7-yloxy)acetic acid.

76. (3-(2-Hydroxy-5,5-diphenylpropyl)benzofuran-7-yloxy)-acetic acid.

77. (2-((3,3-Diphenylpropyloxy)methyl)benzofuran-7-yloxy)acetic acid.

78. (2-((2,2-Diphenylethoxy)methyl)benzofuran-7-yloxy)-acetic acid.

79. (2-((3-Diphenylmethoxy)propyloxy)methyl)benzofuran-7-yloxy)acetic acid.

80. (2-((2-Diphenylmethoxy)ethoxy)methyl)benzofuran-7-yloxy)acetic acid.

81. (2-(Diphenylmethoxymethyl)benzofuran-7-yloxy)acetic acid.

82. (1-(2-(p-Tolylsulfonylamino)ethyl)indole-4-yloxy)-acetic acid.

83. (1-(2-(2-Phenylethylsulfonylamino)ethyl)indole-4-yloxy)acetic acid.

84. (1-(2-(Phenylsulfonylamino)ethyl)indole-4-yloxy)-acetic acid.

85. (1-(2-(Benzylsulfonylamino)ethyl)indole-4-yloxy)-acetic acid.

86. (1-(2-(3-Phenylpropyloxy)ethyl)indole-4-yloxy)acetic acid.

87. (1-(2-(2-Phenylethoxy)ethyl)indole-4-yloxy)acetic acid.

88. (1-(2-(2,2-Diphenylethoxy)ethyl)indole-4-yloxy)acetic acid.

89. (1-(2-(Diphenylmethoxy)ethyl)indole-4-yloxy)acetic acid.

90. (1-(2-(3,3-Diphenylpropyloxy)ethyl)indole-4-yloxy)-acetic acid.

91. (1-(5-Phenylpentyl)indole-4-yloxy)acetic acid.

92. (1-(2-Diphenylmethylthio)ethyl)indole-4-yloxy)acetic acid.

93. (1-(4,4-Diphenylbutyl)indole-4-yloxy)acetic acid.

94. (1-(2-(N-(Diphenylmethyl)amino)ethyl)indole-4-yloxy)-acetic acid.

95. (1-(2-(N,N-Dibenzylamino)ethyl)indole-4-yloxy)acetic acid.

96. (1-(2-(Diphenylmethylthio)ethyl)indoline-4-yloxy)-acetic acid.

97. (1-(2-(Diphenylmethoxy)ethyl)indoline-4-yloxy)acetic acid.

98. (1-(2-(2,2-Diphenylethoxy)ethyl)indoline-4-yloxy)-acetic acid.

99. (1-(2-(3,3-Diphenylpropyloxy)ethyl)indoline-4-yloxy)-acetic acid.

100. 3-(3-(2-Diphenylmethoxyethyl)benzofuran-7-yloxy)-propionic acid.

101. 4-(3-(2-Diphenylmethoxyethyl)benzofuran-7-yloxy)-butyric acid.

102. (3-(2-Diphenylmethoxyethyl)benzofuran-7-ylthio)acetic acid.

103. (3-(3-(2-Diphenylmethoxyethyl)benzofuran-7-ylthio)-propionic acid.

104. 4-(3-(2-Diphenylmethoxyethyl)benzofuran-7-ylthio)-butyric acid.

105. 3-(3-(2-Diphenylmethoxyethyl)benzofuran-7-yl)-propionic acid.

106. 4-(3-(2-Diphenylmethoxyethyl)benzofuran-7-yl)butyric acid.

107. 5-(3-(2-Diphenylmethoxyethyl)benzofuran-7-yl)valeric acid.

108. A methyl ester of a compound according to any one of claims 9 to 107.

109. A ethyl ester of a compound according to any one of claims 9 to 107.

110. A propyl ester of a compound according to any one of claims 9 to 107.

111. A isopropyl ester of a compound according to any one of claims 9 to 107.

112. A butyl ester of a compound according to any one of claims 9 to 107.

113. A t-butyl ester of a compound according to any one of claims 9 to 107.

114. A pentyl ester of a compound according to any one of claims 9 to 107.

115. A compound according to claim 1, of the formula:

(I-a) (wherein R3, R5, R8, Y, m and n are as defined in claim 1).

116. A compound according to claim 1, of the formula:

(wherein R3 and R8 are as defined in claim 1 and R52 is hydrogen or C1-C5 alkyl).

117. A compound according to claim 1, of the formula:

(wherein R3, R8 and m are as defined in claim 1, Y1 is -O-, -S(O)p- [where p is as defined in claim 1], -O-N=CR9- [where R9 is as defined in claim 1] or -CH(OH)-, and R52 is hydrogen or C1-C5 alkyl).

118. A compound according to claim 117, wherein Y1 is -O-.

119. A compound according to claim 117, wherein Y1 is -S(O)p- where p is 0, 1 or 2.

120. A compound according to claim 117, wherein Y1 is -O-N=CR9- [where R9 is phenyl] and R8 is phenyl.

121. A compound according to claim 117, wherein Y1 is -CH(OH)-.

122. A compound according to claim 1, of the formula:

(wherein R3, R8, Y and m are as defined in claim 1 and R5a is C1-C5 hydroxyalkyl or acetoxy-C1-C5 alkyl).

123. A compound according to claim 122, wherein m is 2, Y is S and R5a is 2-hydroxyethyl, 2-acetoxyethyl, 3-hydroxy-propyl or 3-acetoxypropyl.

124. A compound according to claim 1, of the formula:

(wherein R3 and R8 are as defined in claim 1).

125. A compound according to claim 1, of the formula:

(I-b) (wherein R3 is as defined in claim l, and R80 is Cl-C5 alkyl substituted with one or two aryl groups or C2-C8 alkoxyalkyl substituted with one or two aryl groups, the aryl group being phenyl, thienyl, furyl or naphthyl).

126. A compound according to claim 1, of the formula:

(I-c) (wherein R3, R8, Y, m and n are as defined in claim 1).

127. A compound according to claim 126, of the formula:

(wherein R3 and R8 have the meanings given in claim 126).

128. A compound according to claim 1 of the formula:

(I-d) (wherein R3, R6, R7, R8, Y, m and n are as defined in claim 1).

l29. A compound according to claim 128, of the formula:

(wherein R3, R6, R7 and R8 have the meanings given in claim l28).

l30. A compound according to claim l26, of the formula:

(wherein R60 is hydrogen or benzyl, and R3 and R8 have the meanings given in claim l26).

l3l. A compound according to claim l, of the formula:

(wherein R61 is C2-C10 alkyl substituted with one or two phenyl groups which may be substituted as defined in claim 1, and R3, R6 and R7 are as defined in claim 1).

132. A compound according to claim 128, of the formula:

(wherein R3, R6, R7 and R8 have the meanings given in claim 128).

133. A pharmaceutical thromboxane A2 receptor antagonist comprising an effective amount of the compound according to any one of claims 1-132 in admixture with a pharmaceutically acceptable carrier or diluent.

134. A pharmaceutical composition for therapy or prevention of hypertension, thrombosis, ischemic heart diseases, cerebral circulatory diseases, peripheral circulatory diseases, arterio-sclerosis, platelet function disorder, hyperlipidemia, nephritis or asthma which comprises an effective amount of the compound according to any one of claims 1 to 132 in admixture with a pharmaceutically acceptable carrier or diluent.

l35. Use of the compound according to any one of claims l-132, as a thromboxane A2 receptor antagonist.

l36. Use of the compound according to any one of claims l-l32, as a pharmaceutical for therapy or prevention of hypertension, thrombosis, ischemic heart diseases, cerebral circulatory diseases, peripheral circulatory diseases, arterio-sclerosis, platelet function disorder, hyperlipidemia, nephritis or asthma.