AU2299899A - New compound - Google Patents

Description

WO99/40108 PCT/JP99/00538 1 DESCRIPTION NEW COMPOUND TECHNICAL FIELD 5 The present invention relates to new polypeptide compound and a salt thereof which are useful as a medicament. BACKGROUND ART In U.S. Pat. No. 5,376,634 and WO 96/11210, there are 10 disclosed the polypeptide compound and a pharmaceutically acceptable salt thereof, which have antimicrobial activities (especially antifungal activity). DISCLOSURE OF INVENTION 15 The present invention relates to new polypeptide compound and a salt thereof. More particularly, it relates to newpolypeptide compound and a salt thereof, which have antimicrobial activities [especially, antifungal activities, in which the fungi may 20 include Aspergillus, Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophyte, Malassezia, Fusarium and the like.], inhibitory activity on 8-1,3-glucan synthase, and further which are expected to be useful for the prophylactic and/or therapeutic treatment of Pneumocystis carinii 25 infection (e.g. Pneumocystis carinii pneumonia) in a human being or an animal, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a methods for the prophylactic and/or therapeutic treatment of infectious disease including Pneumocystis carinii infection 30 (e.g. Pneumocystis carinii pneumonia) in a human being or an animal. The object polypeptide compounds of the present invention are new and can be represented by the following general formula 35 [I]: WO 99/40108 PCT/JP99/00538 2 OH 0 HO NH

H

3 C NI N R 5 N 0 HO 0 HN OH 0 NH= 0 CH 3

H

2 N O N 10 R2 NH OH -- OH O 15 R4 R Wherein

R

1 is hydrogen; arylamino (lower) alkanoyl which may have one or more 20 suitable substituent(s); aroyl substituted with heterocyclic group which may have one or more suitable substituent(s); aroyl substituted with aryl having higher alkyl; aroyl substituted with aryl having lower alkyl; 25 aryl(C 2

-C

6 )alkanoyl substituted with aryl having lower alkyl; lower alkanoyl substituted with unsaturated condensed heterocyclic group which may have one or more suitable substituent(s); 30 lower alkanoyl substituted with pyridyl which may have one or more suitable substituent(s); amino protective group; heptylnaphthoyl; hexylnaphthoyl; 35 aroyl substituted with heterocyclic carbamoyl which WO99/40108 PCT/JP99/00538 3 may have one or more suitable substituent(s); lower alkanoyl substituted with cyclo(lower)alkyl which may have one or more suitable substituent(s); lower alkanoyl substituted with thienyl having 5 heterocyclic group which may have one or more suitable substituent(s); or lower alkenoyl substituted with heterocyclic group which may have one or more suitable substituent(s),

R

2 is hydrogen or hydroxy, 10 R 3 is hydroxy, hydroxysulfonyloxy or lower alkoxy, and

R

4 is hydroxy or lower alkoxy, or a salt thereof. The new polypeptide compound [I] and a salt thereof can be prepared by the process as illustrated in the following 15 reaction schemes.

WO 99/40108 PCT/JP99/00538 4 Process 1 OH O

H

3 C HO NH Ra-OH [III ] H3C NH 5 2 or its reactive derivative N 0O at the carboxy group HO O HN OH or a salt thereof 0 NH O==

CH

3

H

2 N O N

R

2 NH OH 10 - OH O

R

3 R4 [Ib] 15 or its reactive derivative at the amino group or a salt thereof OH 0 20 HO NH H3C NH- Ra N 0 HO 0 HN OH 0 NH O CH 3 25

H

2 N O N

R

2 NH , OH - OH O R3 R \ [1a] or a salt thereof 30 R4 35 WO 99/40108 PCT/JP99/00538 5 Process 2 HO OH 0 HO 5

H

3 C NH- Ra N 0O HO 0 HN OH O NH O CH 3 Reduction

H

2 N O N 10 H NH OH - OH O

R

3 [IJ] or a salt thereof

R

4 15 OH HO0

H

3 C NHR 20 NH- Ra N 0 HO 0 HN OH 0 NH 0 = CH3

H

2 N 0 N 25 2 NH OH - OH O R 3 R [Ia] R4 or a salt thereof 30 35 WO 99/40108 PCT/JP99/00538 6 Process 3 HO OH 5 O

H

3 C NH

N

2 Reduction 10 NH O CH 3

H

2 N O N HO NH OH - OH 0 15 R 3 or a salt thereof

R

4 OH HO 0 20

H

3 C

NI

2 N 0O HO 0 HN OH 0 NH O H CH 3

H

2 N O N 25

R

2 NH OH - OH O R3 [Ib] 30

R

4 or a salt thereof 35 WO 99/40108 PCT/JP99/00538 7 The starting compound [II] and [IV], or a salt thereof can be prepared by the process as illustrated in the following reaction schemes. 5 Process A HO OH HO 0

H

3 C N N 2 R-OH [ III ] -N 0 10 HO 0 HN OH or its reactive derivative at the carboxy group 0 or a salt thereof NH O CH 3

H

2 N O N HO NH OH 15 - OH 0

R

3

R

4 or its reactive derivative at the amino group or a salt thereof 20 HO OH HO 0

H

3 C NH- Ra -N 0)= 25 HO 0IN OH OMI 0 CH 3

H

2 N O N H NH OH 30 - OH 0 R3-- [II] or a salt thereof

R

4 35 WO 99/40108 PCT/JP99/00538 8 Process B HO OH 5

H

3 C NH

N

2 N 0 HO 0 HN OH 0 ON-NH O= -- \CH3 10 H2N 0 HN Hydrolysis H2N O 10 H 2 HO NH OH O - OH 0 II HO-S0 11\ / o / [IVa] HO 15 or its reactive derivative at the sulfonic acid group or a salt thereof HO OH HO 0 20

H

3 C NH NH2

N

2 HO 0 HN OH ONH 0 CH 3 25

H

2 N O N HO NH OH

-

OH 0 HO 30 HO [IVb] or a salt thereof 35 WO 99/40108 PCT/JP99/00538 9 Process C HO OH HO 0 IH 5 H 3 C NH NH 2 N 0 HO 0 HN OH 0 O-NH O CH 3

H

2 N 0O H N Alkylation 10 HO NH OH

-

OH 0 HO/ [IVb] HO or its reactive derivative 15 at the hydroxy group or a salt thereof HO OH HO 0 20

H

3 C

NH

2 -N0 HO 0 HN OH O0 0 NH O - CH 3

H

2 N O N 25 HO NH OH - OH 0 3 Ra[lVC 4~[ We ] Ra 30 or a salt thereof 35 WO99/40108 PCT/JP99/00538 10 wherein

R

2 , R 3 and R 4 are as defined above, Ra is arylamino(lower)alkanoyl which may have one or more suitable substituent(s); 5 aroyl substituted with heterocyclic group which may have one or more suitable substituent(s); aroyl substituted with aryl having higher alkyl; aroyl substituted with aryl having lower alkyl; aryl(C 2

-C

6 )alkanoyl substituted with aryl having 10 lower alkyl; lower alkanoyl substituted with unsaturated condensed heterocyclic group which may have one or more suitable substituent(s); lower alkanoyl substituted with pyridyl which may 15 have one or more suitable substituent(s); amino protective group; heptylnaphthoyl; hexylnaphthoyl; aroyl substituted with heterocyclic carbamoyl which 20 may have one or more suitable substituent(s); lower alkanoyl substituted with cyclo(lower)alkyl which may have one or more suitable substituent(s); lower alkanoyl substituted with thienyl having heterocyclic group which may have one or more suitable 25 substituent(s); or lower alkenoyl substituted with heterocyclic group which may have one or more suitable substituent(s), R3 is lower alkoxy, and R4 is hydroxy or lower alkoxy. 30 Suitable salt of the new polypeptide compound [I] is a pharmaceutically acceptable and conventional non-toxic salt, and may include a salt with a base or an acid addition salt WO99/40108 PCT/JP99/00538 11 such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; 5 a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, diisopropylethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N' dibenzylethylenediamine salt, etc.); 10 an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, 15 toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.). Suitable examples and illustration of the various 20 definitions in the above and subsequent descriptions of the present specification, which the present invention intends to include within the scope thereof, are explained in detail as follows : The term "lower" is used to intend a group having 1 to 25 6 carbon atom(s), unless otherwise provided. The term "higher" is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided. Suitable example of "one or more" may be the number of 1 to 6, in which the preferred one may be the number of 1 to 30 3. Suitable example of "lower alkanoyl" may include straight or branched one such as formyl, acetyl, 2-methylacetyl, 2,2-dimethylacetyl, propionyl, butyryl, isobutyryl, pentanoyl, 2,2-dimethylpropionyl, hexanoyl, and 35 the like.

WO99/40108 PCT/JP99/00538 12 Suitable example of "suitable substituent(s)" in the

R

1 and R may include higher alkoxy, aryl which has one or more higher alkoxy, higher alkyl, lower alkyl, aryl which has one or more lower alkoxy, heterocyclic group which may have one 5 or more higher alkoxy, aryl which has one or more cyclo(lower)alkyl, aryl which has one or more lower alkoxy(higher)alkoxy, aryl which has one or more heterocyclic groups, cyclo(lower)alkyl which has one or more cyclo(lower)alkyl, aryl substituted with aryl which may have 10 one or more lower alkoxy, aryl substituted with aryl which may have one more higher alkoxy, aryl substituted with aryl which may have one or more lower alkoxy having heterocyclic group, aryl which has one or more lower alkoxy(lower)alkoxy, heterocyclic group which may have one or more higher alkyl, 15 aryl substituted with aryl which may have one or more aryloxy(lower)alkoxy, aryl substituted with aryl which may have one or more lower alkenyloxy, aryl substituted with aryl which may have one or more lower alkoxy(higher)alkoxy, aryl substituted with aryl which may have one or more 20 heterocyclic(lower)alkoxy, aryl which has one or more aryloxy(lower)alkoxy, heterocyclic group which may have one or more heterocyclic groups, aryl which has one or more cyclo(lower)alkyloxy, aryl which has one or more heterocyclic groups having lower alkoxy, aryl which has one or more 25 heterocyclic groups having cyclo(lower)alkyloxy, aryl which has one or more heterocyclic groups having aryl(lower)alkyloxy, aryl which has one or more heterocyclic groups having cyclo(lower)alkyl, aryl which has one or more heterocyclic groups having aryl, heterocyclic group which may have one or 30 more aryl having lower alkoxy, heterocyclic group which may have one or more aryl having higher alkoxy(lower)alkyl, heterocyclic group which may have one or more aryl having lower alkoxy(lower)alkoxy, heterocyclic group which may have one or more aryl having cyclo(lower)alkyl, heterocyclic group which WO99/40108 PCT/JP99/00538 13 may have one or more aryl having heterocyclic group, heterocyclic group which may have one or more aryl substituted with heterocyclic(lower)alkyl having aryl, heterocyclic group which may have one or more heterocyclic groups having aryl, 5 aryl substituted with aryl which may have one or more cyclo(lower)alkyloxy, aryl substituted with aryl which may have one or more lower alkoxy(lower)alkyl, aryl substituted with aryl which may have one or more lower alkoxy(lower)alkoxy, aryl substituted with aryl which may have one or more lower 10 alkoxy(lower)alkoxy(lower)alkyl, aryl substituted with aryl which may have one or more lower alkoxy(lower)alkoxy(lower)alkoxy, aryl substituted with aryl which may have one or more heterocyclic groups, aryl which has one or more cyclo(lower)alkyloxy, aryl which has one or more 15 lower alkoxy(higher)alkylthio, aryl which has one or more lower alkoxy having heterocyclic group, cyclo(lower)alkyl which may have one or more lower alkyl, cyclo (lower) alkyl-which may have one or more aryl, aryl, and the like. Suitable example of "lower alkoxy" may include straight 20 or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neo-pentyloxy, hexyloxy, isohexyloxy and the like, in which the preferred one may be methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isohexyloxy. 25 Suitable example of "higher alkoxy" may include straight or branched one such as heptyloxy, octyloxy, 3,5-dimethyloctyloxy, 3,7-dimethyloctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, 30 icosyloxy, and the like, in which the preferred one maybe (C 7

-C

14 )alkoxy, and the more preferred one may be heptyloxy and octyloxy. Suitable example of "lower alkyl" may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, 35 ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, WO99/40108 PCT/JP99/00538 14 tert-butyl, pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like, in which the preferred one may be methyl, pentyl, hexyl and isohexyl. 5 Suitable example of "higher alkyl" may include straight or branched one having 7 to 20 carbon atoms, such as heptyl, octyl, 3,5-dimethyloctyl, 3,7-dimethyloctyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and the like, 10 in which the preferred one may be (C 7

-C

14 )alkyl, and the more preferred one may be heptyl, octyl, nonyl and decyl. Suitable example of "aryl" and "ar" moiety may include phenylwhichmayhave lower alkyl (e.g., phenyl, mesityl, xylyl, tolyl, etc.), naphthyl, anthryl, indanyl, and the like, 15 in which the preferred one may be phenyl andnaphthyl, and this "aryl" and "ar" moiety may have halogen or lower alkoxy. Suitable example of "aroyl" may include benzoyl, toluoyl, naphthoyl, anthrylcarbonyl, and the like, in which the preferred one may be benzoyl and naphthoyl, and 20 this "aroyl" may have lower alkyl. Suitable example of "heterocyclic group" and "heterocyclic" moiety may include unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 nitrogen 25 atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H 1,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; 30 saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 35 4 nitrogen atom(s), for example, indolyl, isoindolyl, WO99/40108 PCT/JP99/00538 15 indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 or 2 oxygen 5 atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 or 2 oxygen 10 atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, morpholino, etc.; unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; 15 unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 20 etc.), dihydrothiazinyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and1 to 3 nitrogen atom(s), for example thiazolidinyl, thiomorpholinyl, thiomorpholino, etc.; 25 unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensed heterocyclic group containing 1 or 30 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing an oxygen atom, 35 for example, furyl, etc.; WO99/40108 PCT/JP99/00538 16 saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing an oxygen atom, for example, tetrahydrofuran, tetrahydropyran, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6 5 membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.; unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example benzothienyl, benzodithiinyl, etc.; 10 unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like and this "heterocyclic group" and "heterocyclic" moiety may have lower alkyl or cyclo(lower)alkyl. 15 Suitable example of "lower alkenyloxy" may include vinyloxy, l-(or 2-)propenyloxy, l-(or 2- or 3-)butenyloxy, 1-(or 2- or 3- or 4-)pentenyloxy, 1-(or 2- or 3- or 4- or 5-)hexenyloxy, and the like, in which the preferred one may be (C 2

-C

6 )alkenyloxy, and the most preferred one may be 20 2-propenyloxy. Suitable example of "cyclo(lower)alkyl" may include cyclopropyl, cylclobutyl, cyclopentyl, cyclohexyl, and the like, in which the preferred one may be cyclo(C 4

-C

6 )alkyl, and the most preferred one may be cyclohexyl and this 25 "cyclo(lower)alkyl" may have lower alkyl. Suitable "amino protective group" may include acyl group as explained below, a conventional protective group such as ar(lower)alkyl which may have 1 to 3 suitable substituent(s) (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, 30 etc.), [5-(lower)alkyl-2-oxo-l,3-dioxol-4-yl](lower)alkyl [e.g. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, etc.] or the like; and the like. Suitable "acyl group" and "acyl" may include aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic 35 aliphatic acyl derived from carboxylic acid, carbonic acid, WO99/40108 PCT/JP99/00538 17 carbamic acid, sulfonic acid, and the like. Suitable example of said "acyl group" may be illustrated as follows. Aliphatic acyl such as lower or higher alkanoyl (e.g., 5 formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); 10 lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); 15 lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); or the like; Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g., phenyl(C 1

-C

6 )alkanoyl (e.g., 20 phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(C 1

-C

6 )alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl(C 3

-C

6 )alkenoyl (e.g., 25 phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(C 3

-C

6 )alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; ar(lower)alkoxycarbonyl [e.g., phenyl (C 1

-C

6 )alkoxycarbonyl 30 (e.g., benzyloxycarbonyl, etc.), fluorenyl(C 1

-C

6 )alkoxy carbonyl (e.g., fluorenylmethyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, 35 phenoxypropionyl, etc.); WO99/40108 PCT/JP99/00538 18 arylcarbamoyl (e.g., phenylcarbamoyl, etc.); arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); 5 arylsulfonyl which may have 1 to 4 lower alkyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like; Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, 10 heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); 15 heterocyclicglyoxyloyl; or the like; in which suitable "heterocyclic" moiety in the terms "heterocycliccarbonyl", "heterocyclic(lower)alkanoyl", heterocyclic(lower)alkenoyl" and "heterocyclicglyoxyloyl" can be referred to aforementioned "heterocyclic" moiety, in 20 which the preferred one may be ar(lower)alkoxycarbonyl, and the more preferred one may be phenyl(C 1

-C

4 )alkoxycarbonyl and fluorenyl(C 1

-C

4 )alkoxycarbonyl, and the most preferred one may be benzyloxycarbonyl and fluorenylmethyloxycarbonyl. 25 Suitable example of "arylamino" moiety in the term of "arylamino(lower)alkanoyl which may have one or more suitable substituent(s)"maybe phenylamino, mesitylamino, tolylamino, naphthylamino, anthrylamino, and the like, in which the preferred one may be naphthylamino. 30 Suitable example of "lower alkanoyl" moiety in the term of "arylamino(lower)alkanoyl which may have one or more suitable substituent(s)" can be referred to aforementioned "lower alkanoyl", in which the preferred one may be formyl. Suitable example of "suitable substituent(s)" moiety in 35 the term of "arylamino(lower)alkanoyl which may have one or WO99/40108 PCT/JP99/00538 19 more suitable substituent(s)" can be referred to aforementioned "suitable substituent(s)", in which the preferred one maybe higher alkoxy, and the most preferred one may be heptyloxy. 5 Suitable example of "arylamino(lower)alkanoyl which may have one or more suitable substituent(s)" may be naphthylaminocarbonyl having higher alkoxy, in which the preferred one may be naphthylaminocarbonyl having heptyloxy. 10 Suitable example of "aroyl" moiety in the term of "aroyl substituted with heterocyclic group which may have one or more suitable substituent(s)" can be referred to aforementioned "aroyl", in which the preferred one may be benzoyl. Suitable example of "heterocyclic group" moiety in the 15 term of "aroyl substituted with heterocyclic group which may have one or more suitable substituent(s)" can be referred to aforementioned "heterocyclic group", in which the preferred one may be saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 3 to 8-membered 20 heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) and unsaturated condensedheterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen 25 atom(s) and the more preferred one may be piperazinyl, thiadiazolyl, oxadiazolyl, imidazothiadiazolyl and isoxazolyl. Suitable example of "suitable substituent(s)" moiety in the term of "aroyl substituted with heterocyclic group which 30 may have one or more suitable substituent(s)" can be referred to aforementioned "suitable substituent(s)", in which the preferred one may be aryl which has one or more higher alkoxy, aryl which has one or more lower alkoxy, aryl which has one or more cyclo(lower)alkyl, aryl which has one or more lower 35 alkoxy(higher)alkoxy, aryl which has one or more heterocyclic WO99/40108 PCT/JP99/00538 20 groups, cyclo(lower)alkyl which may have one or more cyclo(lower)alkyl, aryl substituted with aryl which may have one or more lower alkoxy, aryl substituted with aryl which may have one or more higher alkoxy, aryl substitutedwitharylwhich 5 may have one or more lower alkoxy having heterocyclic group, aryl which has one or more lower alkoxy(lower)alkoxy, heterocyclic group which may have one or more higher alkyl, aryl substituted with aryl which may have one or more aryloxy(lower)alkoxy, aryl substituted with aryl which may 10 have one or more lower alkenyloxy, aryl substituted with aryl which may have one or more lower alkoxy(higher)alkoxy, aryl substituted with aryl which has one or more heterocyclic(lower)alkoxy, in which heterocyclic group may have one or more lower alkyl, aryl which has one or more 15 aryloxy(lower)alkoxy, heterocyclic group which may have one or more heterocyclic groups, aryl which has one or more cyclo(lower)alkyloxy, aryl which has one or more heterocyclic groups having lower alkoxy, aryl which has one or more heterocyclic groups having cyclo(lower)alkyloxy, aryl which 20 has one or more heterocyclic groups having aryl(lower)alkyloxy, aryl which has one or more heterocyclic groups having cyclo(lower)alkyl, aryl which has one or more heterocyclic groups having aryl, heterocyclic group which may have one or more aryl having lower alkoxy, heterocyclic group which may 25 have one or more aryl having higher alkoxy(lower)alkyl, heterocyclic group which may have one or more aryl having lower alkoxy(lower)alkoxy, heterocyclic group which may have one or more aryl having cyclo(lower)alkyl, heterocyclic group which may have one or more aryl having heterocyclic group, 30 heterocyclic group which may have one or more aryl substituted with heterocyclic(lower)alkyl having aryl, heterocyclic group which may have one or more heterocyclic groups having aryl, aryl substituted with aryl which may have one or more cyclo(lower)alkyloxy, aryl substituted with aryl which may 35 have one or more lower alkoxy(lower)alkyl, aryl substituted WO99/40108 PCT/JP99/00538 21 with aryl which may have one or more lower alkoxy(lower)alkoxy, aryl substituted with aryl which may have one or more lower alkoxy(lower)alkoxy(lower)alkyl, aryl substituted with aryl which may have one or more lower 5 alkoxy(lower)alkoxy(lower)alkoxy, aryl substituted with aryl which may have one or more heterocyclic groups, aryl which has one or more cyclo(lower)alkyloxy, aryl which has one or more lower alkoxy(higher)alkylthio, aryl which has one or more lower alkoxy having heterocyclic group, cyclo(lower)alkyl 10 which may have one or more lower alkyl, cyclo(lower)alkylwhich may have one or more aryl, aryl, in which the preferred one may be phenyl having (C 7

-C

14 )alkoxy, phenyl having (C 4 C 6 )alkoxy, phenyl having cyclo(C 4

-C

6 )alkyl, phenyl having

(C

1

-C

4 )alkoxy(C 7

-C

14 )alkoxy, phenyl having saturated 3 to 15 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), cyclo(C 4

-C

6 )alkyl having cyclo(C 4

-C

6 )alkyl, phenyl substituted with phenyl having (C 1

-C

6 )alkoxy, phenyl substituted with phenyl having (C 7

-C

14 )alkoxy, phenyl substituted with phenyl which has (C 1

-C

4 )alkoxy having 20 saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), phenyl having (C 1

-C

4 )alkoxy(C 4 C 6 )alkoxy, unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s) having (C 7

-C

14 )alkyl, phenyl substituted with phenyl having phenyloxy(C 1

-C

4 )alkoxy, 25 phenyl substituted with phenyl having (C 3

-C

6 )alkenyloxy, phenyl substituted with phenyl having (C 1

-C

4 )alkoxy(C 7 C 14 )alkoxy, phenyl substituted with phenyl which has (C l C 4 )alkoxy having saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen 30 atom(s) having 1 to 4 (C 1

-C

4 )alkyl, phenyl having phenyloxy

(C

1

-C

4 )alkoxy, phenyl having (C 1

-C

4 )alkoxy(C 7

-C

14 )alkoxy, unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), 35 phenyl having cyclo(C 4

-C

6 )alkyloxy, phenyl which has WO99/40108 PCT/JP99/00538 22 saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having (C 1

-C

4 )alkoxy, phenyl which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclo(C 4

-C

6 )alkyloxy, phenyl 5 which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having phenyl(C 1

-C

4

)

alkyloxy, phenyl which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclo(C 4

-C

6 )alkyl, phenyl which has saturated 3 to 10 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with cyclo(C 4

-C

6 )alkyl having di(C 1

-C

4 )alkyl, phenyl which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with cyclo(C 4

-C

6 )alkyl having (C 1

-C

4 )alkyl, 15 phenyl which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with

(C

1

-C

4 )alkoxy and phenyl having halogen, phenyl which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with phenyl, phenyl which 20 has unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having (C 1

-C

6 )alkoxy, unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which has phenyl having (C 1

-C

6 )alkoxy, 25 unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which has phenyl having (C 7

-C

14

)

alkoxy(C 1

-C

6 )alkyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which has phenyl having (C 4

-C

6 )alkyl, unsaturated 3 to 8 30 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which has phenyl having saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which has phenyl substituted with 35 (C 1

-C

6 )alkyl having saturated 3 to 8-membered WO 99/40108 PCT/JP99/00538 23 heteromonocyclic group containing 1 to 4 nitrogen atom(s) having phenyl, unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 5 nitrogen atom(s) having phenyl, phenyl substituted with phenyl which has cyclo(C 4

-C

6 )alkyloxy, phenyl substituted with phenyl which has (C 1

-C

6 )alkoxy(C 1

-C

6 )alkyl, phenyl substitutedwithphenyl which has (C 1

-C

6 )alkoxy(C 1

-C

6 )alkoxy, phenyl substituted with phenyl which has (C 1

-C

6 )alkoxy(C 10 C 6 )alkoxy(C 1

-C

6 )alkyl, phenyl substituted with phenyl which has (C 1

-C

6 )alkoxy(C 1

-C

6 )alkoxy(C 1

-C

6 )alkoxy, phenyl substituted with phenyl which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclo(C 4

-C

6 )alkyl, phenyl substituted with phenyl 15 which has saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with cyclo(C 4

-C

6 )alkyl having di(Cl-C 4 )alkyl, phenyl which has cyclo(C 4

-C

6 )alkyloxy, phenyl which has (C 1

-C

6 )alkoxy(C 7 C 14 )alkylthio, phenyl which has (C 1

-C

6 )alkoxy having 20 saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), phenyl which has (C 1

-C

6 )alkoxyhaving saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), phenyl which has (C 1

-C

6 )alkoxy having saturated 3 to 8-membered 25 heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) having di(C 1

-C

4 )alkyl, phenyl which has (C 1

-C

6 )alkoxy having saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), cyclo(C 4

-C

6 )alkyl which has (C 1 30 C 6 )alkyl, cyclo(C 4

-C

6 )alkyl which has phenyl, indanyl, phenyl substituted with saturated 3 to 8-membered heteromonocyclic groupcontaining 1 or2 oxgenatom(s)and 1to 3nitrogenatom(s), phenyl substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) 35 having (C 1

-C

6 )alkyl, phenyl substituted with saturated 3 to WO99/40108 PCT/JP99/00538 24 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) having di(C 1

-C

4 )alkyl, and phenyl substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 5 1 to 3 nitrogenatom(s), andthemostpreferredonemaybephenyl having octyloxy, phenyl having hexyloxy, phenyl having cyclohexyl, phenyl having piperidyl, cyclohexyl having cyclohexyl, phenyl having methoxyoctyloxy, phenyl having methoxyheptyloxy, phenyl having butoxy, phenyl having 10 pentyloxy, phenyl substituted with phenyl having methoxy, phenyl substituted with phenyl having propyloxy, phenyl substituted with phenyl having butoxy, phenyl substituted with phenyl having pentyloxy, phenyl substituted with phenyl having hexyloxy, phenyl substituted with phenyl having heptyloxy, 15 phenyl substituted with phenyl which has propyloxy having piperidyl, phenyl having methoxyhexyloxy, isoxazolyl having decyloxy, phenyl substituted with phenyl having phenyloxypropyloxy, phenyl substituted with phenyl having propenyloxy, phenyl substituted with phenyl having 20 phenyloxybutoxy, phenyl substituted with phenyl having methoxyoctyloxy, phenyl substituted with phenyl which has propoxy having dimethyl, phenyl having phenyloxypropoxy, phenyl having phenyloxybutoxy, phenyl having phenyloxypentyloxy, phenyl having methoxypentyloxy, phenyl 25 having methoxyheptyloxy, pyridyl having piperidyl, phenyl having cyclohexyloxy, phenyl which has piperidyl having propoxy, phenyl which has piperidyl having cyclohexyl, phenyl which has piperidyl having phenymethoxy, phenyl which has piperazinyl having cyclohexyl, phenyl which has piperazinyl 30 substituted with cyclohexyl having dimethyl, phenyl which has piperazinyl substituted with cyclohexyl having methyl, phenyl which has piperidyl substituted with methoxy and chlorophenyl, phenyl which has piperidyl substituted with phenyl, phenyl which has piperazinyl substituted with phenyl, phenyl which 35 has thiadiazolyl substituted with pentyloxyphenyl, pyrazolyl WO99/40108 PCT/JP99/00538 25 which has hexyloxyphenyl, pyrazolyl which has heptyloxymethylphenyl, piperazinyl which has phenyl having cyclohexyl, pyrazolyl which has phenyl having piperidyl, pyrazolyl which has phenyl having pyrrolidinyl, pyrazolyl 5 which has phenyl substituted with piperazinylmethyl having phenyl, pyridyl which has piperidyl having phenyl, phenyl substituted with phenyl which has cyclohexyloxy, phenyl substituted with phenyl which has ethoxymethyl, phenyl substituted with phenyl which has ethoxypropoxy, phenyl 10 substituted with phenyl which has ethoxyethoxy, phenyl substituted with phenyl which has methoxypropoxy, phenyl substituted with phenyl which has methoxyethoxy, phenyl substituted with phenyl which has methoxypentyloxy, phenyl substituted with phenyl which has methoxyethoxymethyl, phenyl 15 substituted withphenyl which has methoxyethoxyethoxy, phenyl substituted with phenyl which has piperazinyl having cyclohexyl, phenyl substituted with phenyl which has morpholinyl having dimethyl, phenyl which has cyclohexyloxy, phenyl which has methoxyheptylthio, phenyl which has 20 piperidinobutoxy, phenyl which has piperidinopentyloxy, phenyl which has piperidinohexyloxy, phenyl which has morpholinopentyloxy, phenyl which has morpholinopentyloxy having dimethyl, phenyl which has morpholinohexyloxy having dimethyl, phenyl which has thiomorpholinopentyloxy, 25 cyclohexyl which has pentyl, cyclohexyl which has phenyl, indanyl, phenyl having piperidyl, phenyl having morpholinyl, phenyl having thiomorpholino, phenyl substituted with phenyl having methoxybutoxy, phenyl substituted with piperazinyl having ethyl, and phenyl substituted with morpholinyl having 30 dimethyl. Suitable example of "aroyl substituted with heterocyclic group which may have one or more suitable substituent(s)" may be benzoyl substituted with piperazinyl which has phenyl having octyloxy, benzoyl substituted with piperazinyl which 35 has phenyl having hexyloxy, benzoyl substituted with WO99/40108 PCT/JP99/00538 26 thiadiazolyl which has phenyl having hexyloxy, benzoyl substituted with oxadiazolyl which has phenyl having hexyloxy, benzoyl substituted with piperazinyl which has phenyl having cyclohexyl, benzoyl substituted with thiadiazolyl which has 5 phenyl having methoxyoctyloxy, benzoyl substituted with thiadiazolyl which has phenyl having piperidyl, benzoyl substituted with piperazinyl which has cyclohexyl having cyclohexyl, benzoyl substituted with piperazinyl which has phenyl having methoxyoctyloxy, benzoyl substituted with 10 piperazinyl which has phenyl having methoxyheptyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having butyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having pentyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl having 15 methoxy, benzoyl substituted with oxadiazolyl which has phenyl substituted withphenyl havingpropyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl having butyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl having pentyloxy, benzoyl 20 substituted with oxadiazolyl which has phenyl substituted with phenyl having hexyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl having heptyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl which has propyloxy having piperidyl, 25 benzoyl substituted with thiadiazolyl which has phenyl having methoxyhexyloxy, benzoyl substituted with oxadiazolyl which has pyrazolyl having decyl, benzoyl substituted with thiadiazolyl which has pyrazolyl having decyl, benzoyl substituted with oxadiazolyl which has phenyl substituted with 30 phenyl having phenyloxypropyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl having propenyloxy, benzoyl substituted with thiadiazolyl which has phenyl having methoxyhexyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl having 35 phenyloxybutyloxy, benzoyl substituted with oxadiazolyl which WO99/40108 PCT/JP99/00538 27 has phenyl substituted with phenyl having methoxyoctyloxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl which has propyloxy having dimethylmorpholinyl, benzoyl substituted with thiadiazolyl 5 which has phenyl having phenyloxybutyloxy, benzoyl substituted with thiadiazolyl which has phenyl having phenyloxypentyloxy, benzoyl substituted with thiadiazolyl which has phenyl having phenyloxypropyloxy, benzoyl substituted with thiadiazolyl which has phenyl having 10 methoxypentyloxy, benzoyl substituted with thiadiazolyl which has phenyl having methoxyheptyloxy, benzoyl substituted with thiadiazolyl which has pyridyl having piperidyl, benzoyl substituted with imidazothiadiazolyl which has phenyl having pentyloxy, benzoyl substituted with imidazothiadiazolyl which 15 has phenyl having cyclohexyloxy, benzoyl substituted with isoxazolyl which has phenyl having pentyloxy, benzoyl substituted with thiadiazolyl having phenyl which has piperidyl having propoxy, benzoyl substituted with thiadiazolyl having phenyl which has piperidyl having 20 cyclohexyloxy, benzoyl substituted with thiadiazolyl having phenyl which has piperidyl having phenylmethoxy, benzoyl substituted with imidazothiadiazolyl having phenyl which has piperazinyl having cyclohexyl, benzoyl substituted with thiadiazolyl having phenyl which has piperazinyl substituted 25 with cyclohexyl having dimethyl, benzoyl substituted with thiadiazolyl having phenyl which has piperazinyl having cyclohexyl, benzoyl substituted with thiadiazolyl having phenyl which has piperazinyl substituted with cyclohexyl having methyl, benzoyl substituted with thiadiazolyl having 30 phenyl which has piperidyl substituted with methoxy and chlorophenyl, benzoyl substituted with thiadiazolyl having phenyl which has piperidyl substituted with phenyl, benzoyl substituted with thiadiazolyl having phenyl which has piperazinyl substituted with phenyl, benzoyl substituted with 35 thiadiazolyl having phenyl which has thiadiazolyl substituted WO99/40108 PCT/JP99/00538 28 with pentyloxyphenyl, benzoyl substituted with thiadiazolyl having pyrazolyl which has hexyloxyphenyl, benzoyl substituted with thiadiazolyl having pyrazolyl which has heptyloxymethylphenyl, benzoyl substituted with piperidyl 5 having piperazinyl which has phenyl having cyclohexyl, benzoyl substituted with thiadiazolyl having pyrazolyl which has phenyl having piperidyl, benzoyl substituted with thiadiazolyl having pyrazolyl which has phenyl having pyrrolidinyl, benzoyl substituted with thiadiazolyl having 10 pyrazolyl which has phenyl substituted with piperazinylmethyl having phenyl, benzoyl substituted with thiadiazolyl having pyridyl which has piperidyl having phenyl, benzoyl substituted with thiadiazolyl having phenyl substituted with phenyl which has cyclohexyloxy, benzoyl substituted with thiadiazolyl 15 having phenyl substituted with phenyl which has ethoxymethyl, benzoyl substituted with thiadiazolyl having phenyl substituted with phenyl which has ethoxypropoxy, benzoyl substituted with thiadiazolyl having phenyl substituted with phenyl which has ethoxyethoxy, benzoyl substituted with 20 thiadiazolyl having phenyl substituted with phenyl which has methoxypropoxy, benzoyl substituted with thiadiazolyl having phenyl substituted with phenyl which has methoxyethoxy, benzoyl substituted with piperazinyl having phenyl substituted with phenyl which has methoxypentyloxy, benzoyl 25 substituted with thiadiazolyl having phenyl substituted with phenyl which has methoxyethoxymethyl, benzoyl substituted with thiadiazolyl having phenyl substituted with phenyl which has methoxyethoxyethoxy, benzoyl substituted with thiadiazolyl having phenyl substituted with phenyl which has 30 piperazinyl having cyclohexyl, benzoyl substituted with thiadiazolyl having phenyl substituted with phenyl which has morpholinyl having dimethyl, benzoyl substituted with oxadiazolyl which has phenyl having cyclohexyloxy, benzoyl substituted with thiadiazolyl which has phenyl having 35 cyclohexyloxy, benzoyl substituted withpiperazinylwhichhas WO99/40108 PCT/JP99/00538 29 phenyl having cyclohexyloxy, benzoyl substituted with piperazinyl which has phenyl having methoxyheptylthio, benzoyl substituted with imidazothiadiazolyl which has phenyl having piperidinobutoxy, benzoyl substituted with 5 imidazothiadiazolyl which has phenyl having piperidinopentyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having piperidinohexyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having 10 morpholinopentyloxy, benzoyl substituted with imidazothiadiazolyl having phenyl which has morpholinopentyloxy having dimethyl, benzoyl substituted with imidazothiadiazolyl having phenyl which has morpholinohexyloxy having dimethyl, benzoyl substituted with 15 imidazothiadiazolyl having phenyl which has thiomorpholinopentyloxy, benzoyl substituted with piperazinyl which has cyclohexyl having pentyl, benzoyl substituted with piperazinyl which has cyclohexyl having phenyl, benzoyl substituted with piperazinyl which has indanyl, 20 benzoyl substituted with imidazothiadiazolyl having phenyl which has piperazinyl having ethyl, benzoyl substituted with imidazothiadiazolyl which has phenyl having butoxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having methoxypentyloxy, benzoyl substituted with piperazinyl which 25 has phenyl having cyclohexyl, dimethylbenzoyl substituted with thiadiazolyl which has phenyl having methoxyhexyloxy, naphthoyl substituted with oxadiazolyl having phenyl substituted with phenyl having butoxy, naphthoyl substituted with thiadiazolyl which has phenyl having methoxyhexyloxy, 30 benzoyl substituted with thiazolyl which has phenyl having pentyloxy, benzoyl substituted with thiazolyl which has phenyl having hexyloxy, benzoyl substituted with thiazolyl which has phenyl having heptyloxy, benzoyl substituted with thiazolyl having phenyl substituted withphenyl havingpropoxy, benzoyl 35 substituted with imidazothiadiazolyl which has phenyl having WO99/40108 PCT/JP99/00538 30 methoxyhexyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having methoxyheptyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having methoxyoctyloxy, benzoyl substituted with 5 imidazothiadiazolyl which has phenyl having morpholino, benzoyl substituted with imidazothiadiazolyl which has phenyl having dimethylmorpholino, benzoyl substituted with imidazothiadiazolyl which has phenyl having thiomorpholino, benzoyl substituted with imidazothiadiazolyl which has phenyl 10 having pentyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl havinghexyloxy, benzoyl substituted with thiadiazolyl which has phenyl having cyclohexyl, benzoyl substituted with oxadiazolyl which has phenyl having cyclohexyl, benzoyl substituted with 15 thiadiazolyl which has phenyl substituted with phenyl having propoxy, benzoyl substituted with thiadiazolyl which has phenyl substituted with phenyl having ethoxy, benzoyl substituted with thiadiazolyl which has phenyl substituted with phenyl having methoxybutoxy, and benzoyl substituted with 20 thiadiazolyl which has phenyl substituted with phenyl having butoxy. Suitable example of "aroyl" moiety in the term of "aroyl substituted with aryl having higher alkyl" can be referred to 25 aforementioned "aroyl", in which the preferred one may be benzoyl. Suitable example of "aryl" moiety in the term of "aroyl substituted with aryl having higher alkyl" can be referred to aforementioned "aryl", in which the preferred one may be 30 phenyl. Suitable example of "higher alkyl" moiety in the term of "aroyl substituted with aryl having higher alkyl" can be referred to aforementioned "higher alkyl", in which the preferred one maybe (C 7

-C

14 )alkyl, and the more preferred one 35 may be heptyl.

WO99/40108 PCT/JP99/00538 31 Suitable example of "aroyl substituted with aryl having higher alkyl" may be benzoyl substituted with phenyl having

(C

7

-C

14 )alkyl, in which the preferred one may be benzoyl substituted with phenyl having heptyl. 5 Suitable example of "aroyl" moiety in the term of "aroyl substituted with aryl having lower alkyl" can be referred to aforementioned "aroyl", in which the preferred one may be benzoyl. 10 Suitable example of "aryl" moiety in the term of "aroyl substituted with aryl having lower alkyl" can be referred to aforementioned "aryl", in which the preferred one may be phenyl. Suitable example of "lower alkyl" moiety in the term of 15 "aroyl substituted with aryl having lower alkyl" can be referred to aforementioned "lower alkyl", in which the preferred one may be (C4-C 6 )alkyl, and the more preferred one may be hexyl. Suitable example of "aroyl substituted with aryl having 20 lower alkyl" may be benzoyl substituted with phenyl having

(C

4

-C

6 )alkyl, in which the preferred one may be benzoyl substituted with phenyl having hexyl. Suitable example of "aryl" moiety in the term of 25 "aryl(C 2

-C

6 )alkanoyl substituted with aryl having lower alkyl" can be referred to aforementioned "aryl", in which the preferred one may be phenyl. Suitable example of "(C 2

-C

6 )alkanoyl" moiety in the term of "aryl(C 2

-C

6 )alkanoyl substituted with aryl having lower 30 alkyl" may be acetyl, propionyl, butyryl, etc., in which the preferred one may be (C 2

-C

4 )alkanoyl, and the more preferred one may be propionyl. Suitable example of "lower alkyl" moiety in the term of "aryl(C 2

-C

6 )alkanoyl substituted with aryl having lower 35 alkyl" can be referred to aforementioned "lower alkyl", in WO99/40108 PCT/JP99/00538 32 which the preferred one may be (C 4

-C

6 )alkyl, and the more preferred one may be pentyl. Suitable example of "aryl(C 2

-C

6 )alkanoyl substituted with aryl having lower alkyl" may be phenylpropionyl 5 substituted with phenyl having pentyl. Suitable example of "lower alkanoyl" moiety in the term of "lower alkanoyl substituted with unsaturated condensed heterocyclic group which may have one or more suitable 10 substituent(s)" can be referred to aforementioned "lower alkanoyl", in which the preferred one may be (C 1

-C

3 )alkanoyl, and the more preferred one may be formyl. Suitable example of "unsaturated condensed heterocyclic group" moiety in the term of "lower alkanoyl substituted with 15 unsaturated condensed heterocyclic group which may have one or more suitable substituent(s)" can be referred to aforementioned "heterocyclic group", in which the preferred one may be unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), and the more 20 preferred one may be benzoxazolyl. Suitable example of "suitable substituent(s)" moiety in the term of "lower alkanoyl substituted with unsaturated condensed heterocyclic group which may have one or more suitable substituent(s)" may be heterocyclic group which may 25 have one or more higher alkoxy and aryl which may have one or more lower alkoxy, in which the preferred one maybe unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having (C 7 -Cl 4 )alkoxy and phenyl having

(C

4

-C

6 )alkoxy, and the more preferred one maybepyridylhaving 30 octyloxy and phenyl having hexyloxy. Suitable example of "lower alkanoyl substituted with unsaturated condensed heterocyclic group which may have one or more suitable substituent(s)" may be benzoxazolylcarbonyl which has pyridyl having (C 7

-C

14 )alkoxy and 35 benzoxazolylcarbonyl which has phenyl having (C 4

-C

6 )alkoxy, WO99/40108 PCT/JP99/00538 33 in which the preferred one may be benzoxazolylcarbonyl which has pyridyl having octyloxy and benzoxazolylcarbonyl which has phenyl having hexyloxy. 5 Suitable example of "lower alkanoyl" moiety in the term of "lower alkanoyl substituted with pyridyl which may have one or more suitable substituent(s)" can be referred to aforementioned "lower alkanoyl", in which the preferred one may be (C 1

-C

3 )alkanoyl, and the more preferred one may be 10 formyl. Suitable example of "suitable substituent(s)" moiety in the term of "lower alkanoyl substituted with pyridyl which may have one or more suitable substituent(s)" can be referred to aforementioned "suitable substituent(s)", in which the 15 preferred one maybe higher alkoxy, and the more preferred one may be (C 7

-C

14 )alkoxy, and the most preferred one may be heptyloxy and octyloxy. Suitable example of "lower alkanoyl substituted with pyridyl which may have one or more suitable substituent(s)" 20 may be pyridylcarbonyl having (C 7

-C

14 )alkoxy, in which the preferred one may be pyridylcarbonyl having octyloxy and pyridylcarbonyl having heptyloxy. Suitable example of "aroyl" moiety in the term of "aroyl 25 substituted with heterocyclic carbamoyl which may have one or more suitable substituent(s)" can be referred to aforementioned "aroyl", in which the preferred one may be benzoyl. Suitable example of "heterocyclic" moiety in the term of 30 "aroyl substituted with heterocyclic carbamoyl which may have one or more suitable substituent(s)" can be referred to aforementioned "heterocyclic" moiety, in which the preferred one may be unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), 35 and the more preferred one may be thiadiazolyl.

WO99/40108 PCT/JP99/00538 34 Suitable example of "suitable substituent(s)" moiety in the term of "aroyl substituted with heterocyclic carbamoyl which may have one or more suitable substituent(s)" can be referred to aforementioned "suitable substituent(s)", in 5 which the preferred one may be phenyl having (C 1

-C

6 )alkoxy, and the more preferred one may be phenyl having pentyloxy. Suitable example of "aroyl substituted with heterocyclic carbamoyl which may have one or more suitable substituent(s)" may be benzoyl substituted with thiadiazolyl carbamoyl which 10 has phenyl having pentyloxy. Suitable example of "lower alkanoyl" moiety in the term of "lower alkanoyl substituted with cyclo(lower)alkyl which may have one or more suitable substituent(s)" can be referred 15 to aforementioned "lower alkanoyl", in which the preferred one may be formyl. Suitable example of "cyclo(lower)alkyl" moiety-in the term of "lower alkanoyl substituted with cyclo(lower)alkyl which may have one or more suitable substituent(s)" can be 20 referred to aforementioned "cyclo(lower)alkyl", in which the preferred one may be cyclohexyl. Suitable example of "suitable substituent(s)" moiety in the term of "lower alkanoyl substituted with cyclo(lower)alkyl which may have one or more suitable substituent(s)" can be 25 referred to aforementioned "suitable substituent(s)", in which the preferred one may be heterocyclic group which may have one or more aryl having lower alkoxy(lower)alkoxy, and the more preferred one may be thiadiazolyl which has phenyl having methoxyhexyloxy. 30 Suitable example of "lower alkanoyl" moiety in the term of "lower alkanoyl substituted with thienyl having heterocyclic group which may have one or more suitable substituent(s)" can be referred to aforementioned "lower 35 alkanoyl", in which the preferred one may be formyl.

WO99/40108 PCT/JP99/00538 35 Suitable example of " heterocyclic group " moiety in the term of "lower alkanoyl substituted with thienyl having heterocyclic group which may have one or more suitable substituent(s)" can be referred to aforementioned 5 "heterocyclic group", in which the preferred one may be unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), and the more preferred one may be oxadiazolyl. Suitable example of "suitable substituent(s)" moiety in 10 the term of "lower alkanoyl substituted with thienyl having heterocyclic group which may have one or more suitable substituent(s)" can be referred to aforementioned "suitable substituent(s)", in which the preferred one may be aryl substituted with aryl which may have one or more lower alkoxy, 15 and the more preferred one maybephenyl substituted with phenyl having pentyloxy. Suitable example of "lower alkenoyl" moiety in the term of "lower alkenoyl substituted with heterocyclic group which 20 may have one or more suitable substituent(s)" may be acryloyl, butenoyl, pentenoyl, hexenoyl, 2,4-hexendienoyl, and the like, in which the preferred one may be 2,4-hexenedienoyl. Suitable example of "heterocyclic group" moiety in the term of "lower alkenoyl substituted with heterocyclic group 25 which may have one or more suitable substituent(s)" can be referred to aforementioned "heterocyclic group" moiety, in which the preferred one may be unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), and the more preferred one may be 30 thiadiazolyl. Suitable example of "suitable substituent(s)" moiety in the term of "lower alkenoyl substituted with heterocyclic group which may have one or more suitable substituent(s)" can be referred to aforementioned "suitable substituent(s)", in 35 which the preferred one may be aryl having lower WO99/40108 PCT/JP99/00538 36 alkoxy(lower)alkoxy, and the more preferred one may be phenyl having methoxyhexyloxy. The processes for preparing the object polypeptide 5 compound [I] and the starting compound [II] or a salt thereof of the present invention are explained in detail in the following. Process 1 10 The object polypeptide compound [Ia] or a salt thereof can be prepared by reacting the compound [Ib] or its reactive derivative at the amino group or a salt thereof with the compound [III] or its reactive derivative at the carboxy group or a salt thereof. 15 Suitable reactive derivative at the carboxy group of the compound [III] may include an acid halide, an acid anhydride, an activatedamide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as 20 substituted phosphoric acid [e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g., methanesulfonic acid, 25 etc.], aliphaticcarboxylicacid [e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivaric acid, pentanoic acid, isopentanoicacid, 2-ethylbutyric acid, trichloroacetic acid, etc.]; or aromatic carboxylic acid [e.g., benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with 30 imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester [e.g., cyanomethyl ester, methoxymethyl ester, + dimethyliminomethyl [(CH 3

)

2 N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, WO99/40108 PCT/JP99/00538 37 trichlorophenyl ester, pentachloropentyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl 5 thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to 10 the mind of the compound [III] to be used. Suitable salts of the compound [III] and its reactive derivative can be referred to the ones as exemplified for the object polypeptide compound [I]. The reaction is usually carried out in a conventional 15 solvent suchaswater, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These 20 conventional solvent may also be used in a mixture with water. In this reaction, when the compound [III] is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; 25 N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methylimidazole); 30 pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine, ethoxyacetylene; 1-alkoxy-2-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); 35 phosphorus trichloride; thionyl chloride; oxalyl chloride; WO99/40108 PCT/JP99/00538 38 lower alkyl haloformate [e.g., ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5 (m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 5 1-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, methanesulfonyl chloride, etc.; or the like. 10 The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine, pyridine, di (lower) alkylaminopyridine (e.g., 4-dimethylaminopyridine, etc.), N-(lower)alkylmorpholine, N,N 15 di(lower)alkylbenzylamine, or the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming. Process 2 The object compound [I a] or a salt thereof can be prepared 20 by reducing a compound [II] or a salt thereof. Suitable salts of the compounds [I a ] and [II] may be the same as those exemplified for the compound [I]. The reaction can be carried out in a conventional manner, namely, chemical reduction or catalytic reduction. 25 Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionicacid, trifluoroaceticacid, p-toluenesulfonic 30 acid, hydrochloric acid, hydrobromic acid, hydride transfer reagent such as aluminum hydride compound (e.g. lithium aluminum hydride, lithium hydridotri-t-butoxyaluminate, etc.), borohydride compound (e.g. sodium borohydride, sodium cyanoborohydride, etc.) or the like etc.]. 35 Suitable catalysts to be used in catalytic reduction are WO99/40108 PCT/JP99/00538 39 conventional ones such as platinum catalyst [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinumoxide, platinumwire, etc.], palladium catalyst [e.g., spongy palladium, palladium black, palladium oxide, palladium 5 on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalyst [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst [e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper 10 catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc.] or the like. The reaction of this process is usually carried out in a solvent such as water, alcohol [e.g. methanol, ethanol, propanol, etc.], acetic acid, diethyl ether, dioxane, 15 tetrahydrofuran, methylene chloride, etc. or a mixture thereof. The reaction is preferably carried out under somewhat milder conditions such as under cooling to warming. It is included within the scope of the present invention 20 that "hydroxy" in R 2 may be reduced to "hydrogen" during the reaction. Process 3 The object compound [Ib] or a salt thereof can be prepared by reducing the starting compound [IV] or a salt thereof to 25 reduction reaction. This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained 30 in Process 2. Process A The object compound [II] or a salt thereof can be prepared by reacting the starting compound [TV] or its reactive derivative at the amino group or a salt thereof with the 35 compound [III] or its reactive derivative at the carboxy group WO99/40108 PCT/JP99/00538 40 or a salt thereof. This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, 5 etc.] of this reaction are to be referred to those as explained in Process 1. Process B The compound [IVb] or a salt thereof can be prepared by subjecting the compound [IVa] or its reactive derivative at 10 the sulfonic acid group or a salt thereof to hydrolysis reaction of the sulfonic acid group. The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid. Suitable base may include an inorganic base and an organic 15 base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene, or the like. 20 Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionoc acid, trichloroacetic acid, trifluoroacetic acid, etc], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. 25 The elimination using Lewis acid such as trihaloacetic acid [e.g., trichloroaceticacid, trifluoroaceticacid, etc.], or the like preferably carried out in the presence of cation trapping agent [e.g., anisole, phenol, etc.]. The reaction is usually carried out in a conventional 30 solvent such as water, alcohol [e.g. methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N dimethylformamide, N,N-dimethylacetamide or anyother organic solvent which do not adversely affect the reaction, or the 35 mixture thereof.

WO 99/40108 PCT/JP99/00538 41 The reaction temperature is not critical and the reaction is usually carried out under cooling to warming. The starting compound [IVa] is known compound. It can be prepared by fermentation and synthetic processes disclosed 5 in EP 0462531 A2. Process C The compound [IVc] or a salt thereof can be prepared by subjecting the compound [IVb] or its reactive derivative at the hydroxy group or a salt thereof with the diazo compound 10 [e.g., diazomethane, phenyldiazomethane, diphenyldiazomethane, trimethylsilyldiazomethane, B diazopropionic acid etc.] or a salt thereof to alkylation reaction of the hydroxy group. This reaction is usually carried out in the solvent such 15 as water, alcohol [e.g. methanol, ethanol, etc.], benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether, acetonitrile or any other solvents which do not adversely affect the reaction, or the mixture thereof. 20 The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. The reaction may be usually carried out in the presence of an acid including Lewis acid. Suitable acid may include an organic acid [e.g., formic 25 acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like. 30 The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkali metal hydroxide [e.g., sodium hydroxide, potassium hydroxide, etc.], an alkali metal hydrogencarbonate [e.g., sodiumhydrogencarbonate, potassium 35 hydrogencarbonate, etc.], alkaline metal carbonate [e.g., WO99/40108 PCT/JP99/00538 42 sodium carbonate, potassium carbonate, etc.], tri(lower)alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine, etc.], alkali metal hydride [e.g., sodium hydride, etc.], alkali metal (lower)alkoxide [e.g., 5 sodiummethoxide, sodium ethoxide, etc.], pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like. When the base, the acid and/or the starting compound are 10 in liquid, they can be used also as a solvent. The compounds obtained by the above Processes 1 to 3 and Processes A to _ can be isolated and purified by a conventional method such as pulverization, recrystallization, 15 column-chromatography, high-performance liquid chromatography (HPLC), reprecipitation, desalting resin column chromatography, or the like. The compounds obtained by the above Processes 1 to 3 and Processes Ato _maybe obtained as its hydrate, and its hydrate 20 is included within the scope of present invention. It is to be noted that each of the object compound (I) may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and the mixture thereof 25 are included within the scope of the present invention. The object compound (I) or a salt thereof includes solvated compound [e.g., enclosure compound (e.g., hydrate, etc.)] The object compound (I) or a salt thereof includes both 30 its crystal form and non-crystal form. It should be understood that the compounds in the present invention may include the prodrug form. The patent applications and publications cited herein are incorporated by reference. 35 This application is based on application No. PP1728/98 WO99/40108 PCT/JP99/00538 43 and application No. PP3138/98 filed in Australia, the content of which is incorporated hereinto by reference. Biological property of the polypeptide 5 compound [II of the present invention In order to show the usefulness of the polypeptide compound [I] of the present invention, the biological data of the representative compound is explained in the following. 10 Test (Antimicrobial activity) : In vitro antimicrobial activity of the object compound of Example 12 disclosed later was determined bymicrodilution method as described below. Test Method: 15 The antifungal susceptibility assays were performed by the microdilution method according to M27-A guidelines recommended by the National Committee for Clinical Laboratory Standards (NCCLS) to determine the MICs of the compounds. RPMI 1640 medium with L-glutamine, without sodium bicarbonate, 20 andbuffered with 165 mMmorpholinepropanesulfonic acidbuffer (pH 7.0) was used as a test medium. Inoculum suspension of 10 6 CFU/ml were prepared by a hemocytometric procedure, and diluted to obtain an inoculum size of approximately 0.5 X 103 to 2.5 X 103 CFU/ml. Microplates were incubated at 35 0 C 25 and readings were taken when good growth in the growth control. The MICs were defined as the lowest concentrations at which no visible growth was observed. Test Result : 30 MIC (Pg/ml) Test compound The object compound Test organism of Example 12 candida albicans FP-633 0.0625 From the test result, it is realized that the object WO99/40108 PCT/JP99/00538 44 polypeptide compound [I] of the present invention has an antimicrobial activity (especially, antifungal activity) The pharmaceutical composition of the present invention 5 can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object polypeptide compound [I] or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is 10 suitable for rectal; pulmonary (nasal or buccal inhalation); ocular; external (topical); oral administration; parenteral (including subcutaneous, intravenous and intramuscular) administrations; insufflation (including aerosols from metered dose inhalator); nebulizer; or dry powder inhalator. 15 The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsules, or suppositories; creams; ointments; aerosols; powders for insufflation; 20 in a liquid form such as solutions, emulsions, or suspensions for injection; ingestion; eye drops; and any other form suitable for use. And, if necessary, there may be included in the above preparation auxiliary substance such as stabilizing, thickening, wetting, emulsifying and coloring 25 agents; perfumes or buffer; or any other commonly may be used as additives. The object polypeptide compound [I] or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired 30 antimicrobial effect upon the process or condition of diseases. For applying the composition to human, it is preferable to apply it by intravenous, intramuscular, pulmonary, oral administration, or insufflation. While the dosage of 35 therapeutically effective amount of the object polypeptide WO99/40108 PCT/JP99/00538 45 compound [I] varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-20 mg of the object polypeptide compound [I] per kg weight of humanbeing 5 in the case of intramuscular administration, a daily dose of 0.1-20 mg of the object polypeptide compound [I] per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the object polypeptide compound [I] per kg weight of human being is generally given for treating or 10 preventing infectious diseases. Especially in case of the treatment of prevention of Pneumocystis carinii infection, the followings are to be noted. For administration by inhalation, the compounds of the 15 present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized as powders which may be formulated and the powder compositions may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose 20 inhalation aerosol, which may be formulated as a suspension or solution of compound in suitable propellants such as fluorocarbons or hydrocarbons. Because of desirability to directly treat lung and bronchi, aerosol administration is a preferred method of 25 administration. Insufflation is also a desirable method, especially where infection may have spread to ears and other body cavities. Alternatively, parenteral administration maybe employed using drip intravenous administration. 30 The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail. Preparation 1 A solution of 4-hydroxybenzoic acid methyl ester (100 g) 35 and 1,6-dibromohexane (481 g) in N,N-dimethylformamide (500 WO99/40108 PCT/JP99/00538 46 ml) was treated with potassium carbonate (109 g) then heated at 60 0 C for 2 hours. After cooling, the mixture was diluted with ethyl acetate (3 L) and washed with water (7 x 1 L). The organic layer was dried over magnesium sulfate, filtered, and 5 evaporated to give a crude oil. Hexane (~-100 ml) was added and the resulting precipitate removed by filtration and discarded and the filtrate loaded onto a silica gel column (2 kg). Elution with hexane, followed by 9:1 hexane-ethyl acetate and 8:1 hexane-ethyl acetate afforded methyl 4-(6 10 bromo-n-hexyloxy)benzoate (186 g) as a white solid. NMR (CDCl 3 , 5) : 1.46-1.55 (4H, m), 1.78-1.97 (4H, m), 3.38-3.46 (2H, m), 3.88 (3H, s), 4.01 (2H, t, J=6.3Hz), 6.90 (2H, d, J=8.9Hz), 7.98 (2H, d, J=8.9Hz) 15 MASS (m/z) : 315, 317 (M +) The following compound was obtained in a manner similar to that of Preparation 1. Preparation 2 Methyl 4-(7-bromo-n-heptyloxy)benzoate 20 NMR (DMSO-d 6 , 5) : 1.2-1.6 (6H, m), 1.6-2.0 (4H, m), 3.53 (2H, t, J=6.7Hz), 3.81 (3H, s), 4.04 (2H, t, J=6.4Hz), 7.03 (2H, d, J=8.9Hz), 7.90 (2H, d, J=8.9Hz) MASS (m/z) : 329 (M+1), 331 (M+3) 25 Preparation 3 Asolutionofmethyl 4-(6-bromo-n-hexyloxy)benzoate (186 g) in methanol (1 L) was treated with 28% sodium methoxide in methanol (340ml) and the solution refluxed for 2 hours. After cooling, the stirred solution was adjusted to pH 2 with 30 1M-hydrochloric acid then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated to give a crude oil. This oil was purified on a silica gel column (2 kg, 9:1 hexane ethyl acetate elution) to give methyl 4-(6-methoxy-n 35 hexyloxy)benzoate (127 g) as an oil.

WO 99/40108 PCT/JP99/00538 47 NMR (CDCl 3 , 5) : 1.37-1.68 (6H, m), 1.74-1.88 (2H, m), 3.33 (3H, s), 3.39 (2H, t, J=6.3Hz), 3.88 (3H, s), 4.01 (2H, t, J=6.4Hz), 6.90 (2H, d, J=8.9Hz), 7.97 (2H, d, J=8.9Hz) 5 The following compound was obtained in a manner similar to that of Preparation 3. Preparation 4 Methyl 4-(7-methoxy-n-heptyloxy)benzoate NMR (DMSO-d 6 , 5) : 1.2-1.6 (8H, m), 1.6-1.9 (2H, m), 10 3.21 (3H, s), 3.29 (2H, t, J=6.4Hz), 3.81 (3H, s), 4.04 (2H, t, J=6.5Hz), 7.03 (2H, d, J=8.9Hz), 7.90 (2H, d, J=8.9Hz) MASS (m/z) : 281 (M+I) Preparation 5 15 A solution of methyl 4-(6-methoxy-n-hexyloxy)benzoate (17.05 g) in 1:1 tetrahydrofuran-methanol (300 ml) was treated with hydrazine monohydrate (66 ml) and refluxed for 15 hours then cooled to room temperature. The reaction mixture was poured into water and the resulting precipitate collected by 20 filtration, washed thoroughly with water then dried under hi-vacuum at 50 0 C to give 4-(6-methoxy-n hexyloxy)benzohydrazide (15.63 g) as a white solid. NMR (DMSO-d 6 , 5) : 1.29-1.58 (6H, m), 1.65-1.78 (2H, m), 3.21 (3H, s), 3.30 (2H, t, J=6.4Hz), 4.00 (2H, 25 t, J=6.4Hz), 4.40 (2H, s), 6.96 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.8Hz), 9.59 (1H, s) MASS (m/z) : 267 (M+l) The following compound was obtained in a manner similar to that of Preparation 5. 30 Preparation 6 4-(7-Methoxy-n-heptyloxy)benzohydrazide NMR (DMSO-d 6 , 5) : 1.2-1.6 (8H, m), 1.6-1.9 (2H, m), 3.21 (3H, s), 3.30 (2H, t, J=6.4Hz), 4.00 (2H, t, J=6.4Hz), 4.40 (2H, s), 6.96 (2H, d, J=8.7Hz), 7.78 35 (2H, d, J=8.9Hz), 9.59 (1H, s) WO 99/40108 PCT/JP99/00538 48 MASS (m/z) : 281 (M+1) Preparation 7 A mixture of 4-(6-methoxy-n-hexyloxy)benzohydrazide (106.82 g) and pyridine (162 ml) in tetrahydrofuran (1 L) at 5 00-50C was treated portionwise with 4-methoxycarbonylbenzoyl chloride (83.75 g) over 30 minutes. After a further 1 hour at 0 0 -5°C, and 2 hours at room temperature, tlc indicated complete reaction and the reaction mixture was poured into water (7 L). The resulting precipitate was collected by 10 filtration, washed thoroughly with water, and dried under hi-vacuum at 50'C to give N-[4-(6-methoxy-n-hexyloxy) benzoyl]-N'-(4-methoxycarbonylbenzoyl)hydrazine (171.9 g) as a white solid. NMR (DMSO-d 6 , 6) : 1.40-1.80 (8H, m), 3.22 (3H, s), 15 3.31 (2H, t, J=6.4Hz), 3.90 (3H, s), 4.05 (2H, t, J=6.3Hz), 7.04 (2H, d, J=8.8Hz), 7.90 (2H, d, J=8.8Hz), 8.03 (2H, d, J=8.6Hz), 8.10 (2H, d, J=8.6Hz), 10.41 (1H, s), 10.64 (1H, s) The following compound was obtained in a manner similar 20 to that of Preparation 7. Preparation 8 N-[4-(7-Methoxy-n-heptyloxy)benzoyl]-N'-(4-methoxy carbonylbenzoyl)hydrazine NMR (DMSO-d 6 , 6) : 1.2-1.6 (8H, m), 1.6-1.9 (2H, m), 25 3.21 (3H, s), 3.30 (2H, t, J=6.4Hz), 3.90 (3H, s), 4.05 (2H, t, J=6.4Hz), 7.04 (2H, d, J=8.8Hz), 7.90 (2H, d, J=8.8Hz), 8.03 (2H, d, J=8.6Hz), 8.10 (2H, d, J=8.6Hz), 10.42 (1H, s), 10.63 (1H, s) MASS (m/z) : 443 (M+1) 30 Preparation 9 A mixture of N-[4-(6-methoxy-n-hexyloxy)benzoyl]-N' (4-methoxycarbonylbenzoyl)hydrazine (193.4 g) andphosphorus pentasulfide (113.34 g) in tetrahydrofuran (2.5 L) was heated to reflux for 1 hour then cooled to room temperature and poured 35 into water (7 L) . The resulting precipitate was collected by WO 99/40108 PCT/JP99/00538 49 filtration, washed thoroughly with water then partially dried. The solid was added to 1:1 CH 3

CN-H

2 0 (200 ml), stirred then filtered. This procedure was repeated a further 2 times, and the resulting yellow powder washed thoroughly with 5 acetonitrile (500 ml x 5) then dried under hi-vacuum at 50 0 C to give methyl 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl] 1,3,4-thiadiazol-2-yl]benzoate (179.6 g) as a yellow powder. NMR (CDCl 3 , 5) : 1.40-1.87 (8H, m), 3.34 (3H, s), 3.40 (2H, t, J=6.2Hz), 3.96 (3H, s), 4.03 (2H, t, J=6.5Hz), 10 6.99 (2H, d, J=8.8Hz), 7.95 (2H, d, J=8.8Hz), 8.07 (2H, d, J=8.5Hz), 8.16 (2H, d, J=8.5Hz) The following compound was obtained in a manner similar to that of Preparation 9. Preparation 10 15 Methyl 4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,3,4 thiadiazol-2-yl] benzoate NMR (CDCl 3 , 5) : 1.3-2.0 (10H, m), 3.34 (3H, s), 3.38 (2H, t, J=6.4Hz), 3.96 (3H, s), 4.03 (2H, t, J=6.5Hz), 6.99 (2H, d, J=8.8Hz), 7.95 (2H, d, J=8.8Hz), 8.07 20 (2H, d, J=8.4Hz), 8.43 (2H, d, J=8.4Hz) MASS (m/z) : 441 (M+1) Preparation 11 A mixture of methyl 4-[5-[4-(6-methoxy-n-hexyloxy) phenyl]-1,3,4-thiadiazol-2-yl]benzoate (179.6 g), sodium 25 hydroxide (25.3 g), water (250 ml), methanol (1 L), and tetrahydrofuran (750 ml) was heated under refluxing for 1 hour then cooled to room temperature and poured into water (7 L). The pH of the stirred mixture was adjusted to 2.0 with 6N hydrochloric acid and the precipitate collected by filtration, 30 washed thoroughly with water, followed by acetonitrile, then dried under hi-vacuum at 50°C to give 4-[5-[4-(6-methoxy n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid (167 g) as a yellow powder. NMR (DMSO-d 6 , 6) : 1.27-1.85 (8H, m), 3.22 (3H, s), 35 3.32 (2H, t, J=6.4Hz), 4.06 (2H, t, J=6.3Hz), 7.12 WO 99/40108 PCT/JP99/00538 50 (2H, d, J=8.8Hz), 7.97 (2H, d, J=8.7Hz), 8.12 (4H, s), 13.28 (1H, br s) The following compound was obtained in a manner similar to that of Preparation 11. 5 Preparation 12 4- [5-[4-(7-Methoxy-n-heptyloxy)phenyl]-1,3,4 thiadiazol-2-yl]benzoic acid IR (KBr) : 2939.0, 2867.6, 2642.0, 1712.5, 1604.5, 1440.6, 1402.0, 1253.5 cm - I 10 MASS (m/z) : 427 (M+1) Preparation 13 A mixture of 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl] 1,3,4-thiadiazol-2-yl]benzoic acid (50 g), 1-hydroxybenzotriazole (18 g) and 1-ethyl-3-(3' 15 dimethylaminopropyl)carbodiimide, hydrochloride (34.86 g) in methylene chloride (1 L) was stirred for 16 hours at room temperature then evaporated under reduced pressure and dried for 1 hour under hi-vacuum. Water (1 L) was added to the residue and the resulting precipitate collected by filtration, 20 washed with water (1 L x 5), acetonitrile (1 L x 5), isopropyl ether (250 ml x 2), then dried under hi-vacuum to give 4 [5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2 yl]benzoic acid benzotriazol-1-yl ester (56.92 g) as a yellow powder. 25 IR (KBr) : 1778 cm - I NMR (CDCl 3 , 5) : 1.44-1.89 (8H, m), 3.35 (3H, s), 3.40 (2H, t, J=6.2Hz), 4.05 (2H, t, J=6.4Hz), 7.01 (2H, d, J=8.8Hz), 7.43-7.63 (3H, m), 7.98 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.2Hz), 8.24 (2H, d, 30 J=8.5Hz), 8.41 (2H, d, J=8.5Hz) The following compounds [Preparations 14 and 15] were obtained in a manner similar to that of Preparation 13. Preparation 14 4-[5-[4-(7-Methoxy-n-heptyloxy)phenyl]-1,3,4 35 thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester WO 99/40108 PCT/JP99/00538 51 IR (KBr) : 3446.2, 2937.1, 2865.7, 1778.0, 1602.6, 1253.5 cm-1 NMR (CDC1 3 , 5) : 1.3-2.0 (10H, m), 3.34 (3H, s), 3.39 (2H, t, J=6.4Hz), 4.03 (2H, t, J=6.SHz), 7.01 (2H, 5 d, J=8.8Hz), 7.4-7.7 (3H, m), 7.98 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.2Hz), 8.24 (2H, d, J=8.7Hz), 8.41 (2H, d, J=8.7Hz) MASS (m/z) : 544 (M+1) Preparation 15 10 4-[5-(4-Pentyloxyphenyl)isoxazol-3-yl]benzoic acid benzotriazol-1-yl ester Preparation 16 To 3-hydroxybenzoic acid methyl ester (25 g) and potassium carbonate (25 g) in N,N-dimethylformamide (300 ml) 15 were added 1-bromopentane (25 ml) and the mixture was stirred for 7 hoursat 80 0 C. The reaction mixture was added to amixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was evaporated under reduced 20 pressure to give 3-amyloxybenzoic acid methyl ester (35 g). IR (KBr) : 2954, 2870, 1724, 1587 cm-1 NMR (CDCl 3 , 5) : 0.94 (3H, t, J=7.0Hz), 1.43 (4H, m), 1.80 (2H, m), 3.91 (3H, s), 3.99 (2H, t, J=6.6Hz), 7.09 (1H, ddd, J=7.8, 1.7 and 1.7Hz), 7.32 (1H, t, 25 J=7.8Hz), 7.55 (1H, dd, J=1.7 and 1.1Hz), 7.61 (1H, ddd, J=7.8, 1.7 and 1.1Hz) MASS (m/z) : 223 (M+1) Preparation 17 To 3-amyloxybenzoic acid methyl ester (35 g) in methanol 30 (200 ml) was added iN-sodium hydroxide aqueous solution (200 ml) and the mixture was stirred for 2 days at room temperature. Hydroxy chloride (20 ml) was added to the reaction mixture. The precipitate was filtered and washed with water, acetonitrile and diisopropyl ether to give 3-amyloxybenzoic 35 acid (30 mg).

WO 99/40108 PCT/JP99/00538 52 IR (KBr) : 2954, 2848, 2570, 1691, 1600, 1591 cm -I NMR (DMSO-d 6 , 6) : 0.90 (3H, t, J=7.0Hz), 1.40 (4H, m), 1.73 (2H, m), 4.00 (2H, t, J=6.6Hz), 7.17 (1H, ddd, J=7.7, 2.6 and 1.2Hz), 7.39 (1H, t, J=7.7Hz), 7.42 5 (1H, dd, J=1.5 and 1.2Hz), 7.52 (1H, ddd, J=7.7, 1.5 and 1.2Hz) MASS (m/z) : 209 (M+1) Preparation 18 To a solution of 1-hydroxybenzotriazole (24 g) and 3 10 amyloxybenzoic acid (29.5 g) in dichloromethane (500 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCD*HC1) (41 g) and the mixture was stirred for 5 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over 15 magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3-amyloxybenzoic acid benzotriazol-1-yl ester (42 g). IR (KBr) : 2956, 2935, 2869, 1788, 1600 cm-1 NMR (CDC1 3 , 5) : 0.95 (3H, t, J=7.0Hz), 1.45 (4H, m), 20 1.84 (2H, m), 4.05 (2H, t, J=6.5Hz), 7.30 (1H, d, J=9.4Hz), 7.43-7.56 (4H, m), 7.74 (1H, t, J=2.0Hz), 8.10 (1H, d, J=8.5Hz), 8.53 (1H, d, J=8.5Hz) MASS (m/z) : 326 (M+1) Preparation 19 25 To a solution of 4-n-butyloxybenzoic acid benzotriazol-1-yl ester (15 g) in N,N-dimethylformamide (100 ml) was added thiosemicarbazide (5.27 g) and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The 30 precipitate was collected by filtration to give 1-(4-n butyloxybenzoyl)thiosemicarbazide (11.51 g). NMR (DMSO-d 6 , 5) : 0.93 (3H, t, J=7.0Hz), 1.2-1.5 (2H, m), 1.6-1.8 (2H, m), 4.02 (2H, t, J=6.5Hz), 6.98 (2H, d, J=8.8Hz), 7.56 (1H, s), 7.83 (1H, s), 7.84 (2H, 35 d, J=8.8Hz), 9.26 (1H, s), 10.21 (1H, s) WO 99/40108 PCT/JP99/00538 53 The following compound was obtained in a manner similar to that of Preparation 19. Preparation 20 1-(3-Amyloxybenzoyl)thiosemicarbazide 5 NMR (DMSO-d 6 , 5) : 0.90 (3H, t, J=6.8Hz), 1.39 (4H, m), 1.73 (2H, m), 4.01 (2H, t, J=6.4Hz), 7.10 (1H, d, J=8.0Hz), 7.30-8.00 (5H, m), 9.33 (1H, s), 10.34 (1H, s), 8.53 (1H, d, J=8.5Hz) MASS (m/z) : 282 (M+1) 10 Preparation 21 To a slurry of 1-(4-n-butyloxybenzoyl)thiosemicarbazide (20 g) in toluene (213.3 ml) at 40 0 C, was added dropwise over 30 minutes, methanesulfonic acid (6.92 ml). The mixture was stirred under refluxing for 12 hours. After cooling to 10'C, 15 the sulfonate salt was filtered and dried. The salt was placed in water, the solution was adjusted to pH 9 with IN sodium hydroxide and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2-amino-5 20 (4-n-butyloxyphenyl)-1,3,4-thiadiazole (4.314 g). NMR (CDCl 3 , 5) : 0.94 (3H, t, J=7.0Hz), 1.2-1.6 (2H, m), 1.6-1.9 (2H, m), 4.01 (2H, t, J=6.5Hz), 7.00 (2H, d, J=8.8Hz), 7.28 (2H, s), 7.66 (2H, d, J=8.8Hz) The following compound was obtained in a manner similar 25 to that of Preparation 21. Preparation 22 2-Amino-5-(3-amyloxyphenyl)-1,3,4-thiadiazole IR (KBr) : 3291.9, 3114.5, 2952.5, 1610.3 cm-1 NMR (DMSO-d 6 , 5) : 0.90 (3H, t, J=7.0Hz), 1.39 (4H, 30 m), 1.73 (2H, m), 4.01 (2H, t, J=6.5Hz), 7.00 (1H, d, J=8.5Hz), 7.25-7.42 (5H, m) MASS (m/z) : 264 (M+1) Preparation 23 To a suspension of 2-amino-5-(4-n-butyloxyphenyl) 35 1,3,4-thiadiazole (1.5 g) in ethanol (30 ml) was added ethyl WO 99/40108 PCT/JP99/00538 54 4-bromoacetylbenzoate (1.86 g) and the mixture was stirred under refluxing for 1.5 hours. The reaction mixture was pulverized with ethyl acetate. The precipitate was filtered and dried. To a suspension of the powder in xylene (15 ml) 5 was added trifluoroacetic acid (3 ml) and the mixture was stirred under refluxing for 3 hours. The reaction mixture was pulverized with diisopropyl ether. The precipitate was filtered and dried to give 4-[2-(4-butyloxyphenyl)imidazo [2,1-b] [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester 10 trifluoroacetic acid salt (2.15 g). IR (KBr) : 1714.4, 1602.6, 1278.6, 1255.4, 1178.3 cm The following compound was obtained in a manner similar to that of Preparation 23 15 Preparation 24 4-[2-(3-Amyloxyphenyl)imidazo[2,1 b] [l,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) : 2869.6, 1704.8, 1573.6, 1278.6 cm 20 MASS (m/z) : 436 (M+1) Preparation 25 To a solution of 4-[2-(4-butyloxyphenyl)imidazo[2, 1-b] [l,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (2.05 g) in the mixture of methanol 25 (41 ml) and tetrahydrofuran (20.5 ml) was added 2N NaOH aq. (19.1 ml) and refluxed for 17 hours. The reaction mixture was adjusted to pH 1-2 with 1N HC1 and the resulting precipitate was collected by filtration to give 4-[2-(4 butyloxyphenyl)imidazo[2,1-b] [l,3,4]thiadiazol-6 30 yl]benzoic acid (1.544 g). The following compound was obtained in a manner similar to that of Preparation 25. Preparation 26 4-[2-(3-Amyloxyphenyl)imidazo[2,l-b] [1,3,4] 35 thiadiazol-6-yl]benzoic acid WO 99/40108 PCT/JP99/00538 55 IR (KBr) : 2935.1, 2867.6, 1685.5, 1608.3, 1484.9, 1288.2 cm-1 NMR (DMSO-d 6 , 6) : 0.91 (3H, t, J=7.0Hz), 1.39 (4H, m), 1.75 (2H, m), 4.07 (2H, t, J=6.5Hz), 7.19 (1H, m), 5 7.42-7.49 (3H, m), 8.00 (4H, s), 8.89 (1H, s) MASS (m/z) : 408 (M+1) The Starting Compound used and the Object Compounds (27) to (30) obtained in the following Preparations 27 to 30 are 10 given in the table as below, in which the formula of the starting compound is in the upper column and the formula of the object compounds (27) to (30) are in the lower column, respectively.

WO 99/40108 PCT/JP99/00538 56 Preparation Formula No. HO OH HO

H

3 0...... 2

H

2 N N 0 HN OH 2OO HN H 0 HO NH 0

CH

3 0 H HQ NaO 3 S HO 27 HO OH HQ 0 0 HOC O N

CH

2 HO o N O0H 0 HO NH 0H 3 0N H HQ- N<K/O - OH 0 NaO 3 S 0 /

HO

WO 99/40108 PCT/JP99/00538 57 Preparation Formula No. HO OH HO_ O0 HQC

H

3 ....... 2

H

2 N N S -OH 0 HO H 0 CH 3 H HQ N OH NaO 3 S k / HO 28 HO OH HO NG Hg ...... 0 - H,2

H

2 N N H OH 0 • 'OH 0 HO NH O CH 3 0 H HO- N O.H OH O NaO 3 S \ /

HO

WO 99/40108 PCT/JP99/00538 58 Preparation Formula No. HO OH HO o

H

3 ......

'NH

2

H

2 N O ON H 0

HO

"OH H3 CHO- NH - _O C H 3 H 0H OH NaO 3 S 0 HO 29 HO OH HO 0 N C ON NN-

O(CH

2 3

CH

3

H

2 N N 0 H OH 0HO H 0 CH 3 HO, y .. OH OH 0 NaO 3 So

HO

WO 99/40108 PCT/JP99/00538 59 Preparation Formula No. HO OH HO O S NV\ H 3 .......

H

2 N N0OH OO HN HH 0 HO NH O CH 3 0 H OH NaO 3 S 30 HO HO OH

H

3 C. (CH) 4

CH

3 3C oH S- 2)o

H

2 N 0 O O i H

CH

3 H HO N. OH - OH NaO 3 S /

HO

WO99/40108 PCT/JP99/00538 60 Preparation 27 To a solution of Starting Compound (1 g) in tetrahydrofuran (10 ml) and pH 6.86 standard buffer solution (prepared by Nacalai Tesque, Inc.) (10 ml) was added dropwise 5 with stirring to benzyloxycarbonyl chloride (0.15 ml) in an ice-bath. The solution was then stirred for 2 hours. The reaction mixture was acidified with dilute hydrogen chloride, and evaporated under reduced pressure. The residue was dissolved in water, and subjected to column chromatography on 10 ion exchange resin (DOWEX-50WX4 (Trademark: prepared by Dow Chemical)) eluting with water. The fractions containing the object compound were combined, and subjected to column chromatography on ODS (YMC-gel ODS-AM-S-50 (Trademark: prepared by Yamamura Chemical Lab.)) eluting with 5% 15 acetonitrile aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Object Compound (27) (0.78 g). IR (KBr) : 3462, 3336, 1668, 1539, 1265 cm-1 20 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.6Hz), 1.05 (3H, d, J=5.8Hz), 1.78-5.53 (35H, m), 6.71-8.84 (16H, m) MASS (m/z) : 1068.90 (M-Na +) Preparation 28 To a solution of Starting Compound (54.4 g) and 25 ethyldiisopropylamine (35 ml) in N,N-dimethylformamide (230 ml) was added 9-fluorenylmethyl chloroformate (15.8 g) at room temperature. The solution was stirred for 5 hours at the same temperature. Ethyl acetate (1.5 L) was added to the reaction mixture and the mixture was stirred for 30 minutes. The powder 30 was collected by filtration to give crude material (94.3 g). The crude material was purified by column chromatography on DOWEX and on ODS to give Object Compound (28) (52.6 g). NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.8Hz), 1.03 (3H, d, J=5.6Hz), 1.60-2.00 (3H, m), 35 2.05-2.49 (4H, m), 3.18 (1H, t, J=11.lHz), WO 99/40108 PCT/JP99/00538 61 3.60-4.48 (17H, m), 4.68-5.36 (10H, m), 5.35 (1H, d, J=5.9Hz), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, dd, J=8.2 and 1.6Hz), 6.84 (1H, m), 6.97 (1H, m), 7.04 (1H, d, J=1.6Hz), 7.27-7.46 (6H, m), 7.74-7.78 (3H, 5 m), 7.89 (2H, d, J=7.2Hz), 8.06 (2H, t, J=7.2Hz), 8.77 (1H, s) Preparation 29 To a solution of 1-hydroxybenzotriazole (216 mg) and 4-[2-(4-butyloxyphenyl)imidazo[2,1-b] [1,3,4]thiadiazol-6 10 yl]benzoic acid (420 mg) in N,N-dimethylformamide (20 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (245 mg) and the mixture was stirred for 2 hours at ambient temperature. Then to the reaction mixture was added Starting Compound (1 g) and diisopropylethylamine (0.279 ml) 15 and the mixture was stirred for 5 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration and dried over under reduced pressure. The powder was added to water and subjected to ion-exchange column chromatography on DOWEX-50WX4 and 20 eluted with water. The fractions containing the Object Compound were combined and subjected to column chromatography on ODS (YMC-gel ODS-AM S-50) and eluted with 25-30% acetonitrileaq. The fractions containing the Object Compound were combined and evaporated under reduced pressure to remove 25 acetonitrile. The residue was lyophilized to give Object Compound (29) (891 mg). NMR (DMSO-d 6 , 5) : 0.94 (3H, t, J=7.2Hz), 0.96 (3H, d, J=7.1Hz), 1.11 (3H, d, J=5.5Hz), 1.3-1.6 (2H, m), 1.6-2.1 (5H, m), 2.1-2.7 (4H, m), 3.25 (1H, m), 30 3.6-4.5 (16H, m), 4.7-5.3 (10H, m), 5.53 (1H, d, J=5.8Hz), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d,=8.2Hz), 6.86 (1H, s), 7.05 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.2-7.5 (3H, m), 7.90 (2H, d, J=8.9Hz), 7.9-8.0 (4H, m), 8.10 (1H, d, J=7.7Hz), 8.30 (1H, d, J=6.8Hz), 35 8.70 (1H, d, J=6.8Hz), 8.86 (1H, s) WO 99/40108 PCT/JP99/00538 62 MASS (m/z) : 1356 (M+Na + ) The following compound was obtained in a manner similar to that of Preparation 29. Preparation 30 5 IR (KBr) : 3359, 1673.9, 1648.8, 1257.4 cm

-

1 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.1Hz), 0.96 (3H, d, J=6.7Hz), 1.09 (3H, d, J=5.9Hz), 1.3-1.5 (4H, m), 1.6-2.7 (9H, m), 3.19 (1H, m), 3.6-4.6 (15H, m), 4.7-5.3 (11H, m), 5.53 (1H, d, 10 J=5.9Hz), 6.73 (1H, d, J=8.3Hz), 6.83 (1H, d, J=8.3Hz), 6.88 (1H, s), 7.06 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.2-7.4 (3H, m), 7.90 (2H, d, J=8.9Hz), 7.97 (4H, m), 8.08 (1H, d, J=6Hz), 8.31 (1H, d, J=5Hz), 8.76 (1H, d, J=5Hz), 8.85 (1H, s), 8.86 (1H, s) 15 MASS (m/z) : 1325 (M+Na + ) Elemental Analysis Calcd. for C 57

H

70

N

11

O

22

S

2 Na-8H 2 0 : C 45.87, H 5.81, N 10.32 Found : C 46.04, H 5.77, N 10.28 Preparation 31 20 A solution of 4-(4'-hydroxyphenyl)benzoic acid (25.6 g) in 10% hydrochloric acid-methanol was stirred for 3 days at room temperature. Then the solvent was evaporated in vacuo and the residue was triturated with toluene-ethyl acetate (20:1) to afford methyl 4-(4'-hydroxyphenyl)benzoate (26.5 25 g). NMR (CDCl 3 , 5) : 3.94 (3H, s), 6.93 (2H, d, J=8.4Hz), 7.27 (1H, s), 7.53 (2H, d, J=8.6Hz), 7.60 (2H, d, J=8.4Hz), 8.08 (2H, d, J=8.4Hz) MASS (m/z) : 229 (M+1) 30 Preparation 32 Asolutionof 4-(4'-hydroxyphenyl)benzoic acid (4.98 g), methyliodide (5 ml), and sodium carbonate (7.19 g) in N,N dimethylformamide (50 ml) was stirred for 17 hours at room temperature. The reaction mixture was partitioned between 35 ethyl acetate and water. The aqueous layer was extracted with WO 99/40108 PCT/JP99/00538 63 ethyl acetate. The combined organic layer was washed with water and brine. After dried over magnesium sulfate, the solution was evaporated in vacuo. The residue was triturated with n-hexane to afford methyl 4-(4'-methoxyphenyl)benzoate 5 (5.45 g). IR (KBr) : 1718 cm-1 NMR (CDCl 3 , 5) : 3.86 (3H, s), 3.93 (3H, s), 7.00 (2H, d, J=8.8Hz), 7.57 (2H, d, J=8.8Hz), 7.61 (2H, d, J=8.6Hz), 8.07 (2H, d, J=8.6Hz) 10 MASS (m/z) : 243 (M ++1) Preparation 33 A mixture of methyl 4-[5-[4'-[4"-[3-(piperizin-1-yl) propyloxy]phenyl]lphenyl]-1,3,4-oxadiazol-2-yl]benzoate (1.13 g), 1N sodium hydroxide aqueous solution (3.5 ml), 15 methanol (5 ml) and tetrahydrofuran (5 ml) was refluxed for 17 hours. The mixture was cooled down to room temperature and evaporated in vacuo. To the residue was added 1N hydrochloric acid aqueous solution. The powder was obtained by filtration to give 4-[5-[4'-[4"-[3-(piperizin-1-yl) 20 propyloxy]phenyl]phenyl]-1,3,4-oxadiazol-2-yl]benzoic acid hydrochloric acid salt (1.01 g). IR (KBr) : 3431, 2943, 2877, 2694, 2640, 2571, 2543, 1699 cm

-

1 NMR (DMSO-d 6 , 5) : 1.56 (2H, m), 1.78 (4H, m), 2.19 25 (2H, m), 3.17 (6H, m), 4.14 (2H, t, J=7.0Hz), 7.09 (2H, d, J=8.8Hz), 7.77 (2H, d, J=8.8Hz), 7.92 (2H, d, J=8.6Hz), 8.17 (2H, d, J=8.6Hz), 8.20 (2H, d, J=8.5Hz), 8.27 (2H, d, J=8.5Hz) MASS (m/z) : 484 (M ++1) free 30 Preparation 34 A solution of methyl pyrazole-4-carboxylate (10 g) in N,N-dimethylformamide (100 ml) was treated with potassium carbonate (10.95 g) and 1-bromodecane (19.31 g) and themixture was stirred for 16 hours at room temperature. Ethyl acetate 35 was added and the solution was washed with water (6x), dried WO 99/40108 PCT/JP99/00538 64 over magnesium sulfate and the evaporated residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give methyl 1-decylpyrazole-4-carboxylate (19.4 g) as a white solid. 5 NMR (CDCl 3 , 6) : 0.84-0.90 (3H, m), 1.25 (14H, br s), 1.83-1.90 (2H, m), 3.82 (3H, s), 4.15 (2H, t, J=7Hz), 7.87 (1H, s), 7.90 (1H, s) MASS (m/z) : 267 (M + ) Preparation 35 10 A solution of methyl 4-(4'-hydroxyphenyl)benzoate (2 g) in N,N-dimethylformamide (20 ml) was treated with potassium carbonate (1.21 g) and 3-phenoxypropylbromide (2.07 g) was stirred for 15 hours at room temperature and 4 hours at 85oC. After cooling, the reaction was quenched with water and the 15 precipitate was collected, washed thoroughly with water and dried to give methyl 4-[4'-(3-phenoxypropyloxy)phenyl] benzoate (2.6 g). NMR (DMSO-d 6 , 5) : 2.14-2.26 (2H, m), 3.87 (3H, s), 4.12-4.29 (4H, m), 6.89-6.98 (3H, m), 7.08 (2H, d, 20 J=8.8Hz), 7.25-7.33 (2H, m), 7.70 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.4Hz) MASS (m/z) : 363 (M + ) Preparation 36 A solution of methyl 4-(4'-hydroxyphenyl)benzoate (5 g) 25 in N,N-dimethylformamide (50 ml) was treated with potassium carbonate (6.06 g) and allyl bromide (2.46 ml), then heated at 60 0 C for 3 hours. After cooling, the reaction mixture was poured into ice-water (~200 ml) and the resulting precipitate was collected by filtration, washed with water, then isopropyl 30 ether, then dried to give methyl 4-[4' (allyloxy)phenyl]benzoate (5.55 g) as a solid. mp : 148-149 0 C NMR (CDCl 3 , 6) : 3.93 (3H, s), 4.29-4.61 (2H, m), 5.28 5.49 (2H, m), 5.99-6.18 (1H, m), 7.00 (2H, d, 35 J=8.8Hz), 7.56 (2H, d, J=8.8Hz), 7.61 (2H, d, WO 99/40108 PCT/JP99/00538 65 J=8.5Hz), 8.07 (2H, d, J=8.5Hz) MASS (m/z) : 269 (M

+

) Preparation 37 A solution of 4-(4'-hydroxyphenyl)benzoic acid (4 g) and 5 IN sodium hydroxide (41 ml) in dimethyl sulfoxide (40 ml) was heated for 30 minutes at 85 0 C, then treated with 4-phenoxybutyl bromide (6.42 g) and heating continued for 8 hours. After cooling, the reaction was poured into water and adjusted to pH 2 and the resulting precipitate was collected, 10 washed with water, and dried to give 4-[4'-(4 phenoxybutyloxy)phenyl]benzoic acid (6.7 g). IR (KBr) : 1683.6, 1594.8, 1535.1 cm-1 NMR (DMSO-d 6 , 5) : 1.89 (4H, br s), 3.34 (1H, br s), 4.04-4.10 (4H, m), 6.91-6.95 (3H, m), 7.05 (2H, d, 15 J=7.9Hz), 7.24-7.30 (2H, m), 7.66-7.76 (4H, m), 7.98 (2H, d, J=7.8Hz) Preparation 38 A mixture of 4-[4'-(4-phenoxybutyloxy)phenyl]benzoic acid (5 g), 1-hydroxybenzotriazole (2.24 g) and 1-ethyl-3 20 (3'-dimethylaminopropyl)carbodiimide hydrochloride (3.97 g) in N,N-dimethylformamide (70 ml) was stirred for 18 hours at room temperature, then treated with tert-butylcarbazate (2.19 g) and the mixture was stirred for further 4 hours at ambient temperature. Water was added and the precipitate was 25 collected, washed with water, and dried to give N-(tert butoxycarbonyl)-N'-[4-[4'-(4 phenoxybutyloxy)phenyl]benzoyl]hydrazine (6 g) as a solid. IR (KBr) : 1650.8, 1492.6, 1290.1, 1249.6 cm

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1 NMR (DMSO-d 6 , 5) : 1.44 (9H, br s), 1.90 (4H, br s), 30 4.04-4.10 (4H, m), 6.88-6.96 (3H, m), 7.05 (2H, d, J=8.7Hz), 7.24-7.32 (2H, m), 7.69 (2H, d, J=8.8Hz), 7.75 (2H, d, J=8.5Hz), 7.92 (2H, d, J=8.2Hz), 8.91 (1H, s), 10.21 (1H, s) Preparation 39 35 A solution of N-(tert-butoxycarbonyl)-N'-[4-[4'-(4- WO 99/40108 PCT/JP99/00538 66 phenoxybutyloxy)phenyl]benzoyl]hydrazine (6 g) in trifluoroacetic acid (40 ml) was stirred for 2 hours at room temperature, then evaporated under reduced pressure, dissolved in water, then adjusted to pH 8 with saturated sodium 5 hydrogen carbonate solution. The precipitate was collected, washed with water, and dried to give 4-[4'-(4 phenoxybutyloxy)phenyl]benzoylhydrazine (5 g). IR (KBr) : 3282.3, 1604.5 cm

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1 NMR (DMSO-d 6 , 5) : 1.89 (4H, br s), 4.04-4.09 (4H, m), 10 4.55 (2H, br), 6.83-6.96 (3H, m), 7.04 (2H, d, J=8.6Hz), 7.24-7.28 (2H, m), 7.64-7.72 (4H, m), 7.88 (2H, d, J=8.3Hz), 9.79 (1H, s) MASS (m/z) : 377 (M + ) Preparation 40 15 Asolutionof 4-methoxycarbonylbenzoylhydrazine (432mg) in tetrahydrofuran (15 ml)-pyridine (5 ml) was treated with 4-[4'-(8-methoxy-n-octyloxy)phenyl]benzoic acid benzotriazol-1-yl ester (1.054 g) and the mixture was stirred for 72 hours at room temperature, then water (~100ml) was added 20 to the reaction mixture and the precipitate was collected, washed with water and dried to give N-[4-[4'-(8-methoxy-n octyloxy)phenyl]benzoyl] -N' - (4-methoxycarbonyl benzoyl)hydrazine (1.10 g). IR (KBr) : 3220.5, 2933.2, 2856.1, 1724.0, 1679.7, 25 1654.6 cm -1 NMR (DMSO-d 6 , 5) : 1.20-1.60 (10H, m), 1.60-1.80 (2H, m), 3.21 (3H, s), 3.21-3.33 (2H, m), 3.90 (3H, s), 4.02 (2H, t, J=6.9Hz), 7.05 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.6Hz), 7.79 (2H, d, J=8.3Hz), 7.99 (2H, 30 d, J=8.3Hz), 8.04 (2H, d, J=8.5Hz), 8.11 (2H, d, J=8.5Hz), 10.60 (1H, s), 10.70 (1H, s) MASS (m/z) : 533 (M + ) Preparation 41 A suspension of N-(4-methoxybenzoyl)-N'-(4 35 methoxycarbonylbenzoyl)hydrazine (10 g) and di-phosphorus WO99/40108 PCT/JP99/00538 67 pentasulfide (6.77 g) in tetrahydrofuran (100 ml) was refluxed for 3 hours. The reaction mixture was cooled, poured into water (300 ml), stirred for 30 minutes and extracted with dichloromethane (1500 ml) and methanol (300 ml). The organic 5 layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with acetonitrile. The solid was collected by filtration and dried under reduced pressure to give methyl 4-[5-(4-methoxyphenyl)-1,3,4 10 thiadiazol-2-yl]benzoate (8.15 g). IR (KBr) : 2952.5, 2840.6, 1714.4, 1606.4, 1278.6, 1251.6 cm-1 NMR (CDCl 3 , 5) : 3.89 (3H, s), 3.96 (3H, s), 7.01 (2H, d, J=8.9Hz), 7.97 (2H, d, J=8.9Hz), 8.07 (2H, d, 15 J=8.7Hz), 8.16 (2H, d, J=8.7Hz) MASS (m/z) : 327 (M +1) Preparation 42 To a solutionofborontribromide (2.0Mindichloromethane, 103 ml) was added dropwise methyl 4-[5-(4-methoxyphenyl) 20 1,3,4-thiadiazol-2-yl]benzoate (6.75 g) and dichloromethane (100 ml) at -78 0 C. The reaction mixture was allowed to warm to room temperature, and the mixture was stirred overnight. The reaction mixture was poured into ice-water (1000 ml). The precipitate was collected by filtration, washed with water and 25 dried under reduced pressure at 60 0 C to give a mixture of methyl 4-[5-(4-hydroxyphenyl)-l,3,4-thiadiazol-2-yl]benzoate and 4-[5-(4-hydroxyphenyl)-l,3,4-thiadiazol-2-yl]benzoic acid (6.56 g), that was used crude in the next reaction. Preparation 43 30 To a suspension of a mixture of methyl 4-[5-(4 hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and 4-[5-(4 hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (600 mg), potassium carbonate (531 mg) andN,N-dimethylformamide (3 ml) was added 4-phenoxybutylbromide (880 mg) and the mixture was 35 stirredat 100C (bath temperature) for2hours. Aftercooling, WO99/40108 PCT/JP99/00538 68 the mixture was added to 0.1N hydrochloric acid (100 ml). The resulting precipitate was collected by filtration and washed with water. To this material was added tetrahydrofuran (20 ml), ethanol (20 ml) and 10% sodium hydroxide aqueous solution 5 (1.39 ml). The mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water (100ml), adjusted to pH 1.8 with 1N hydrochloric acid, then extracted with a mixture of dichloromethane (1000 ml), tetrahydrofuran (200 ml) and methanol (200 ml). The organic layer was washed 10 with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile. The solid was collected by filtration and dried to give 4-[5-[4-(4-phenoxybutyloxy)phenyl]-1,3,4 thiadiazol-2-yl]benzoic acid (685 mg). 15 IR (KBr) : 3371.0, 2674.8, 2547.5, 1685.5, 1604.5, 1249.6 cm-1 Preparation 44 To a suspension of a mixture of methyl 4-[5-(4 hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and 4-[5-(4 20 hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (2.0 g), potassium carbonate (14.6 g) andN, N-dimethylformamide (15ml) was added 1,5-dibromopentane (10 ml) and the mixture was stirred at 100'C (bath temperature) for 1.5 hours. The resulting mixture was neutralized by 0.1N hydrochloric acid 25 and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried. To this compound was added phenol (1.43 30 g), potassiumcarbonate (2.10g) andN,N-dimethylformamide (30 ml), and the mixture was stirred at 100 0 C (bath temperature) for 20 hours. After cooling, the reaction mixture was poured into saturated sodium hydrogen carbonate aqueous solution. The resulting precipitate was collected by filtration, washed 35 with water. To this compound was added tetrahydrofuran (20 WO99/40108 PCT/JP99/00538 69 ml), ethanol (20 ml) and 10% sodium hydroxide aqueous solution (2.6 ml). The mixture was refluxed for 1.5 hours. The reaction mixture was diluted with water, acidified with 1N hydrochloric acid (10 ml). The resulting precipitate was 5 collected by filtration, washed with water, dried under reduced pressure to give 4-[5-[4-(5-phenoxy-n pentyloxy)phenyl]-l,3,4-thiadiazol-2-yl]benzoic acid (2.47 g), that was used crude in the next reaction. MASS (m/z) : 461 (M+1) 10 Preparation 45 To a suspension of a mixture of methyl 4-[5-(4 hydroxyphenyl)-l,3,4-thiadiazol-2-yl]benzoate and 4-[5-(4 hydroxyphenyl)-l,3,4-thiadiazol-2-yl]benzoic acid (3.12 g), potassium carbonate (22.07 g) and N,N-dimethylformamide (15 15 ml) was added 1,5-dibromopentane (15 ml) and the mixture was stirredat 100C (bath temperature) for 5hours. The resulting mixture was neutralized by 0.1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were 20 removed under reduced pressure and the residue was triturated withn-hexane. The solidwas collectedby filtrationanddried to give a crude powder (3.71 g). To the crude powder (2.11 g) was added methanol (10 ml) and sodium methoxide (28% in methanol) (10 ml), and refluxed for 2 hours. Then to the 25 reaction mixture was added sodiummethoxide (28% in methanol) (5ml) and refluxed for 1.5 hours. After cooling, the reaction mixture was added to water and tetrahydrofuran, stirred overnight and adjusted to pH 2 with 4N hydrochloric acid. The resulting precipitate was collected by filtration, washed with 30 acetonitrile and dried under reduced pressure to give 4 [5-[4-(5-methoxy-n-pentyloxy)phenyl]-l,3,4-thiadiazol-2 yl]benzoic acid (1.34 g). IR (KBr) : 2940.9, 2865.7, 2663.2, 2549.4, 1685.5, 1604.5, 1432.9, 1413.6, 1292.1, 35 1253.5 cm-1 WO 99/40108 PCT/JP99/00538 70 NMR (DMSO-d 6 , 5) : 1.3-1.7 (4H, m), 1.7-2.0 (2H, m), 3.23 (3H, s), 3.36 (2H, m), 4.07 (2H, t, J=6.4Hz), 7.13 (2H, d, J=8.8Hz), 7.97 (2H, d, J=8.8Hz), 8.12 (4H, s) 5 MASS (m/z) : 399 (M+1) Preparation 46 To a solution of piperidine (2.98 g) and methyl 6 chloronicotinate (5.00 g) inN,N-dimethylformamide (75ml)was added potassium carbonate (12.08 g) . The mixture was stirred 10 at 100 0 C for 3 hours. After cooling to ambient temperature, to the reaction mixture was added water (100 ml) and then the mixture was stirred for 15 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give methyl 6-(1-piperidyl)nicotinate (5.55 g), as 15 a white solid. IR (KBr) : 2941, 2850, 1701, 1608, 1552, 1508, 1435, 1415 cm 1 NMR (CDC1 3 , 5) : 1.5-1.8 (6H, m), 3.6-3.7 (4H, m), 3.86 (3H, s), 6.57 (1H, d, J=9.1Hz), 7.98 (1H, dd, 20 J=9.1 and 2.4Hz), 8.78 (1H, d, J=2.0Hz) MASS (m/z) : 221 (M+1) Preparation 47 To a solution of methyl 6-(1-piperidyl)nicotinate (5.00 g) in a mixed solvent of ethanol (25 ml) and tetrahydrofuran 25 (10 ml) was added hydrazine monohydrate (11.0 ml). The solution was refluxed for 6 hours, during which period additional hydrazine monohydrate (11.0 ml) was added to the mixture. After cooling to ambient temperature, the reaction mixture was added to water (100 ml) and then stirred for 20 30 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give 6-(1 piperidyl)nicotinoylhydrazine (3.44 g), as a white solid. IR (KBr) : 3300, 2931, 2846, 1649, 1608, 1554, 1502, 1417, 1348, 1242 cm-1 35 NMR (CDCl 3 , 5) : 1.5-1.8 (6H, m), 3.4-3.8 (6H, m), 6.61 WO99/40108 PCT/JP99/00538 71 (1H, d, J=8.9Hz), 7.51 (1H, brs), 7.85 (1H, dd, J=9.0 and 2.5Hz), 8.54 (1H, d, J=2.0Hz) MASS (m/z) : 221 (M+1) Preparation 48 5 To a solution of N-[6-(1-piperidyl)nicotinoyl]-N'-(4 methoxycarbonylbenzoyl)hydrazine (2.00 g) inpyridine (40 ml) was added phosphorus pentasulfide (1.74 g). The mixture was refluxed for 4 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water (150 ml) and 10 the mixture was adjusted to pH 11 with IN sodium hydroxide aqueous solution and the mixture was stirred for 30 minutes at ambient temperature. The resulting precipitates were filtered, washed with water and dried to give methyl 4-[5 [6-(1-piperidyl)pyridin-3-yl]-1,3,4-thiadiazol-2 15 yl]benzoate (1.59 g), as a yellow solid. IR (KBr) : 2933, 2848, 1720, 1604, 1433, 1279, 1109 cm

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1 NMR (CDC1 3 , 5) : 1.6-1.8 (6H, m), 3.6-3.8 (4H, m), 3.96 (3H, s), 6.73 (1H, d, J=9.1Hz), 8.06 (2H, d, J=8.7Hz), 20 8.14 (1H, dd, J=9.2 and2.9Hz), 8.16 (2H, d, J=8.6Hz), 8.70 (1H, d, J=2.2Hz) MASS (m/z) : 381 (M+1) Preparation 49 To a refluxing suspension of methyl 4-[5-[2-(1 25 piperidyl)pyridin-5-yl]-1,3,4-thiadiazol-2-yl]benzoate (1.50 g) in a mixed solvent of tetrahydrofuran (75 ml) and ethanol (15ml) was addeddropwise 10% sodium hydroxide aqueous solution (3.15 ml). The mixture was refluxed for 1.5 hours and cooled to ambient temperature. To the reaction mixture 30 was added water (100 ml) and the pH was adjusted to 1 with 1N hydrochloric acid (15 ml). The mixture was stirred for 30 minutes at ambient temperature and the resulting precipitates were filtered, washed with water and dried to give 4-[5 [6-(1-piperidyl)pyridin-3-yl]-1,3,4-thiadiazol-2 35 yl]benzoic acid hydrochloride (1.36 g), as a yellow solid.

WO 99/40108 PCT/JP99/00538 72 IR (KBr) : 3479, 2935, 2854, 1695, 1605, 1431, 1281, 1250 cm -1 NMR (DMSO-d 6 , 5) : 1.5-1.7 (6H, m), 3.6-3.7 (4H, m), 6.99 (1H, d, J=9.1Hz), 8.08 (1H, dd, J=9.1 and2.5Hz), 5 8.11 (4H, s), 8.71 (1H, d, J=2.4Hz) MASS (m/z) : 367 (M ++1) (free) Preparation 50 To a suspension of 4-[5-[6-(1-piperidyl)pyridin-3-yl] 1,3,4-thiadiazol-2-yl]benzoic acid hydrochloride (1.20 g) in 10 methylene chloride (60 ml) was added triethylamine (0.57 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.43 g). The mixture was stirred for 6 hours at ambient temperature. To the reaction mixture was added water and the organic layer was separated, washed with aqueous 15 sodium hydrogen carbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate, and concentrated in vacuo. Diisopropyl ether was added to the residue and the precipitates were filtered, washed with the same solvent, and dried to give 4-[5-[6-(1 20 piperidyl)pyridin-3-yl]-1,3,4-thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester (1.18 g), as a yellow solid. IR (KBr) : 2931, 2854, 1778, 1600, 1547, 1512, 1431, 1358, 1242, 993 cm -I NMR (CDCl 3 , 5) : 1.6-1.8 (6H, m), 3.6-3.8 (4H, m), 6.75 25 (1H, d, J=9.1Hz), 7.4-7.7 (3H, m), 8.13 (1H, d, J=8.2Hz), 8.16 (1H, dd, J=9.1 and 2.5Hz), 8.24 (2H, d, J=8.6Hz), 8.40 (2H, d, J=8.6Hz), 8.72 (1H, d, J=2.3Hz) MASS (m/z) : 484 (M ++I) 30 Preparation 51 A solution of methyl 4- (4'-hydroxyphenyl)benzoate (2.02 g), n-butylbromide (3 ml) and sodium carbonate (3.6 g) in N,N-dimethylformamide was stirred for 17 hours at 80 0 C. The reaction mixture was cooled to room temperature and 35 partitioned between ethyl acetate and water. The aqueous WO 99/40108 PCT/JP99/00538 73 layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After dried over magnesium sulfate, the solution was evaporated in vacuo. The residue was triturated with n-hexane to afford methyl 4 5 (4'-butyloxyphenyl)benzoate (2.45 g). IR (KBr) : 2956, 2935, 2873, 1722 cm - i NMR (DMSO-d 6 , 6) : 0.94 (3H, d, J=7.3Hz), 1.45 (2H, qt, J=7.3 and 6.9Hz), 1.70 (2H, tt, J=6.9 and 6.9Hz), 4.03 (2H, t, J=6.9Hz), 7.04 (2H, d, J=8.8Hz), 7.68 10 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.5Hz) MASS (m/z) : 285 (M +1) The following compounds [Preparations 52 to 54] were obtained in a manner similar to that of Preparation 51. 15 Preparation 52 Methyl 4-(4'-n-pentyloxyphenyl)benzoate IR (KBr) : 2958, 2935, 2866, 1722 cm-1 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.0Hz), 1.39 (4H, m), 1.74 (2H, m), 3.87 (3H, s), 4.02 (2H, t, J=6.4Hz), 20 7.04 (2H, t, J=8.8Hz), 7.69 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.5Hz) MASS (m/z) : 299 (M +1) Preparation 53 Methyl 4-(4'-n-hexyloxyphenyl)benzoate 25 IR (KBr) : 2954, 2933, 2866, 1724 cm - i NMR (DMSO-d 6 , 6) : 0.87 (3H, m), 1.20-1.87 (8H, m), 3.87 (3H, s), 4.02 (2H, m), 7.04 (2H, d, J=8.7Hz), 7.68 (2H, d, J=8.7Hz), 7.78 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.4Hz) 30 MASS (m/z) : 313 (M ++1) Preparation 54 Methyl 4-(4'-n-heptyloxyphenyl)benzoate IR (KBr) : 2956, 2931, 2856, 1724 cm-1 NMR (DMSO-d 6 , 6) : 0.86 (3H, m), 1.20-1.80 (10H, m), 35 3.87 (3H, s), 4.05 (2H, m), 7.04 (2H, d, J=8.7Hz), WO 99/40108 PCT/JP99/00538 74 7.69 (2H, d, J=8.7Hz), 7.78 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.5Hz) MASS (m/z) : 327 (M +1) Preparation 55 5 A solution of methyl 4-[4'-(3 bromopropoxy)phenyl]benzoate (1.5 g), potassium carbonate (1.2 g) and cis-2,6-dimethylmorpholine (990.6 mg) in N,N dimethylformamide was stirred for 15 hours at room temperature, then diluted with ethyl acetate and washed with water (5x), 10 dried over magnesium sulfate, evaporated, then purified by silica gel chromatography (20:1 dichloromethane-ethanol elution) to give methyl 4-[4'-[3-(2,6 dimethylmorpholino)propoxy]phenyl]benzoate (755 mg). NMR (CDC1 3 , 5) : 1.18 (6H, d, J=6.3Hz), 1.70-1.90 (2H, 15 m), 2.00-2.14 (2H, m), 2.50-2.65 (2H, m), 2.82 (2H, d, J=llHz), 3.74 (2H, br s), 3.93 (3H, s), 4.08 (2H, t, J=6.2Hz), 6.98 (2H, d, J=8.7Hz), 7.56 (2H, d, J=8.7Hz), 7.61 (2H, d, J=8.3Hz), 8.08 (2H, d, J=8.3Hz) 20 MASS (m/z) : 384 (M + ) The following compound was obtained in a manner similar to that of Preparation 55. Preparation 56 Methyl 4-[4'-[3-(piperizin-1-yl)propyloxy]phenyl] 25 benzoate IR (KBr) : 2933, 2852, 2771, 1718 cm

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1 NMR (CDC1 3 , 5) : 1.47 (2H, m), 1.64 (4H, m), 2.04 (2H, tt, J=6.3 and 6.3Hz), 2.51 (6H, m), 3.93 (3H, s), 4.07 (2H, t, J=6.3Hz), 6.98 (2H, d, J=8.8Hz), 7.56 30 (2H, d, J=8.8Hz), 7.61 (2H, d, J=8.6Hz), 8.07 (2H, d, J=8.6Hz) MASS (m/z) : 354 (M +1) Preparation 57 A mixture of N-[4-(4'-allyloxyphenyl)benzoyl]-N'-(4 35 methoxycarbonylbenzoyl)hydrazine (1.5 g) and phosphorus WO 99/40108 PCT/JP99/00538 75 oxychloride (15 ml) was heated to reflux for 6 hours, then cooled to room temperature and poured into ice-water, stirred for ~2 hours then filtered. The resulting solid was washed thoroughly with water and dried at 50OC under vacuum to give 5 methyl 4-[5-[4'-[4"-allyloxyphenyl]phenyl]-1,3,4 oxadiazol-2-yl]benzoate as a solid. IR (KBr) : 1720.2, 1650.8, 1284.4, 1255.4 cm - 1 NMR (DMSO-d 6 , 5) : 3.98 (3H, s), 4.61 (2H, d, J=5.3Hz), 5.30-5.50 (2H, m), 6.03-6.17 (1H, m), 7.04 (2H, d, 10 J=8.8Hz), 7.61 (2H, d, J=8.8Hz), 7.74 (2H, d, J=8.5Hz), 8.20 (2H, d, J=8.5Hz), 8.23 (4H, s) MASS (m/z) : 413 (M + ) The following compounds [Preparations 58 to 68] were obtained in a manner similar to that of Preparation 57. 15 Preparation 58 Methyl 4-[5-[4'-(4"-methoxyphenyl)phenyl]-l,3,4 oxadiazol-2-yl] benzoate IR (KBr) : 1716 cm-1 NMR (CDCl 3 , 5) : 3.88 (3H, s), 3.98 (3H, s), 7.02 (2H, 20 d, J=8.8Hz), 7.61 (2H, d, J=8.8Hz) MASS (m/z) : 387 (M +1) Preparation 59 Methyl 4-[5-[4'-(4"-butyloxyphenyl)phenyl]-l,3,4 oxadiazol-2-yl]benzoate 25 IR (KBr) : 2956, 2933, 2871, 1720 cm-1 NMR (CDCl 3 , 5) : 1.00 (3H, t, J=7.3Hz), 1.54 (2H, qt, J=7.3 and 7.0Hz), 1.82 (2H, tt, J=7.0 and 7.0Hz), 3.98 (3H, s), 4.03 (2H, t, J=7.0Hz), 7.00 (2H, d, J=8.7Hz), 7.60 (2H, d, J=8.7Hz), 7.73 (2H, d, 30 J=8.4Hz), 8.22 (6H, m) MASS (m/z) : 429 (M +1) Preparation 60 Methyl 4-[5-[4'-(4"-n-pentyloxyphenyl)phenyl]-1,3,4 oxadiazol-2-yl] benzoate 35 IR (KBr) : 2956, 2931, 2870, 1720 cm

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1 WO 99/40108 PCT/JP99/00538 76 NMR (CDCl 3 , 5) : 0.995 (3H, t, J=7.0Hz), 1.43 (4H, m), 1.83 (2H, tt, J=7.0Hz), 3.98 (3H, s), 4.02 (2H, t, J=7.0Hz), 7.00 (2H, d, J=8.7Hz), 7.60 (2H, d, J=8.7Hz), 7.73 (2H, d, J=8.4Hz), 8.23 (2H, m) 5 MASS (m/z) : 443 (M+1) Preparation 61 Methyl 4-[5-[4'-(4"-n-hexyloxyphenyl)phenyl]-1,3,4 oxadiazol-2-yl] benzoate IR (KBr) : 2954, 2933, 2870, 1722 cm-1 10 NMR (CDCl 3 , 5) : 0.92 (3H, t, J=6.7Hz), 1.39 (6H, m), 1.82 (2H, tt, J=6.9Hz), 3.98 (3H, s), 4.02 (2H, t, J=6.5Hz), 7.00 (2H, d, J=8.6Hz), 7.60 (2H, d, J=8.6Hz), 7.73 (2H, d, J=8.3Hz), 8.22 (6H, m) MASS (m/z) : 457 (M+1) 15 Preparation 62 Methyl 4-[5-[4'-(4"-n-heptyloxyphenyl)phenyl]-1,3,4 oxadiazol-2-yl] benzoate IR (KBr) : 2954, 2931, 2856, 1722 cm - 1 NMR (CDCl 3 , 5) : 0.90 (3H, br), 1.20-2.00 (10H, br), 20 3.98 (3H, s), 4.02 (2H, br), 7.00 (2H, d, J=7.6Hz), 7.59 (2H, d, J=7.6Hz), 7.73 (2H, d, J=6.8Hz), 8.20 (6H, m) MASS (m/z) : 471 (M+1) Preparation 63 25 Methyl 4-[5-[4'-[4"-[3-(piperizin-1 yl)propyloxy]phenyl]lphenyl]-1,3,4-oxadiazol-2-yl]benzoate IR (KBr) : 2931, 2852, 2804, 2769, 1720 cm - 1 NMR (CDC1 3 , 5) : 1.51 (2H, m), 1.74 (4H, m), 2.14 (2H, m), 2.64 (6H, m), 3.98 (3H, s), 4.10 (2H, t, J=6.2Hz), 30 7.00 (2H, d, J=8.8Hz), 7.60 (2H, d, J=8.7Hz), 7.73 (2H, d, J=8.20Hz), 8.20 (2H, d, J=8.5Hz), 8.23 (4H, s) MASS (m/z) : 498 (M+1) Preparation 64 35 Methyl 4-[5-(1-n-decylpyrazol-4-yl)-1,3,4-oxadiazol- WO 99/40108 PCT/JP99/00538 77 2-yl]benzoate NMR (CDC1 3 , 5) : 0.84-0.91 (3H, m), 1.26-1.32 (14H, m), 1.80-2.00 (2H, m), 3.97 (3H, s), 4.21 (2H, t, J=7.1Hz), 7.26 (1H, s), 8.09 (1H, s), 8.26 (4H, s) 5 MASS (m/z) : 411 (M + ) Preparation 65 Methyl 4-[5-[4'-[4"-(3-phenoxypropyloxy) phenyl]phenyl] -1,3,4-oxadiazol-2-yl]benzoate IR (KBr) : 1718.3, 1600.6, 1490.7, 1280.5, 10 1245.8 cm -I NMR (CDCl 3 , 5) : 2.26-2.35 (2H, m), 3.98 (3H, s), 4.16-4.27 (4H, m), 6.91-7.05 (5H, m), 7.26-7.33 (2H, m), 7.60 (2H, d, J=8.7Hz), 7.73 (2H, d, J=8.4Hz), 8.20 (2H, d, J=8.4Hz), 8.23 (4H, s) 15 MASS (m/z) : 507 (M + ) Preparation 66 Methyl 4-[5-[4'-[4"-(4-phenoxybutyloxy) phenyl]phenyl] -1,3,4-oxadiazol-2-yl]benzoate IR (KBr) : 1720.2, 1602.6 cm -I 20 NMR (CDC1 3 , 6) : 2.02 (4H, br s), 3.93 (3H, s), 3.97 4.06 (4H, m), 6.83-7.04 (6H, m), 7.26-7.33 (1H, m), 7.60 (2H, d, J=8.7Hz), 7.89 (2H, d, J=8.7Hz), 8.18-8.23 (6H, m) MASS (m/z) : 521 (M + ) 25 Preparation 67 Methyl 4-[5-[4'-[4"-(8-methoxy-n-octyloxy)phenyl] phenyl]-1,3,4-oxadiazol-2-yl]benzoate IR (KBr) : 1720.2 cm

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1 NMR (CDCl 3 , 5) : 1.20-1.95 (12H, m), 3.34 (3H, s), 30 3.38 (2H, t, J=7Hz), 3.98 (3H, s), 4.02 (2H, t, J=6.5Hz), 7.00 (2H, d, J=8.7Hz), 7.59 (2H, d, J=8.7Hz), 7.73 (2H, d, J=8.5Hz), 8.19 (2H, d, J=8.5Hz), 8.22 (4H, s) MASS (m/z) : 515 (M + ) 35 Preparation 68 WO 99/40108 PCT/JP99/00538 78 Methyl 4-[5-[4'-[4"-[3-(2,6-dimethylmorphino) propyloxy]phenyl]lphenyl]-1, 3,4-oxadiazol-2-yl]benzoate NMR (CDCl 3 , 5) : 1.26 (6H, d, J=6.3Hz), 2.32-2.60 (4H, m), 3.15-3.30 (2H, m), 3.43 (2H, d, J=11.lHz), 3.98 5 (3H, s), 4.10-4.20 (2H, m), 4.30-4.50 (2H, m), 6.98 (2H, d, J=8.7Hz), 7.61 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.5Hz), 8.20 (2H, d, J=8.5Hz), 8.23 (4H, s) MASS (m/z) : 528 (M + ) The following compound was obtained in a manner similar 10 to that of Preparation 9. Preparation 69 Methyl 4-[5- (1-n-decylpyrazol-4-yl)-1,3,4-thiadiazol 2-yl]benzoate NMR (DMSO-d 6 , 5) : 0.84 (3H, br s), 1.23 (14H, br s), 15 1.70-1.90 (2H, m), 3.90 (3H, s), 4.15-4.23 (2H, m), 8.09 (1H, s), 8.13 (4H, s), 8.58 (1H, s) MASS (m/z) : 427 (M + ) The following compound was obtained in a manner similar to that of Preparation 1. 20 Preparation 70 Methyl 4-[4'-(3-bromopropyloxy)phenyl]benzoate NMR (DMSO-d 6 , 6) : 2.22-2.32 (2H, m), 3.69 (2H, t, J=6.6Hz), 3.87 (3H, s), 4.15 (2H, t, J=6Hz), 7.08 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.7Hz), 7.79 (2H, 25 d, J=8.5Hz), 8.01 (2H, d, J=8.4Hz) The following compound was obtained in a manner similar to that of Preparation 19. Preparation 71 1-(4-Cyclohexyloxybenzoyl)-3-thiosemicarbazide 30 NMR (DMSO-d 6 , 5) : 1.32 (6H, m), 1.71 (2H, m), 1.91 (2H, m), 4.45 (1H, m), 7.00 (2H, d, J=8.8Hz), 7.57 (2H, s), 7.84 (2H, d, J=8.7Hz), 9.27 (1H, s), 10.21 (1H, s) MASS (m/z) : 294 (M +1) 35 The following compound was obtained in a manner similar WO 99/40108 PCT/JP99/00538 79 to that of Preparation 21. Preparation 72 2-Amino-5-(4-cyclohexyloxyphenyl)-1,3,4-thiadiazole IR (KBr) : 3272.6, 3114.5, 2937.1, 2856.1, 1604.5, 5 1519.6, 1465.6 cm - I NMR (DMSO-d 6 , 5) : 1.17-1.48 (6H, m), 1.73 (2H, m), 1.92 (2H, m), 4.40 (1H, m), 7.00 (2H, d, J=8.8Hz), 7.27 (2H, s), 7.64 (2H, d, J=8.8Hz) MASS (m/z) : 276 (M +1) 10 The following compound was obtained in a manner similar to that of Preparation 23. Preparation 73 4-[2-(4-Cyclohexyloxyphenyl)imidazo[2,1-b][1,3,4] thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetate 15 IR (KBr) : 2931.3, 2861.8, 1714.4, 1702.8, 1502.3, 1280.5, 1257.4 cm-1 MASS (m/z) : 448 (M +1) The following compound was obtained in a manner similar to that of Preparation 25. 20 Preparation 74 4-[2-(4-Cyclohexyloxyphenyl)imidazo[2,1-b][1,3,4] thiadiazol-6-yl]benzoic acid IR (KBr) : 2931.3, 1679.7, 1606.4, 1473.3, 1421.3, 1290.1, 1249.6 cm-1 25 NMR (DMSO-d 6 , 5) : 1.43 (6H, m), 1.74 (2H, m), 1.94 (2H, m), 4.50 (1H, m), 7.14 (2H, d, J=8.8Hz), 7.88 (2H, d, J=8.8Hz), 8.00 (4H, s), 8.86 (1H, s) MASS (m/z) : 420 (M +1) The following compounds [Preparations 75 to 84] were 30 obtained in a manner similar to that of Preparation 5. Preparation 75 4-(4' -Methoxyphenyl)benzoylhydrazine IR (KBr) : 3292, 3205, 1655, 1622 cm-1 NMR (CDC1 3 , 5) : 1.59 (2H, br), 3.86 (3H, s), 6.99 35 (2H, d, J=7.9Hz), 7.38 (1H, br), 7.55 (2H, d, WO 99/40108 PCT/JP99/00538 80 J=7.9Hz), 7.62 (2H, d, J=7.3Hz), 7.79 (2H, d, J=7.3Hz) MASS (m/z) : 243 (M+1) Preparation 76 5 4-(4'-Butyloxyphenyl)benzoylhydrazine IR (KBr) : 3340, 3277, 3194, 2956, 2918, 2870, 1655, 1610 cm-1 NMR (CDC1 3 , 5) : 0.99 (3H, t, J=7.3Hz), 1.53 (4H, m), 1.80 (2H, tt, J=6.4 and6.4Hz), 4.02 (2H, t, J=6.4Hz), 10 6.98 (2H, d, J=8.8Hz), 7.38 (1H, s), 7.54 (2H, d, J=8.8Hz), 7.62 (2H, d, J=8.4Hz), 7.79 (2H, d, J=8.4Hz) MASS (m/z) : 285 (M+1) Preparation 77 15 4-(4'-n-Pentyloxyphenyl)benzoylhydrazine IR (KBr) : 3288, 3205, 3059, 2958, 2937, 2868, 1655, 1622, 1601 cm-1 NMR (CDC1 3 , 6) : 0.94 (3H, t, J=6.8Hz), 1.44 (4H, m), 1.60 (2H, br), 1.82 (2H, m), 4.00 (2H, t, J=6.8Hz), 20 6.98 (2H, t, J=8.5Hz), 7.38 (1H, br), 7.54 (2H, d, J=8.5Hz), 7.62 (2H, d, J=8.1Hz), 7.79 (2H, d, J=8.lHz) MASS (m/z) : 299 (M+1) Preparation 78 25 4-(4 ' -n-Hexyloxyphenyl)benzoylhydrazine IR (KBr) : 3288, 3207, 3057, 2954, 2935, 2868, 1655, 1626, 1606 cm - 1 NMR (CDC1 3 , 5) : 0.91 (3H, m), 1.36 (6H, m), 1.81 (2H, m), 4.01 (2H, m), 6.98 (2H, d, J=8.0Hz), 7.20 (1H, 30 br), 7.54 (2H, d, J=8.0Hz), 7.62 (2H, d, J=7.9Hz), 7.78 (2H, d, J=7.9Hz) MASS (m/z) : 313 (M+1) Preparation 79 4-(4' -n-Heptyloxyphenyl)benzoylhydrazine 35 IR (KBr) : 3286, 3205, 3061, 2956, 2931, 2856, 1654, WO 99/40108 PCT/JP99/00538 81 1623, 1608 cm -1 NMR (CDC1 3 , 5) : 0.90 (3H, m), 1.32 (8H, m), 1.81 (2H, m), 4.00 (2H, m), 6.98 (2H, d, J=8.4Hz), 7.40 (1H, br), 7.52 (2H, d, J=8.4Hz), 7.64 (2H, d, J=8.4Hz), 5 7.77 (2H, d, J=8.4Hz) MASS (m/z) : 327 (M +1) Preparation 80 4-[4'-[3-(Piperazin-1-yl)propyloxy]phenyl] benzoylhydrazine 10 IR (KBr) : 3275, 3105, 3041, 2956, 2933, 2870, 2852, 2814, 2767, 1643 cm

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1 NMR (CDC1 3 , 5) : 1.47 (2H, m), 1.63 (4H, m), 2.03 (2H, tt, J=6.3Hz), 2.50 (6H, m), 4.06 (2H, t, J=6.3Hz), 6.98 (2H, d, J=8.8Hz), 7.41 (1H, s), 7.54 (2H, d, 15 J=8.8Hz), 7.62 (2H, d, J=8.5Hz), 7.79 (2H, d, J=8.5Hz) MASS (m/z) : 354 (M +1) Preparation 81 1-n-Decyl-4-pyrazolylcarbonylhydrazine 20 NMR (DMSO-d 6 , 5) : 0.82-0.95 (3H, m), 1.22 (14H, br s), 1.62-1.81 (2H, m), 4.08 (2H, t, J=6.9Hz), 4.29 (2H, d, J=4Hz), 7.82 (1H, s), 8.12 (1H, s), 9.28 (1H, br s) MASS (m/z) : 267 (M + ) 25 Preparation 82 4-[4 ' - (3-Phenoxypropyloxy)phenyl] benzoylhydrazine NMR (DMSO-d 6 , 5) : 2.16-2.26 (2H, m), 4.11-4.23 (4H, m), 4.54 (2H, s), 6.89-6.98 (3H, m), 7.06 (2H, d, J=8.8Hz), 7.25-7.33 (2H, m), 7.67 (2H, d, J=8.7Hz), 30 7.70 (2H, d, J=8.4Hz), 7.89 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS (m/z) : 363 (M + ) Preparation 83 4-[4' -Allyloxyphenyl]benzoylhydrazine 35 NMR (DMSO-d 6 , 5) : 4.51 (2H, s), 4.60-4.65 (2H, m), WO 99/40108 PCT/JP99/00538 82 5.25-5.47 (2H, m), 5.98-6.17 (1H, m), 7.06 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.8Hz), 7.70 (2H, d, J=8.4Hz), 7.89 (2H, d, J=8.4Hz), 9.80 (1H, s) MASS (m/z) : 269 (M + ) 5 Preparation 84 4-[4'- [3-(2,6-Dimethylmorpholino)propyloxy]phenyl] benzoylhydrazine NMR (DMSO-d 6 , 5) : 1.04 (6H, d, J=6.3Hz), 1.58 (2H, t, J=10.6Hz), 1.86-1.92 (2H, m), 2.40 (2H, t, J=7Hz), 10 2.75 (2H, d, J=10.2Hz), 3.51-3.58 (2H, m), 4.05 (2H, t, J=6.2Hz), 4.50 (2H, s), 7.02 (2H, d, J=8.8Hz), 7.64-7.71 (4H, m), 7.88 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS (m/z) : 384 (M + ) 15 The following compounds [Preparations 85 to 96] were obtained in a manner similar to that of Preparation 7. Preparation 85 1-[4-(4 '-Methoxyphenyl)benzoyl] -2-(4-methoxycarbonyl benzoyl)hydrazine 20 IR (KBr) : 3228, 2956, 2840, 1720, 1680, 1655 cm - 1 NMR (DMSO-d 6 , 5) : 3.82 (3H, s), 3.90 (3H, s), 7.06 (2H, d, J=8.8Hz), 7.72 (2H, d, J=8.8Hz), 7.79 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.5Hz), 8.05 (2H, d, J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 10.60 (1H, s), 25 10.72 (1H, s) MASS (m/z) : 405 (M +1) Preparation 86 1-[4-(4 '-Butyloxyphenyl)benzoyl] -2-(4 methoxycarbonylbenzoyl)hydrazine 30 IR (KBr) : 3242, 3088, 3028, 2956, 2933, 2872, 1724, 1682, 1655, 1605 cm-1 NMR (DMSO-d 6 , 5) : 0.95 (3H, t, J=7.3Hz), 1.45 (2H, qt, J=7.3 and 6.4Hz), 1.73 (2H, tt, J=6.4 and 6.4Hz), 3.91 (3H, s), 4.03 (2H, t, J=6.4Hz), 7.05 (2H, d, 35 J=8.8Hz), 7.70 (2H, d, J=8.8Hz), 7.90 (2H, d, WO 99/40108 PCT/JP99/00538 83 J=8.4Hz), 8.00 (2H, d, J=8.4Hz), 8.05 (2H, d, J=8.4Hz), 8.05 (2H, d, J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 10.60 (1H, s), 10.72 (1H, s) MASS (m/z) : 447 (M+1) 5 Preparation 87 1-[4-(4'-Pentyloxyphenyl)benzoyl]-2-(4 methoxycarbonylbenzoyl)hydrazine IR (KBr) : 3226, 3030, 2958, 2931, 2870, 1724, 1680, 1655, 1605 cm - I 10 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=6.7Hz), 1.40 (4H, m), 1.74 (2H, m), 3.90 (3H, s), 4.03 (2H, t, J=6.5Hz), 7.05 (2H, d, J=8.6Hz), 7.70 (2H, d, J=8.6Hz), 7.78 (2H, d, J=8.3Hz), 8.00 (2H, d, J=8.3Hz), 8.07 (2H, d, J=8.6Hz), 8.09 (2H, d, J=8.6Hz), 10.60 (1H, s), 15 10.72 (1H, s) MASS (m/z) : 461 (M+1) Preparation 88 1-[4-(4 '-n-Hexyloxyphenyl)benzoyl]-2-(4 methoxycarbonylbenzoyl)hydrazine 20 IR (KBr) : 3242, 3219, 3091, 3028, 2956, 2933, 2866, 1724, 1680, 1655, 1605 cm NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.2Hz), 1.35 (6H, m), 1.74 (2H, m), 3.90 (3H, s), 4.03 (2H, t, J=6.9Hz), 7.05 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.7Hz), 7.79 25 (2H, d, J=8.3Hz), 8.00 (2H, d, J=8.3Hz), 8.06 (2H, d, J=8.6Hz), 8.10 (2H, d, J=8.6Hz), 10.60 (1H, s), 10.72 (1H, s) MASS (m/z) : 475 (M+1) Preparation 89 30 1-[4-(4'-n-Heptyloxyphenyl)benzoyl]-2-(4 methoxycarbonylbenzoyl)hydrazine IR (KBr) : 3219, 3091, 3029, 2956, 2931, 2856, 1722, 1679, 1652, 1604 cm NMR (DMSO-d 6 , 5): 0.88 (3H, br), 1.29 (8H, br), 1.75 35 (2H, br), 3.90 (3H, s), 4.02 (2H, br), 7.03 (2H, d, WO 99/40108 PCT/JP99/00538 84 J=8.4Hz), 7.70 (2H, d, J=8.4Hz), 7.80 (2H, d, J=8.8Hz), 8.00 (2H, d, J=8.8Hz), 8.45 (2H, br) MASS (m/z) : 489 (M +1) Preparation 90 5 1-[4-[4'-[3-(Piperidin-1-yl)propyloxy]phenyll benzoyl] -2-(4-methoxycarbonylbenzoyl)hydrazine IR (KBr) : 3061, 3026, 2933, 2852, 2805, 2771, 2391, 1724 cm

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1 NMR (DMSO-d 6 , 5) : 1.49 (6H, m), 1.88 (2H, tt, J=6.2 10 and 6.2Hz), 2.36 (6H, m), 3.90 (3H, s), 4.06 (2H, t, J=6.2Hz), 7.05 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.7Hz), 7.78 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.4Hz), 8.05 (2H, d, J=8.5Hz), 8.11 (2H, d, J=8.5Hz), 10.6 (1H, s) 15 MASS (m/z) : 516 (M +1) Preparation 91 N-(4-Methoxycarbonylbenzoyl)-N' - (1-n-decyl-4 pyrazolylcarbonyl)hydrazine NMR (DMSO-d 6 , 5) : 0.82-0.89 (3H, m), 1.24 (14H, br s), 20 1.70-1.90 (2H, m), 3.90 (3H, s), 4.14 (2H, t, J=7Hz), 7.95 (1H, s), 8.02 (2H, d, J=8.5Hz), 8.10 (2H, d, J=8.5Hz), 8.28 (1H, s), 10.18 (1H, s), 10.50 (1H, s) MASS (m/z) : 429 (M + ) 25 Preparation 92 N-[4-[4'-(3-Phenoxypropyloxy)phenyl]benzoyl]-N'-(4 methoxycarbonylbenzoyl)hydrazine IR (KBr) : 3210.9, 1724.0, 1650.8, 1602.6, 1560.1, 1523.5, 1502.3, 1469.5, 1432.9, 1284.4, 30 1247.7 cm - 1 NMR (DMSO-d 6 , 5) : 2.18-2.24 (2H, m), 3.90 (3H, s), 4.13-4.21 (4H, m), 6.95-6.99 (3H, m), 7.09 (2H, d, J=7.9Hz), 7.25-7.33 (2H, m), 7.69-7.81 (4H, m), 7.98-8.09 (6H, m), 10.61 (1H, s), 10.73 (1H, s) 35 MASS (m/z) : 525 (M + ) WO 99/40108 PCT/JP99/00538 85 Preparation 93 N-[4-(4'-Allyloxyphenyl)benzoyl]-N'-(4 methoxycarbonylbenzoyl)hydrazine IR (KBr) : 3228.3, 3023.8, 1724.0, 1679.7, 1654.6, 5 1604.5, 1554.3, 1513.8, 1492.6, 1434.8 cm-1 NMR (DMSO-d 6 , 5) : 3.90 (3H, s), 4.64 (2H, d, J=5.1Hz), 5.26-5.47 (2H, m), 5.98-6.17 (1H, m), 7.08 (2H, d, J=8.7Hz), 7.72 (2H, d, J=8.7Hz), 7.80 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.5Hz), 8.05 (2H, d, 10 J=8.6Hz), 8.11 (2H, d, J=8.6Hz), 10.60 (1H, s), 10.72 (1H, s) MASS (m/z) : 431 (M + ) Preparation 94 N-[4-[4 '- (4-Phenoxybutyloxy)phenyl]benzoyl]-N'-(4 15 methoxycarbonylbenzoyl)hydrazine IR (KBr) : 3228.3, 1724.0, 1679.7, 1654.6, 1602.6 cm-1 NMR (DMSO-d 6 , 5) : 1.90 (4H, br s), 3.90 (3H, s), 4.05-4.11 (4H, m), 6.88-6.96 (3H, m), 7.05-7.09 (2H, 20 m), 7.25-7.28 (2H, m), 7.69-8.09 (10H, m), 10.60 (1H, s), 10.72 (1H, s) Preparation 95 N-[4-[4'-[3-(2,6-Dimethylmorpholino)propyloxy] phenyl]benzoyl] -N'-(4-methoxycarbonylbenzoyl)hydrazine 25 IR (KBr) : 1720.2, 1681.6, 1645.0, 1604.5 cm - 1 NMR (DMSO-d 6 , 5) : 1.05 (6H, d, J=6.3Hz), 1.53-1.64 (2H, m), 1.87-1.93 (2H, m), 2.41 (2H, t, J=7.1Hz), 2.76 (2H, d, J=10.4Hz), 3.52-3.59 (2H, m), 3.90 (3H, s), 4.00-4.10 (2H, m), 7.05 (2H, d, J=8.7Hz), 7.71 30 (2H, d, J=8.7Hz), 7.79 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.6Hz), 8.02-8.13 (4H, m), 10.60 (1H, s), 10.72 (1H, s) MASS (m/z) : 546 (M ) Preparation 96 35 N-[6- (1-Piperidyl)nicotinoyl]-N'- (4-methoxycarbonyl- WO 99/40108 PCT/JP99/00538 86 benzoyl)hydrazine IR (KBr) : 3240, 2933, 2852, 1724, 1686, 1643, 1603, 1547, 1497, 1437 cm-1 NMR (DMSO-d 6 , 5) : 1.4-1.7 (6H, m), 3.6-3.7 (4H, m), 5 3.90 (3H, s), 6.92 (1H, d, J=9.0Hz), 7.9-8.2 (5H, m), 8.65 (1H, s), 10.34 (1H, s), 10.62 (1H, s) MASS (m/z) : 383 (M+1) The following compounds [Preparations 97 to 108] were obtained in a manner similar to that of Preparation 11. 10 Preparation 97 4-[5-[4 '-[4"-(8-Methoxy-n-octyloxy)phenyl] phenyl] 1,3,4-oxadiazol-2-yl]benzoic acid NMR (DMSO-d 6 , 5) : 1.20-1.60 (10H, m), 1.60-1.80 (2H, m), 3.21 (3H, s), 3.25-3.50 (3H, m), 3.90-4.10 (2H, 15 m), 6.95-7.10 (2H, m), 7.50-7.80 (4H, m), 7.80-8.00 (2H, m), 8.10-8.30 (4H, m) MASS (m/z) : 501 (M + ) Preparation 98 4-[5-[4'-(4"-Methoxyphenyl)phenyl]-1,3,4-oxadiazol-2 20 yl]benzoic acid IR (KBr) : 2960, 2904, 2839, 2675, 2543, 1684, 1604 cm - I NMR (DMSO-d 6 , 5) : 3.83 (3H, s), 7.08 (2H, d, J=8.5Hz), 7.91 (2H, d, J=8.5Hz), 8.17 (2H, d, J=8.5Hz), 8.20 25 (2H, d, J=8.5Hz), 8.28 (2H, d, J=8.5Hz) MASS (m/z) : 373 (M ++l) Preparation 99 4-[5-[4'-(4"-Butyloxyphenyl)phenyl]-1,3,4-oxadiazol 2-yl]benzoic acid 30 IR (KBr) : 2958, 2935, 2871, 1687 cm

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1 NMR (DMSO-d 6 , 5) : 0.95 (3H, t, J=7.3Hz), 1.46 (2H, qt, J=7.3 and 7.5Hz), 1.73 (2H, tt, J=7.5 and 6.3Hz), 4.04 (2H, t, J=6.3Hz), 7.07 (2H, d, J=8.9Hz), 7.75 (2H, d, J=8.9Hz), 7.91 (2H, d, J=8.4Hz), 8.16 (2H, 35 d, J=8.3Hz), 8.20 (2H, d, J=8.3Hz), 8.28 (2H, d, WO 99/40108 PCT/JP99/00538 87 J=8.4Hz) MASS (m/z) : 415 (M+1) Preparation 100 4-[5-[4'-(4"-Pentyloxyphenyl)phenyl]-1,3,4-oxadiazol 5 2-yl]benzoic acid IR (KBr) : 2958, 2933, 2865, 2673, 2546, 1685 cm

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1 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.0Hz), 1.40 (4H, m), 1.75 (2H, tt, J=6.6 and 6.6Hz), 4.04 (2H, t, J=6.6Hz), 7.07 (3H, d, J=8.8Hz), 7.74 (2H, d, 10 J=8.8Hz), 7.91 (2H, d, J=8.5Hz), 8.15 (2H, d, J=8.4Hz), 8.20 (2H, d, J=8.1Hz), 8.27 (2H, d, J=8.5Hz) MASS (m/z) : 429 (M+1) Preparation 101 15 4-[5-[4'-(4"-Hexyloxyphenyl)phenyl]-1,3,4-oxadiazol 2-yl]benzoic acid IR (KBr) : 2954, 2933, 2864, 2675, 2546, 1686 cm

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1 NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.8Hz), 1.30 (6H, m), 1.74 (2H, tt, J=7.7and6.4Hz), 4.04 (2H, t, J=6.4Hz), 20 7.07 (2H, d, J=8.8Hz), 7.74 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.0Hz), 8.16 (2H, d, J=8.6Hz), 8.20 (2H, d, J=8.0Hz), 8.27 (2H, d, J=8.6Hz) MASS (m/z) : 433 (M +1) Preparation 102 25 4-[5-[4'-(4"-n-Heptyloxyphenyl)phenyl]-1,3,4 oxadiazol-2-yl]benzoic acid IR (KBr) : 2956, 2931, 2856, 2671, 2545, 1686 cm - 1 MASS (m/z) : 457 (M+1) Preparation 103 30 4-[5- (1-n-Decylpyrazol-4-yl)-1,3,4-oxadiazol-2-yl] benzoic acid NMR (DMSO-d 6 , 5) : 0.75-0.95 (3H, m), 1.23 (14H, br s), 1.83 (2H, br s), 3.33 (1H, br s, CO 2 H), 4.22 (2H, t, J=6.8Hz), 8.14 (1H, s), 8.17 (4H, s), 8.65 (1H, 35 s) WO 99/40108 PCT/JP99/00538 88 MASS (m/z) : 397 (M + ) Preparation 104 4-[5- [1-n-Decylpyrazol-4-yl]-1,3,4-thiadiazol-2-yl] benzoic acid 5 NMR (DMSO-d 6 , 5) : 0.80-0.90 (3H, m), 1.23 (14H, br s), 1.70-1.90 (2H, m), 3.34 (1H, br s), 4.19 (2H, t, J=6.9Hz), 8.08 (1H, s), 8.10 (4H, s), 8.58 (1H, s) Preparation 105 4-[5-[4'-[4"-(3-Phenoxypropyloxy)phenyl]phenyl] 10 1,3,4-oxadiazol-2-yl]benzoic acid IR (KBr) : 1685.5, 1602.6, 1548.6, 1490.7, 1469.5, 1429.0, 1400.1, 1290.1, 1249.6 cm - I 1 NMR (DMSO-d 6 , 5) : 2.18-2.24 (2H, m), 4.13-4.25 (4H, m), 6.90-6.99 (3H, m), 7.11 (2H, d, J=8.8Hz), 15 7.26-7.33 (2H, m), 7.75 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.5Hz), 8.15-8.30 (6H, m), 13.20-13.60 (1H, br) MASS (m/z) : 493 (M + ) Preparation 106 4-[5-[4'-[4"-Allyloxyphenyll]phenyl]-1,3,4-oxadiazol 20 2-yl]benzoic acid IR (KBr) : 1685.5, 1652.7, 1604.5, 1577.5, 1548.6, 1488.8, 1429.0, 1288.2, 1253.5, 823.5 cm -1 NMR (DMSO-d 6 , 6) : 4.65 (2H, d, J=5Hz), 5.27-5.48 (2H, m), 5.99-6.15 (1H, m), 7.10 (2H, d, J=8.7Hz), 7.75 25 (2H, d, J=8.6Hz), 7.91 (2H, d, J=8.3Hz), 8.15-8.30 (6H, m), 12.38 (1H, br s) MASS (m/z) : 399 (M + ) Preparation 107 4-[5-[4'-[4"-(4-Phenoxybutyloxy)phenyl]phenyl]-1,3,4 30 oxadiazol-2-yl]benzoic acid IR (KBr) : 1733.7, 1697.1, 1650.8, 1602.6 cm -I NMR (DMSO-d 6 , 5) : 1.91 (4H, br s), 3.33 (1H, br s), 4.05-4.12 (4H, m), 6.88-6.96 (2H, m), 7.07-7.11 (2H, m), 7.25-7.28 (2H, m), 7.66-8.00 (5H, m), 8.14-8.36 35 (6H, m) WO 99/40108 PCT/JP99/00538 89 Preparation 108 4-[5-[4'-[4"-[3-(2,6-Dimethylmorpholino)propyloxy] phenyl]phenyl]-1,3,4-oxadiazol-2-yl]benzoic acid MASS (m/z) : 514 (M + ) 5 The following compounds [Preparations 109 to 123] were obtained in a manner similar to that of Preparation 13. Preparation 109 4-[5-[4'- (4"-Methoxyphenyl)phenyl] -1,3,4-oxadiazol-2 yl]benzoic acid benzotriazol-1-yl ester 10 IR (KBr) : 1782 cm-1 NMR (CDCl 3 , 5) : 3.89 (3H, s), 7.03 (2H, d, J=8.7Hz), 7.53 (3H, m), 7.62 (2H, d, J=8.7Hz), 7.76 (2H, d, J=8.4Hz), 8.13 (1H, d, J=8.2Hz), 8.23 (2H, d, J=8.4Hz), 8.41 (2H, d, J=8.4Hz), 8.48 (2H, d, 15 J=8.7Hz) MASS (m/z) : 490 (M+1) Preparation 110 4-[5-[4'-(4"-Butyloxyphenyl)phenyl]-1,3,4-oxadiazol 2-yl]benzoic acid benzotriazol-1-yl ester 20 IR (KBr) : 2956, 2933, 2872, 1776 cm-1 NMR (CDCl 3 , 5) : 1.00 (3H, t, J=7.3Hz), 1.52 (2H, qt, J=7.3 and 6.4Hz), 1.79 (2H, tt, J=6.4 and 6.4Hz), 4.04 (2H, t, J=6.4Hz), 7.02 (2H, d, J=8.7Hz), 7.45-7.57 (3H, m), 7.61 (2H, d, J=8.7Hz), 7.76 (2H, 25 d, J=8.4Hz), 8.14 (1H, d, J=8.2Hz), 8.22 (2H, d, J=8.4Hz), 8.40 (2H, d, J=8.7Hz), 8.47 (2H, d, J=8.7Hz) MASS (m/z) : 532 (M+1) Preparation 111 30 4-[5-[4'-(4"-n-Pentyloxyphenyl)phenyl]-1,3,4 oxadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 2956, 2935, 2868, 1779 cm-1 NMR (CDCl 3 , 5) : 0.95 (3H, t, J=6.9Hz), 1.44 (4H, m), 1.77 (2H, m), 4.03 (2H, t, J=6.5Hz), 7.02 (2H, d, 35 J=8.7Hz), 7.45-7.57 (3H, m), 7.60 (2H, d, J=8.7Hz), WO 99/40108 PCT/JP99/00538 90 7.75 (2H, d, J=8.4Hz), 8.14 (1H, d, J=8.2Hz), 8.22 (2H, d, J=8.4Hz), 8.22 (2H, d, J=8.4Hz), 8.40 (2H, d, J=8.7Hz), 8.47 (2H, d, J=8.7Hz) MASS (m/z) : 546 (M+1) 5 Preparation 112 4-[5-[4'-(4"-n-Hexyloxyphenyl)phenyl] -1,3,4 oxadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 2953, 2931, 2866, 1776 cm

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1 NMR (CDC1 3 , 5) : 0.92 (3H, t, J=6.7Hz), 1.36-1.49 (6H, 10 m), 1.82 (2H, m), 4.03 (2H, t, J=6.5Hz), 7.02 (2H, d, J=8.8Hz), 7.45-7.57 (3H, m), 7.61 (2H, d, J=8.8Hz), 7.76 (2H, d, J=8.4Hz), 8.14 (2H, d, J=8.2Hz), 8.22 (2H, d, J=8.4Hz), 8.41 (2H, d, J=8.8Hz), 8.48 (2H, d, J=8.8Hz) 15 MASS (m/z) : 560 (M+1) Preparation 113 4-[5-[4'-(4"-n-Heptyloxyphenyl)phenyl]-1,3,4 oxadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 2954, 2929, 2856, 1776 cm - 1 20 NMR (CDC1 3 , 5) : 0.91 (3H, m), 1.34 (8H, m), 1.75 (2H, m), 4.03 (2H, t, J=6.5Hz), 7.02 (2H, t, J=8.7Hz), 7.47-7.57 (3H, m), 7.61 (2H, d, J=8.7Hz), 7.76 (2H, d, J=8.3Hz), 8.14 (1H, d, J=8.2Hz), 8.22 (2H, d, J=8.3Hz), 8.41 (2H, d, J=8.5Hz), 8.48 (2H, d, 25 J=8.5Hz) MASS (m/z) : 574 (M++1) Preparation 114 4-[5- (1-n-Decylpyrazol-4-yl)-1,3,4-oxadiazol-2-yl] benzoic acid benzotriazol-1-yl ester 30 IR (KBr) : 1783.8, 1623.8, 1234.2, 989.3 cm-1 NMR (CDC1 3 , 5) : 0.84-0.91 (3H, m), 1.26-1.34 (14H, m), 1.80-2.00 (2H, m), 4.23 (2H, t, J=7.1Hz), 7.44-7.63 (3H, m), 8.11-8.15 (3H, m), 8.35 (2H, d, J=8.7Hz), 8.45 (2H, d, J=8.7Hz) 35 MASS (m/z) : 514 (M + ) WO 99/40108 PCT/JP99/00538 91 Preparation 115 4-[5- (1-n-Decylpyrazol-4-yl)-1,3,4-thiadiazol-2-yl] benzoic acid benzotriazol-1-yl ester IR (KBr) : 1776.1, 1575.6, 1234.2, 983.5 cm

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1 5 NMR (CDCl 3 , 5) : 0.84-0.91 (3H, m), 1.26-1.34 (14H, m), 1.94 (2H, br s), 4.21 (2H, t, J=7.1Hz), 7.43-7.63 (3H, m), 7.99 (1H, s), 8.09 (1H, s), 8.10-8.15 (1H, m), 8.22 (2H, d, J=8.5Hz), 8.40 (2H, d, J=8.5Hz) MASS (m/z) : 530 (M + ) 10 Preparation 116 4-[5-[4'-[4"-(3-Phenoxypropyloxy)phenyl] phenyl] 1,3,4-oxadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 1778.0, 1602.6, 1490.7, 1471.4, 1238.1 cm

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1 15 NMR (CDC1 3 , 5) : 2.27-2.34 (2H, m), 4.16-4.26 (4H, m), 6.91-7.05 (5H, m), 7.26-7.33 (2H, m), 7.44-7.62 (5H, m), 7.74 (2H, d, J=7.9Hz), 8.13 (1H, d, J=8.5Hz), 8.21 (2H, d, J=7.9Hz), 8.37-8.48 (4H, m) MASS (m/z) : 610 (M + ) 20 Preparation 117 4-[5-[4'-[4"-Allyloxyphenyl]phenyl] -1,3,4-oxadiazol 2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 1776.1, 1602.6, 1488.9, 1232.3 cm - 1 NMR (CDC1 3 , 5) : 4.61 (2H, d, J=5.2Hz), 5.30-5.50 (2H, 25 m), 6.00-6.19 (1H, m), 7.04 (2H, d, J=8.7Hz), 7.44-7.63 (4H, m), 7.75 (2H, d, J=8.4Hz), 8.11-8.30 (4H, m), 8.38-8.49 (4H, m) MASS (m/z) : 516 (M + ) Preparation 118 30 4-[5-[4'-[4"-(4-Phenoxybutyloxy)phenyl]phenyl]-1,3,4 oxadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 1776.1 cm - 1 NMR (CDC1 3 , 5) : 2.02 (4H, br s), 4.06-4.11 (4H, m), 6.83-7.04 (5H, m), 7.26-7.33 (1H, m), 7.48-7.63 (6H, 35 m), 7.76 (2H, d, J=8.4Hz), 8.14 (1H, d, J=8.2Hz), WO 99/40108 PCT/JP99/00538 92 8.22 (2H, d, J=8.3Hz), 8.41 (2H, d, J=8.7Hz), 8.48 (2H, d, J=8.7Hz) MASS (m/z) : 624 (M + ) Preparation 119 5 4-[5-[4'-[4"-(8-Methoxy-n-octyloxy)phenyl]phenyl] 1,3,4-oxadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 2931.3, 2856.1, 1776.1 cm

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1 NMR (CDCl 3 , 6) : 1.30-1.70 (10H, m), 1.70-1.90 (2H, m), 3.34 (3H, s), 3.38 (2H, t, J=6.4Hz), 4.02 (2H, t, 10 J=6.5Hz), 7.02 (2H, d, J=8.7Hz), 7.45-7.63 (5H, m), 7.76 (2H, d, J=8.5Hz), 8.12-8.31 (3H, m), 8.41 (2H, d, J=8.8Hz), 8.48 (2H, d, J=8.8Hz) MASS (m/z) : 618 (M + ) Preparation 120 15 4-[5-[4'-(4-Phenoxybutyloxy)phenyl]-1,3,4-thiadiazol 2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 3058.5, 2956.3, 2873.4, 1778.0, 1602.6, 1236.1 cm NMR (CDC1 3 , 5) : 2.0-2.1 (4H, m), 4.0-4.2 (4H, m), 20 6.9-7.0 (3H, m), 7.03 (2H, d, J=8.8Hz), 7.3-7.4 (2H, m), 7.4-7.6 (3H, m), 7.99 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.2Hz), 8.25 (2H, d, J=8.6Hz), 8.42 (2H, d, J=8.6Hz) MASS (m/z) : 564 (M+1) 25 Preparation 121 4-[5-[4'-(5-Phenoxy-n-pentyloxy)phenyl]-1,3,4 thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) : 2946.7, 2871.5, 1785.8, 1600.6, 1255.4, 1234.2 cm -I 30 NMR (CDC1 3 , 6) : 1.5-2.1 (6H, m), 3.9-4.2 (4H, m), 6.8-7.1 (5H, m), 7.2-7.4 (2H, m), 7.4-7.7 (3H, m), 7.98 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.2Hz), 8.25 (2H, d, J=8.6Hz), 8.41 (2H, d, J=8.6Hz) MASS (m/z) : 578 (M+1) 35 Preparation 122 WO 99/40108 PCT/JP99/00538 93 4- [5- [4'- (5-Methoxy-n-pentyloxy)phenyl]-1,3,4 thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester NMR (CDCl 3 , 5) : 1.5-2.1 (6H, m), 3.54 (3H, s), 3.43 (2H, t, J=6.1Hz), 4.06 (2H, t, J=6.3Hz), 7.02 (2H, 5 d, J=8.8Hz), 7.4-7.7 (3H, m), 7.98 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.2Hz), 8.25 (2H, d, J=8.5Hz), 8.41 (2H, d, J=8.5Hz) MASS (m/z) : 516 (M ++1) Preparation 123 10 4-Cyclohexyloxybenzoic acid benzotriazol-1-yl ester IR (KBr) : 2939, 2854.1, 1776.1, 1602.6, 1508.1 cm-1 NMR (CDCl 3 , 5) : 1.25-1.67 (6H, m), 1.85 (2H, m), 2.01 (2H, m), 4.43 (1H, m), 7.03 (2H, d, J=7.0Hz), 7.38-7.54 (3H, m), 8.08 (1H, d, J=8.2Hz), 8.19 (2H, 15 d, J=7.0Hz) MASS (m/z) : 338 (M +1) Preparation 124 To a solution of 4-methoxybenzoic acid benzotriazol-1-yl ester (80 g) in N,N-dimethylformamide (700 ml) was added 20 thiosemicarbazide (28 g) and the mixture was stirred for 23 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-methoxybenzoyl)-3 thiosemicarbazide (57 g). 25 Preparation 125 To a slurry of 1- (4-methoxybenzoyl) -3-thiosemicarbazide (57 g) in toluene (300 ml), was addedmethanesulfonic acid (25 ml) dropwise over 30 minutes at 40 0 C. The mixture was stirred under refluxing for 24 hours. After cooling to 10 0 C, the 30 sulfonate salt was filtered and dried. The salt was placed in water, and the solution was adjusted to pH 9 with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2-amino-5 35 (4-methoxyphenyl)-1,3,4-thiadiazole (31.1 g).

WO 99/40108 PCT/JP99/00538 94 IR (KBr) : 3251, 3114.5, 1610.3, 1525 cm -I 1 NMR (DMSO-d 6 , 6) : 3.80 (3H, s), 7.00 (2H, d, J=8.5Hz), 7.28 (2H, s), 7.69 (2H, d, J=8.5Hz) MASS (m/z) : 208 (M+H') 5 Preparation 126 A mixture of 4-bromobenzenethiol (6 g), 1,7 dibromoheptane (16.37 g), and potassium carbonate (8.77 g) in dimethylformamide (30 ml) was stirred at room temperature for 5.5 hours. The reaction mixture was pulverized with water and 10 extractedwith ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-bromo-4-(7 bromoheptylthio)benzene (7.62 g). IR (KBr) : 1465.6, 1089.6, 800.3 cm

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1 15 NMR (CDC1 3 , 5) :1.37-1.88 (10H,m), 2.89 (2H, t, J=7.2Hz), 3.40 (2H, t, J=6.8Hz), 7.14-7.21 (2H, m), 7.36-7.43 (2H, m) Preparation 127 To a solution of 1-bromo-4- (7-bromoheptylthio)benzene (5 20 g) in methanol (25 ml) was added 28% sodium methylate in methanol (7.9 g) and the mixture was stirred under refluxing for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue was adjusted to pH 2 with dilute HCl aq. and extracted with ethyl acetate. The organic layer was 25 separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with n hexane/ethyl acetate (50:1) to give 1-bromo-4-(7 methoxyheptylthio)benzene (3.59 g). 30 IR (KBr) : 1471.4, 1118.5, 1093.4 cm

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1 NMR (CDC1 3 , 6) :1.30-1.67 (10H, m), 2.88 (2H, t, J=7.3Hz), 3.33 (3H, s), 3.36 (2H, t, J=6.2Hz), 7.13-7.20 (2H, m), 7.35-7.42 (2H, m) MASS (m/z) : 317.1 WO99/40108 PCT/JP99/00538 95 Preparation 128 To a solution of 4-(4-chlorophenyl)-4-hydroxypiperidine (5.0 g) in dichloromethane (50 ml) was added di-tert-butyl dicarbonate (5.7 g). After stirring for 5 hours at room 5 temperature, the solvent was evaporated in vacuo and the residue was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica 10 gel eluting with a mixture of hexane and ethyl acetate (3:1) The eluted fractions containing the desired product were collected and evaporated in vacuo to give 1-tert butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxypiperidine (7.58 g). 15 IR (Film) : 2976, 2926, 1668 cm-1 NMR (CDC1 3 , 6) : 1.47 (9H, s), 1.6-1.8 (3H, m), 1.9-2.1 (2H, m), 3.1-3.3 (2H, m), 3.9-4.1 (2H, m), 7.2-7.5 (4H, m) (+) APCI MS : 212 (M+H)+-101 20 Preparation 129 To a solution of 1-tert-butoxycarbonyl-4-(4 chlorophenyl)-4-hydroxypiperidine (1.0 g) in N,N-dimethyl formamide (10 ml) was added sodium hydride (0.14 g) under ice cooling. Then the reaction mixture was stirred for 30 minutes 25 at room temperature and for 2 hours at 60 0 C. To the reaction mixture was addediodomethane (4.0ml) at 60 0 C. After stirring for 6 hours at 60 0 C, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium 30 sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 1-tert-butoxycarbonyl-4-(4 35 chlorophenyl)-4-methoxypiperidine (0.75 g).

WO 99/40108 PCT/JP99/00538 96 IR (Film) : 2976, 2935, 1680 cm-1 NMR (CDCl 3 , 6) : 1.47 (9H, s), 1.7-2.1 (4H, m), 2.97 (3H, s), 3.0-3.3 (2H, m), 3.9-4.1 (2H, m), 7.2-7.4 (4H, m) 5 (+) APCI MS : 226 (M+H)+-101 Preparation 130 To a solution of 2-indanol (4 g) and triethylamine (5.8 ml) indichloromethane (40ml) was addeddropwisewithstirring methanesulfonylchloride (2.8 ml) in an ice-bath. The mixture 10 was then stirred for 1.5 hours. The reactionmixture was added to a mixture of water and dichloromethane. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give methanesulfonic acid indan 15 2-yl ester (6.29 g). IR (KBr) : 3029.6, 1328.7, 1162.9 cm-1 NMR (CDCl 3 , 5) : 3.02 (3H, s), 3.19-3.44 (4H, m), 5.48-5.58 (1H, m), 7.18-7.28 (4H, m) MASS(m/z) : 119.2(M-OMs+l) 20 Preparation 131 To a solution of 4-(5-amino-1,3,4-thiadiazol-2 yl)benzoic acid methyl ester trifluoroacetic acid salt (8 g) in water was added 1N sodium hydroxide and the mixture was adjusted to pH 8. The precipitate was collected by filtration 25 to give 4-(5-amino-l,3,4-thiadiazol-2-yl)benzoic acid (5.05 g). Preparation 132 A mixture of 1-(4-nitrophenyl)-1H-pyrazol-4-carboxylic acid methyl ester (19.44 g), Fe powder, NH 4 Cl, methanol and 30 H 2 0 was heated for 30 minutes at 80 0 C and 3 hours at 100 0 C. The reaction mixture was concentrated by evaporation, added into dichloromethane, and was filtered. The filtrate was extracted with water, dried over magnesium sulfate and concentrated by evaporation to give 1-(4-aminophenyl)-1H 35 pyrazol-4-carboxylic acid methyl ester (9.84 g).

WO 99/40108 PCT/JP99/00538 97 IR (KBr) : 1701, 1521, 1248 cm-1 NMR (CDCl 3 , 6) : 3.86 (2H, brs), 3.90 (3H, s),6.75 (2H, d, J=8.8Hz), 7.45 (2H, d, J=8.8Hz), 8.05 (1H, s), 8.26 (1H,s) 5 MASS (m/z) : 218(M+1) Preparation 133 Amixture of 1- (4-formylphenyl) -1H-pyrazol-4-carboxylic acid methyl ester (1.00 g), methanol (10 ml) and tetrahydrofuran (25 ml) was treated with sodium borohydride 10 at 00C. After 15 minutes, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated by evaporation to give 1-(4-hydroxymethylphenyl)-1H-pyrazol 4-carboxylic acid methyl ester (1.04 g). 15 IR (KBr) : 1724, 1558, 1521, 1443, 1392, 1255 cm-1 NMR (CDCl 3 , 5) : 3.88 (3H, s), 4.76 (2H, s), 7.48 (2H, d, J=8.7Hz), 7.69 (2H, d, J=8.7Hz), 8.10 (1H, s), 8.41 (1H,s) MASS (m/z) : 233(M+1) 20 Preparation 134 A solution of 1-(4-formylphenyl)-1H-pyrazol-4 carboxylic acid methyl ester (5.0 g) in dichloromethane (100 ml) was treated with 3-chloroperbenzoic acid for 5 minutes at room temperature. The solution was heated at 500C for 4 hours, 25 during which period additional 3-chloroperbenzoic acid (1.87 g) was added. After concentration, methanol (150 ml) and potassium carbonate (9.00 g) were added to the residue, and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was poured into water, adjusted to pH 8 30 with IN HCl and the resulting precipitate was collected by filtration to give 1-(4-hydroxyphenyl)-1H-pyrazol-4 carboxylic acid methyl ester (0.51 g). IR (KBr) : 1718, 1691, 1554, 1523, 1250 cm-1 NMR (CDC1 3 , 5) : 3.87 (3H, s), 6.92 (2H, d, J=9.0Hz), 7.55 35 (2H, d, J=9.0Hz), 8.07 (1H, s), 8.30 (1H,s) WO 99/40108 PCT/JP99/00538 98 MASS (m/z) : 219(M+1) Preparation 135 A solution of 4-(4-hydroxypiperidin-l-yl)benzoic acid ethyl ester (5.4 g), silver oxide (5.31 g) and 3 5 bromocyclohexene (3.24 ml) in tetrahydrofuran (52 ml) was stirred for 1 day at room temperature. The reaction mixture was filtered off, and the filtrate was concentrated by evaporation under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitate was collected by 10 filtration and dried. The residue was purified by silica gel chromatography (3:2 hexane-ethyl acetate elution) to give 4-[4-(2-cyclohexenyloxy)piperidin-1-yl]benzoic acid ethyl ester (3.84 g). NMR (CDCl 3 , 6) : 1.36 (3H, t, J=7.1Hz), 1.40-2.15 (10H, 15 m), 3.00-3.20 (2H, m), 3.50-3.75 (3H, m), 3.90-4.05 (1H, m), 4.32 (2H, q, J=7.1Hz), 5.60-5.90 (2H, m ), 6.86 (2H, d, J=9.1Hz), 7.90 (2H, d, J=9.1Hz) APCI MASS : 330(M++l) Preparation 136 20 To a solution of 4-[4-(2-cyclohexenyloxy)piperidin-1 yl]benzoic acid ethyl ester (3.82 g) in methanol (80 ml) was added 10% palladium on carbon (1.0 g), and hydrogen gas at atmosphere pressure for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated by evaporation 25 under reduced pressure to give 4- (4-cyclohexyloxypiperidin-1 yl)benzoic acid ethyl ester (2.38 g). NMR (CDC1 3 , 5) : 1.10-1.32 (4H, m), 1.36 (3H, t, J=7.1Hz), 1.40-2.00 (9H, m) , 2.90-3.15 (2H, m), 3.20-3.45 (1H, m), 3.50-3.75 (3H, m), 4.32 (2H, q, J=7.1Hz), 6.86 30 (2H, dd, J=2.2 and 9.1Hz), 7.85-8.00 (2H, m) APCI MASS (positive) : 332.3(M++1) Preparation 137 To a suspension of 4-[2-(4-methoxyphenyl)imidazo[2,1 b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester 35 trifluoroacetic acid salt (1.0 g) in dichloromethane (10 ml) WO 99/40108 PCT/JP99/00538 99 was added borone tribromide (1.0M solution in dichloromethane)(8.0 ml) at 0 0 C and the mixture was stirred at ambient temperature for 1 week. The reaction mixture was pulverized with cold water. The precipitate was collected by 5 filtration and dried to give 4-[2-(4-hydroxyphenyl)imidazo [2,1-b] [l,3,4]thiadiazol-6-yl]benzoic acid (893 mg). IR (KBr) : 3209, 1689.3, 1604.5, 1484.9 cm -1 NMR (DMSO-d 6 , 5) : 6.97 (2H, d, J=8.5Hz), 7.81 (2H, d, J=8.5Hz), 8.00 (4H, s), 8.84 (1H,s) 10 MASS (m/z) : 338(M+H + ) Preparation 138 To a solution of 5-(4-pentyloxyphenyl)-1,3,4 thiadiazol-2-yl-amine (20 g) in pyridine (200 ml) was added 4-methoxycarbonylbenzoylchloride (15 g) and the mixture was 15 stirred at ambient temperature for 2 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried to give N-[5-(4- pentyloxyphenyl)-1,3,4-thiadiazol-2-yl]lterephthalamic acid methyl ester (30.3 g). 20 IR (KBr) :2946, 2863, 1724, 1670, 1604, 1538, 1521, 1457, 1317, 1276, 1249, 1174, 1106 cm-1 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.0Hz), 1.2-1.5 (4H, m), 1.6-1.9 (2H, m), 3.90 (3H, s), 4.05 (2H, t, J=6.5Hz), 7.09 (2H, d, J=8.8Hz), 7.91 (2H, d, 25 J=8.8Hz), 8.12 (2H, d, J=8.4Hz), 8.25 (2H, d, J=8.4Hz), MASS (m/z) : 426(M+H + ) Preparation 139 To a solution of N-tert-butoxycarbonyl-4-piperidinone 30 (3.3 g) and 1-(4-cyclohexylphenyl)piperazine (4.0 g) in dichloromethane (20ml) was added titanium(IV) isopropoxide (8 ml) and the mixture was stirred at ambient temperature for 2 hours. Then, to the reaction mixture was added ethanol (20 ml) and sodiumcyanoborohydride (1 g) in several portions, the 35 reactionmixture was stirred at ambient temperature for2 hours.

WO 99/40108 PCT/JP99/00538 100 The reaction mixture was pulverized with water. The precipitate was filtered off and the filtrate was extracted with dichloromethane. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, 5 and the filtrate was evaporated under reduced pressure and chromatographed (Silica gel 60 (Trademark : prepared by Merck)) eluting with hexane/ethyl acetate to afford 1 tert-butoxycarbonyl-4-[4-(4-cyclohexylphenyl)piperazin-l yl]piperidine (1.35 g). 10 NMR (CDCl 3 , 5) : 1.3-1.6 (6H, m), 1.45 (9H, s), 1.6-2.0 (8H, m), 2.3-2.6 (2H, m), 2.6-3.0 (6H, m), 3.0-3.3 (4H, m), 4.17 (2H, d, J=13Hz), 6.86 (2H, d, J=8.7Hz), 7.11 (2H, d, J=8.7Hz) MASS (m/z) : 428(M+H + ) 15 Preparation 140 To a solution of 4-[4-[4-(4 cyclohexylphenyl)piperazin-1-yl ] piperidin-1 yl]benzonitrile (1.95 g) in acetic acid (10 ml) was added concentrated hydrogen chloride (20 ml) and the mixture was 20 stirred at 120 0 C for 10 hours. The reaction mixture was added to water and the resulting precipitate was collected by filtration to give 4-[4-[4-(4-cyclohexylphenyl)piperazin 1-yl]piperidin-1-yl]benzoic acid (959 mg). IR (KBr) : 3400, 2927, 2620, 2514, 1714, 1608, 1513, 1452, 25 1274, 1226, 1182, 1010 cm -1 NMR (DMSO-d 6 , 5) : 1.2-1.5 (5H, m), 1.6-1.9 (7H, m), 2.2 (2H, m), 2.4 (1H, m), 2.84 (2H, t, J=8.5Hz), 3.20 (4H, d, J=8.5Hz), 3.4-3.8 (5H, m), 4.08 (2H, d, J=12.5Hz), 6.93 (2H, d, J=8.8Hz), 7.03 (2H, d, 30 J=8.8Hz), 7.12 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.8Hz), 11.13 (1H, s) MASS (m/z) : 448(M+H + ) Preparation 141 Amixture of 1- (4-formylphenyl) -1H-pyrazol-4-carboxylic 35 acidmethyl ester (5.0 g), 1-phenylpiperazine (4.21g), acetic WO99/40108 PCT/JP99/00538 101 acid (3.7 ml), sodiumcyanoborohydride (1.55 g), methanol (110 ml), tetrahydrofuran (75 ml) and dichloromethane (20 ml) was stirred for 15 minutes at 0 0 C and for 14 hours at ambient temperature. The reaction mixture was poured into saturated 5 NaHCO 3 aqueous solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (1:1 hexane-ethyl acetate elution) and recrystallized from diisopropyl ether and acetone to give 10 1-[4-(4-phenylpiperazin-1-yl-methyl)phenyl]-H-pyrazol-4 carboxylic acid methyl ester (3.90 g). IR (KBr) : 1702, 1600, 1560, 1271 cm-1 NMR (DMSO-d 6 , 5) : 2.4-2.6 (4H, m), 3.14 (3H, t, J=4.8Hz), 3.58 (2H, s), 3.81 (3H, s), 6.76 (1H, t, J=7.2Hz), 15 6.91 (2H, d, J=7.8Hz), 7.20 (2H, t, J=7.8Hz), 7.48 (2H, t, J=8.6Hz), 7.90 (2H, d, J=8.6Hz), 8.15 (1H, s), 9.11 (1H, s) MASS (m/z) : 377(M+1) Preparation 142 20 To an ice-cooled solution of methyl 4-(4 hydroxyphenyl)benzoate (3.00 g) and N phenyltrifluoromethanesulfonide (4.84 g) in tetrahydrofuran (60 ml) was added triethylamine (1.98 ml), then the solution was stirred at this temperature for 1 hour and at ambient 25 temperature for further 18 hours. Water (200 ml) was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered and evaporated to give acrudeoil. This oil was purified on a silica gel column chromatography 30 eluting successively with the following solvents: (1)2.5% ethyl acetate in n-hexane, (2)5% ethyl acetate in n-hexane. The fractions containing the object compound were concentrated to give methyl 4-(4-trifluoromethanesulfonyloxyphenyl) benzoate (5.30 g) as a white solid. 35 IR (KBr) : 1713, 1691, 1606, 1522, 1495, 1420 cm-1 WO 99/40108 PCT/JP99/00538 102 NMR (CDCl 3 , 5) : 3.95 (3H, s), 7.31-7.46 (2H, m), 7.56-7.75 (4H, m), 8.08-8.20 (2H, m) MASS (m/z) : 361(M+1) Preparation 143 5 To a suspension of 4-piperazin-1-yl-benzoic acid ethyl ester dihydrochloride (1 g) and potassium bicarbonate (1.57 g) in acetonitrile (10 ml) was added methanesulfonic acid indane-2-yl ester (0.69 g) and the mixture was stirred under refluxing for 8 hours. The reaction mixture was pulverized 10 with water. The precipitate was collected by filtration and dried over under reduced pressure. The powder was purified by column chromatography on silica gel using methanol/dichloromethane (50:1) as the eluent to give 4 (4-indan-2-yl-piperazin-1-yl)benzoic acid ethyl ester (0.38 15 g). IR (KBr) : 1697.1, 1606.4, 1349.9, 1238.1 cm -I 1 NMR (CDC1 3 , 5) : 1.37 (3H, t, J=7.1Hz), 2.67-2.72 (4H, m), 2.88-3.40 (9H, m), 4.33 (2H, q, J=7.1Hz), 6.85-6.90 (2H, m), 7.12-7.23 (4H, m), 7.91-7.96 (2H, 20 m) MASS (m/z) : 351.3(M+l) Preparation 144 To a solution of 2-amino-4'-bromoacetophenone hydrochloride (5.0 g), 4-heptyloxybenzoic acid (4.72 g) and 25 1-hydroxybenzotriazole (2.7 g) in dichloromethane (50 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSCD)(3.65 ml) and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was diluted with dichloromethane (200 ml), and washed with water, 1N 30 hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in ethyl acetate and collected by 35 filtration to give 2-(4-heptyloxybenzoylamino)-4'- WO 99/40108 PCT/JP99/00538 103 bromoacetophenone (6.73 g). IR (KBr) : 3318.9, 2937.1, 2858.0, 1699.0, 1639.2, 1556.3, 1508.1, 1255.4 cm-1 NMR (CDCl 3 , 5) : 0.80-1.10 (3H, m), 1.20-1.60 (8H, m), 5 1.75-1.95 (2H, m), 4.01 (2H, t, J=6.5Hz), 4.91 (2H, d, J=4.2Hz), 6.94 (2H, d, J=8.8Hz), 7.14 (1H, brs), 7.67 (2H, d, J=8.6Hz), 7.83 (2H, d, J=8.8Hz), 7.90 (2H, d, J=8.6Hz) APCI-MS (m/z) : 432, 434 10 Preparation 145 A solution of 2-(4-heptyloxyphenyl)-5-(4 bromophenyl)thiazole (2.06 g) in dry tetrahydrofuran (60 ml) was cooled to -60 0 C, and a solution of n-butyllithium (1.56M inn-hexane, 4.05ml) was added slowly to maintain the reaction 15 temperature at -60 0 C. After stirring for 1 hour, dry-ice (4 g) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes. To the reaction mixture was added water (20ml) and0.5Nhydrochloricacid (80ml), then extracted with dichloromethane (700 ml). The organic layer was washed 20 with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in acetonitrile and collected by filtration to give 4-[5-(4 heptyloxyphenyl)thiazol-2-yl]benzoic acid (1.68 g). 25 IR (KBr) : 2929.3, 2856.1, 2674.8, 2549.4, 1683.6, 1604.5, 1432.9, 1297.9, 1253.5 cm-1 NMR (DMSO-d 6 , 5) : 0.70-1.00 (3H, m), 1.10-1.60 (8H, m), 1.60-1.90 (2H, m), 4.04 (2H, t, J=6.4Hz), 7.07 (2H, d, J=8.7Hz), 7.83 (2H, d, J=8.2Hz), 7.91 (2H, d, 30 J=8.7Hz), 8.00 (2H, d, J=8.2Hz), 8.39 (1H, s) APCI-MS (m/z) : 396 The following compound was obtained in a manner similar to that of Preparation 19. Preparation 146 35 N-[4-[5-(4-Pentyloxyphenyl)-1,3,4-thiadiazol-2- WO 99/40108 PCT/JP99/00538 104 yl]benzoyl]-N' - (4-methoxycarbonylbenzoyl)hydrazine NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=6.9Hz), 1.28-1.52 (4H, m), 1.68-1.86 (2H, m), 3.91 (3H, s), 4.08 (2H, t, J=6.5Hz), 7.14 (2H, d, J=8.8Hz), 7.98 (2H, d, 5 J=8.8Hz), 8.01-8.24 (8H, m), 10.82 (2H, s) MASS (m/z) : 545 (MW+1) Preparation 147 To a solution of 1-tert-butoxycarbonyl-4-(4 10 chlorophenyl)-4-methoxypiperidine (0.72 g) in ethyl acetate (10 ml) was added 4N HCl in ethyl acetate (5.5 ml). After stirring for 6.7 hours, the reaction mixture was poured into a mixture of ethyl acetate and water, followed by alkalification of the solution to pH 12. The organic layer 15 was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated invacuo to give 4-(4-chlorophenyl)-4-methoxypiperidine (0.39 g). IR (Film) : 2943, 2827, 1541 cm-1 MR (CDC1 3 , 5) : 1.7-2.1 (4H, m), 2.17 (1H, s), 2.9-3.2 20 (7H, m), 7.33 (4H, s) The following compound was obtained in a manner similar to that of Preparation 147. Preparation 148 1-[4-(5-Methoxypentyloxy)biphenyl-4-yl]piperazine 25 dihydrochloride IR (KBr) : 2940.9, 2508.9, 1498.4, 1249.6 cm-1 NMR (CDCl 3 , 5) : 1.51-1.83 (6H, m), 3.34 (3H, s), 3.40 (2H, t, J=6.2Hz), 3.93 (2H, t, J=6.4Hz), 4.00-4.40 (8H, m), 6.84-6.89 (2H, m), 7.36-7.40 (2H, m), 30 7.58-7.62 (2H, m), 7.87-7.92 (2H, m), 9.90-10.15 (1H, m) MASS (m/z) : 355 (M+I) Preparation 149 To a solution of 4-hydroxyacetophenone (10 g) and 35 pyridiniumhydrobromide perbromide (23.5 g) in acetic acid (80 WO99/40108 PCT/JP99/00538 105 ml) was addedhydrogenbromide (30% in acetic acid solution) (40 ml) and the mixture was stirred overnight at ambient temperature. The reaction mixture was added to ice water and extracted with ethyl acetate. The organic layer was taken and 5 dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to afford 2-bromo-1-(4-hydroxyphenyl)ethanone (1.72 g). NMR (CDCl 3 , 6) : 4.40 (2H, s), 5.78 (1H, s), 6.92 (2H, d, J=8.8Hz), 7.94 (2H, d, J=8.8Hz) 10 MASS (m/z) : 217 (M+H ) The following compound was obtained in a manner similar to that of Preparation 149. Preparation 150 2-Bromo-1-(4-pentyloxyphenyl)ethanone 15 NMR (CDC1 3 , 5) : 0.94 (3H, t, J=6.8Hz), 1.3-1.5 (4H, m), 1.82 (2H, q, J=6.8Hz), 4.03 (2H, t, J=6.8Hz), 4.40 (2H, s), 6.94 (2H, d, J=9.0Hz), 7.96 (2H, d, J=9.0Hz) MASS (m/z) : 287 (M+H ) Preparation 151 20 A solution of l-(4-aminophenyl)-1H-pyrazol-4-carboxylic acidmethyl ester (3.0 g) inN,N-dimethylformamide (30 ml) was treated with potassium carbonate (5.72 g), sodium iodide (4.14 g) and 1,5-dibromopentane, and the mixture was stirred for 20 hours at room temperature and 6 hours at 80 0 C, during which 25 period additional N,N-dimethylformamide (20 ml), 1.5 dibromopentane (1.14 g) andpotassium carbonate (0.95 g) were added. The reaction mixture was cooled to room temperature and poured into water. The precipitate was collected by filtration, dried over under reduced pressure. The residue 30 was purified by silica gel chromatography (dichloromethane elution) to give 1-(4-piperidylphenyl)-1H-pyrazol-4 carboxylic acid methyl ester (1.34 g). IR (KBr) : 1720, 1521, 1248 cm

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1 NMR (CDCl 3 , 6) : 1.5-1.8 (6H, m), 3.21 (4H, t, J=5.3Hz), 35 3.86 (3H, s), 6.98 (2H, d, J=9.1Hz), 7.53 (2H, d, WO 99/40108 PCT/JP99/00538 106 J=9.1Hz), 8.06 (1H, s), 8.29 (1H, s) MASS (m/z) : 286 (M++l) The following compound was obtained in a manner similar to that of Preparation 151. 5 Preparation 152 1-(4-Pyrrolidinylphenyl) -1H-pyrazol-4-carboxylic acid methyl ester IR (KBr) : 1720, 1541, 1525, 1246 cm-1 NMR (CDC1 3 , 5) : 2.0-2.1 (4H, m), 3.2-3.4 (4H, m), 3.86 10 (3H, s), 6.59 (2H, dd, J=6.9 and 2.1Hz), 7.49 (2H, dd, J=6.9 and 2.1Hz), 8.05 (1H, s), 8.25 (1H, s) MASS (m/z) : 294 (M++23) Preparation 153 To a suspension of cyclohexane-1-4-dicarboxylic acid 15 monomethyl ester (1.57 g) in thionyl chloride (3.14 ml) was added N,N-dimethylformamide (2 drops) and the mixture was stirred under refluxing for 1 hour. The reaction mixture was concentrated by evaporation under reduced pressure to give 4-chlorocarbonylcyclohexane carboxylic acid methyl ester 20 (1.78 g). NMR (CDCl 3 , 5) : 1.38-1.64 (4H, m), 2.09-2.32 (5H, m), 2.64-2.77 (1H, m), 3.68 (3H, s) Preparation 154 Thionyl chloride (8.47 ml) was addeddropwise to methanol 25 (54 ml) at 10 0 C. To the solution was added trans-1,4 cyclohexane dicarboxylicacid (4 g) and the mixture was stirred for 24 hours at ambient temperature. The reaction mixture was evaporated under reduced pressure to give cyclohexane-1,4 dicarboxylic acid dimethyl ester (4.68 g). 30 IR (KBr) : 1729.8, 1195.6 cm -1 NMR (CDCl 3 , 5) : 1.34-2.15 (8H, m), 2.23-2.34 (2H, m), 3.67 (6H, s) MASS (m/z) : 201 (M+1) The following compounds [Preparations 155 to 157] were 35 obtained in a manner similar to that of Preparation 154.

WO 99/40108 PCT/JP99/00538 107 Preparation 155 2,5-Dimethyl-terephthalic acid dimethyl ester IR (KBr) : 1722.1, 1261.2, 1101.2 cm-1 NMR (CDCl 3 , 5) : 2.57 (6H, s), 3.91 (6H, s), 7.76 (2H, 5 s) MASS (m/z) : 223 (M+1) Preparation 156 2,4-Hexendioic acid dimethyl ester IR (KBr) : 1702.8, 1612.2, 1249.6 cm-1 10 NMR (CDC1 3 , 5) : 3.71 (6H, s), 6.49 (2H, dd, J=3.1 and 11.5Hz), 7.40 (2H, dd, J=3.1 and 11.5Hz) MASS (m/z) : 171 (M+1) Preparation 157 Naphthalene-1,4-dicarboxylic acid dimethyl ester 15 NMR (CDCl 3 , 5) : 4.03 (6H, s), 7.65 (2H, q, J=3.3Hz), 8.09 (2H, s), 8.83 (2H, q, J=3.3Hz) MASS (m/z) : 245 (M+1) The following compounds [Preparations 158 to 162] were obtained in a manner similar to that of Preparation 153. 20 Preparation 158 5-Chlorocarbonylthiophene-2-carboxylic acid methyl ester IR (KBr) : 1724.0, 1666.2, 1251.6 cm - 1 NMR (CDCl 3 , 6) : 3.86 (3H, s), 7.73-7.87 (2H, m) 25 Preparation 159 4-Chlorocarbonyl-2, 5-dimethylbenzoic acid methyl ester IR (KBr) : 1756.8, 1718.3, 1220.7 cm - 1 NMR (CDCl 3 , 6) : 2.54 (3H, s), 2.60 (3H, s), 3.93 (3H, s), 7.78 (1H, s), 8.03 (1H, s) 30 Preparation 160 5-Chlorocarbonyl-2,4-pentenoic acid methyl ester IR (KBr) : 1745.3, 1714.4, 1243.9 cm-1 NMR (CDC1 3 , 6) : 3.70 (3H, s), 6.29-6.64 (2H, m), 7.24-7.64 (2H, m) WO 99/40108 PCT/JP99/00538 108 Preparation 161 4-Chlorocarbonylnaphtalene-1-carboxylic acid methyl ester IR (KBr) : 1762.6, 1724.0, 1257.4 cm-1 5 NMR (CDC1 3 , 5) : 3.98 (3H, s), 7.68-7.77 (2H, m), 8.14 (2H, s), 8.66-8.82 (2H, m) Preparation 162 6-Chlorocarbonylnaphtalene-2-carboxylic acid methyl ester 10 IR (KBr) : 1743.3, 1714.4, 1290.1 cm -1 NMR (CDC1 3 , 5) : 3.94 (3H, s), 8.04-8.08 (2H, m), 8.21-8.27 (2H, m), 8.68-8.71 (2H, m) Preparation 163 To a solution of 4-piperidin-1-yl-benzonitrile (3 g) and 15 thiosemicarbazide (1.8 g) in toluene (30 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred at 600C for 6 hours. The reaction mixture was placed in water, the solution was adjusted to pH 9 with 1N sodium hydroxide and the precipitate was collected by filtration to give 5-(4 20 piperidin-1-yl-phenyl)-[1,3,4]thiadiazol-2-yl-amine (3.58 g). IR (KBr) : 2933, 2838, 1604, 1502, 1463, 1386, 1349 1245, 1126, 1043, 821 cm - I 1 NMR (DMSO-d 6 , 5) : 1.57 (6H, m), 3.24 (4H, m), 6.96 (2H, 25 d, J=8.8Hz), 7.19 (2H, s), 7.54 (2H, d, J=8.8Hz) MASS (m/z) : 261 (M+H') The following compounds [Preparations 164 to 169] were obtained in a manner similar to that of Preparation 163. Preparation 164 30 5-(4-Morpholinylphenyl) -[1,3,4]thiadiazol-2-yl-amine IR (KBr) : 3274, 3106, 1604, 1508, 1465, 1378, 1324, 1267, 1238, 1122 cm -1 NMR (DMSO-d 6 , 5) : 3.19 (4H, t, J=4.8Hz), 3.74 (4H, t, J=4.8Hz), 7.00 (2H, d, J=8.8Hz), 7.22 (2H, s), 7.59 35 (2H, d, J=8.8Hz) WO 99/40108 PCT/JP99/00538 109 MASS (m/z) : 263 (M+H + ) Preparation 165 5-[4-(cis-2,6-Dimethylmorpholin-4-yl)phenyl] [1,3,4]thiadiazol-2-yl-amine 5 IR (KBr) :3272, 3106, 1608, 1525, 1469, 1376, 1346, 1245, 1176, 1145, 1081 cm-1 NMR (DMSO-d 6 , 5) : 1.16 (6H, d, J=6.2Hz), 2.31 (2H, t, J=11.5Hz), 3.6-3.8 (4H, m), 7.00 (2H, d, J=8.8Hz), 7.21 (2H, s), 7.58 (2H, d, J=8.8Hz) 10 MASS (m/z) : 291 (M+H ) Preparation 166 5-(4-Thiomorpholinophenyl)-[1,3,4]thiadiazol-2-yl amine IR (KBr) : 3340, 3270, 3129, 1604, 1506, 1467, 1384, 1295, 15 1230, 1195 cm

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1 NMR (DMSO-d 6 , 5) : 2.64 (4H, t, J=5.0Hz), 3.66 (4H, t, J=5.0Hz), 6.97 (2H, d, J=8.8Hz), 7.21 (2H, s), 7.57 (2H, d, J=8.8Hz), MASS (m/z) : 279 (M+H') 20 Preparation 167 5-[4-(4-Ethylpiperazinylphenyl)]-[1,3,4]thiadiazol-2 yl-amine IR (KBr) : 3278, 3120, 2967, 2829, 1685, 1608, 1517, 1467, 1388, 1240, 1203, 1130 cm - 1 25 NMR (DMSO-d 6 , 5) : 1.04 (3H, t, J=7.2Hz), 2.41 (2H, q, J=7.2Hz), 2.51 (4H, m), 3.23 (4H, m), 6.99 (2H, d, J=8.8Hz), 7.21 (2H, s), 7.57 (2H, d, J=8.8Hz) MASS (m/z) : 290 (M+H ) Preparation 168 30 5-[4-(4-Cyclohexylpiperazinylphenyl) ] [1,3,4]thiadiazol-2-yl-amine IR (KBr) :3016, 2950, 2865, 1743, 1672, 1606, 1513, 1456, 1430, 1402, 1201, 1133 cm-1 NMR (DMSO-d 6 , 5) : 1.0-1.6 (5H, m), 1.63 (1H, d, J=10Hz), 35 1.85 (2H, d, J=10Hz), 2.09 (2H, d, J=10Hz), 2.8- WO 99/40108 PCT/JP99/00538 110 3.3 (5H, m), 3.55 (2H, m), 3.99 (2H, d, J=10Hz), 7.09 (2H, d, J=8.8Hz), 7.65 (2H, d, J=8.8Hz) MASS (m/z) : 344 (M+H ) Preparation 169 5 4-(5-Amino-[1,3,4]thiadiazol-2-yl)benzoic acid methyl ester trifluoroacetic acid salt IR (KBr) : 3004, 2746, 1726, 1675, 1645, 1608, 1436, 1284, 1211, 1186, 1137, 1112 cm-1 NMR (DMSO-d 6 , 5) : 3.88(3H, s), 7.19 (2H, s), 7.90 (2H, 10 d, J=8.5Hz), 8.04 (2H, d, J=8.5Hz) MASS (m/z) : 236 (M+H') Preparation 170 To a mixture of 4-methoxycarbonylphenylboronic acid (2.01 g) and 1-bromo-4-ethoxymethylbenzene (2.00 g) in amixed 15 solvent of ethylene glycoldimethyl ether (20ml) and2Maqueous sodium carbonate solution (6 ml) was added tetrakis(triphenylphosphine)palladium (0) (0.54 g). The mixture was heated at 80 0 C for 5 hours. After cooling to room temperature, water (150 ml) was added to the reaction mixture 20 and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a crude solid. This solid was purified by column chromatography on silica gel (60 g) eluting successively with the following solvents: (1)n-hexane : ethyl acetate=50:l, (2) n-hexane : ethyl 25 acetate=10:1. The fractions containing the object compound were concentrated and dried to give methyl 4-(4' ethoxymethylphenyl)benzoate as a white solid (1.85 g). NMR (CDCl 3 , 5) : 1.27 (3H, t, J=7.0Hz), 3.58 (2H, q, J=7.0Hz), 3.94 (3H, m), 4.56 (2H, s), 7.44 (2H, d, 30 J=8.7Hz), 7.54-7.61 (4H, m), 8.04-8.15 (2H, m) The following compound was obtained in a manner similar to that of Preparation 170. Preparation 171 Methyl 4-[4'-(2-methoxyethoxymethyl)phenyl]benzoate 35 NMR (CDCl 3 , 5) : 3.41 (3H, m), 3.55-3.70 (4H, m), 3.94 WO 99/40108 PCT/JP99/00538 111 (3H, s), 4.63 (2H, s), 7.45 (2H, d, J=8.3Hz), 7.56-7.74 (4H, m), 8.07-8.20 (2H, m) MASS (m/z) : 301 (M+1) Preparation 172 5 To an ice-cooled solution of 4-bromobenzyl bromide (3.00 g) and 2-methoxyethanol (1.04 ml) in tetrahydrofuran (30 ml) was added sodium hydride (60%) (0.58 g) in a stream of nitrogen. The mixture was stirred at this temperature for 15 minutes and at room temperature for further 4 hours. To the mixture was 10 added water (1 ml) under ice-cooling. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 1-bromo-4- (2-methoxyethoxymethyl)benzene 15 (3.10 g) as a pale yellow oil. NMR (DMSO-d 6 , 5) : 3.25 (3H, m), 3.43-3.60 (2H, m), 4.46 (2H, s), 7.28 (2H, d, J=8.5Hz), 7.49-7.60 t4H, m) The following compounds [Preparations 173 to 175] were obtained in a manner similar to that of Preparation 172. 20 Preparation 173 Ethyl 4-(4-propoxypiperidin-1-yl)benzoate NMR (DMSO-d 6 , 5) : 0.87 (3H, t, J=7.4Hz), 1.28 (3H, t, J=7.1Hz), 1.36-1.60 (4H, m), 1.80-1.98 (2H, m), 3.00-3.20 (2H, m), 3.39 (2H, t, J=6.5Hz), 3.41-3.76 25 (3H, m), 4.23 (2H, q, J=7.1Hz), 6.97 (2H, d, J=9.1Hz), 7.76 (2H, d, J=9.0Hz) MASS (m/z) : 292 (M'+1) Preparation 174 Ethyl 4-(4-benzyloxypiperidin-1-yl)benzoate 30 NMR (DMSO-d 6 , 5) : 1.28 (3H, t, J=7.1Hz), 1.45-1.66 (2H, m), 1.85-2.02 (2H, m), 3.00-3.21 (2H, m), 3.55-3.78 (3H, m), 4.23 (2H, q, J=7.1Hz), 4.55 (2H, s), 6.98 (2H, d, J=9.1Hz), 7.23-7.43 (5H, m), 7.76 (2H, d, J=9.0Hz) 35 MASS (m/z) : 340 (M +1) WO 99/40108 PCT/JP99/00538 112 Preparation 175 1-(4-Heptyloxymethylphenyl) -1H-pyrazol-4-carboxylic acid methyl ester IR (KBr) : 1703, 1558, 1265 cm-1 5 NMR (DMSO-d 6 , 5) : 0.85 (3H, m), 1.1-1.6 (10H, m), 3.44 (2H, t, J=6.4Hz), 3.81 (3H, s), 4.49 (2H, s), 7.45 (2H, d, J=8.5Hz), 7.91 (2H, d, J=8.5Hz), 8.15 (1H, s), 9.11 (1H, s) MASS (m/z) : 331 (M++1) 10 Preparation 176 To a solution of methyl 4-(4-hydroxyphenyl)benzoate (3.00 g) and cyclohexanol (1.58 g) in tetrahydrofuran (60 ml) was added dropwise diethyl azodicarboxylate (2.48 ml) at 0-10 0 C under nitrogen atmosphere, and the mixture was stirred 15 at ambient temperature for 4 hours. After concentration, to the residue was added ethyl acetate (50 ml) and n-hexane (10 ml), and the resulting precipitate was removed by filtration and discarded. To the filtrate was added silica gel (12 g) and the mixture was evaporated. The residue was purified by 20 column chromatography on silica gel (80 g) elutingwith amixed solvent of 5% ethyl acetate in n-hexane to give methyl 4 (4-cyclohexyloxyphenyl)benzoate (1.79 g) as a white solid. IR (KBr) : 1720, 1603, 1525, 1495, 1437 cm-1 NMR (CDCl 3 , 5) : 1.22-1.66 (6H, m), 1.72-1.90 (2H, m), 25 1.95-2.10 (2H, m), 3.93 (3H, s), 4.22-4.37 (1H, m), 6.89-7.03 (2H, m), 7.47-7.76 (4H, m), 8.00-8.13 (2H, m) MASS (m/z) : 311 (M +1) The following compound was obtained in a manner similar 30 to that of Preparation 176. Preparation 177 4-Cyclohexyloxybenzoic acid methyl ester NMR (CDC1 3 , 5) : 1.20-2.10 (10H, m), 3.88 (3H, s), 4.20-4.40 (1H, m), 6.85-6.95 (2H, m), 7.90-8.00 (2H, 35 m) WO 99/40108 PCT/JP99/00538 113 APCI MASS (positive) : 235.2 (M+1) Preparation 178 To an ice-cooled solution of ethyl 4-(piperazin-1 yl)benzoate (2.00 g) and 4-methylcyclohexanone (1.05 ml) in 5 a mixed solvent of methanol (40 ml) and acetic acid (1.47 ml) was added sodium cyanoborohydride (0.59 g) in a stream of nitrogen. The mixture was stirred at this temperature for 1 hour and at room temperature for 17 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen 10 carbonate solution and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a mixture of cis and trans products. This mixture was separated by column chromatography on silica gel eluting with a mixed solvent of methylene chloride-methanol (from 0% to 2% 15 gradient solution) to give ethyl 4-[4-(cis-4 methylcyclohexyl)piperazin-1-yl]benzoate (0.80 g) as a pale green solid and ethyl 4-[4-(trans-4 methylcyclohexyl)piperazin-1-yl]benzoate (0.64 g) as a pale green solid. Trans-product was confirmed by X-ray crystal 20 analysis. Ethyl 4-[4-(cis-4-methylcyclohexyl)piperazin-1 yl]benzoate IR (KBr) : 1697, 1608, 1520, 1446 cm-1 NMR (DMSO-D 6 , 5) : 0.89 (3H, d, J=6.8Hz), 1.28 (3H, t, 25 J=7.1Hz), 1.23-1.52 (6H, m), 1.52-1.76 (3H, m), 2.07-2.25 (1H, m), 2.47-2.63 (4H, m), 3.20-3.40 (4H, m), 4.23 (2H, q, J=7.1Hz), 6.96 (2H, d, J=9.1Hz), 7.78 (2H, d, J=8.9Hz) MASS (m/z) : 331 (M++1) 30 Ethyl 4-[4-(trans-4-methylcyclohexyl)piperazin-1 yl] benzoate IR (KBr) : 1709, 1608, 1518, 1444 cm-1 NMR (DMSO-D 6 , 6) : 0.85 (3H, d, J=6.8Hz), 0.80-1.02 (2H, m), 1.28 (3H, t, J=7.1Hz), 1.09-1.56 (3H, m), 35 1.56-1.88 (4H, m), 2.08-2.34 (1H, m), 2.50-2.67 (4H, WO 99/40108 PCT/JP99/00538 114 m), 3.18-3.34 (4H, m), 4.23 (2H, q, J=7.1Hz), 6.95 (2H, d, J=9.1Hz), 7.77 (2H, d, J=8.9Hz) MASS (m/z) : 331 (M++1) The following compound was obtained in a manner similar 5 to that of Preparation 178. Preparation 179 Ethyl 4-[4-(4,4-dimethylcyclohexyl)piperazin-1 yl]benzoate NMR (CDC1 3 , 5) : 0.91 (6H, s), 1.07-1.55 (6H, m), 1.36 10 (3H, t, J=7.1Hz),l.64-1.82 (2H, m), 2.10-2.30 (1H, m), 2.72 (4H, t, J=5.1Hz), 3.33 (4H, t, J=5.1Hz), 4.32 (2H, q, J=7.1Hz), 6.86 (2H, d, J=9.1Hz), 7.87-7.99 (2H, m) MASS (m/z) : 345 (M +1) 15 Preparation 180 To amixture of cesium carbonate (1.90 g), palladium (II) acetate (46.7 mg) and 2,2'-bis(diphenylphosphino)-1,1' binaphthyl (194 mg) in toluene (3.3 ml) was successively added a solution of cis-2,6-dimethyl morpholine (0.58 g) in toluene 20 (5 ml) and methyl 4-(4-trifluoromethanesulfonyloxyphenyl) benzoate (1.50 g) in a stream of nitrogen. The mixture was stirred at ambient temperature for 30 minutes and refluxed for further 6 hours. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted 25 with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was pulverized with acetonitrile and collected by filtration to give methyl 4-[4-(cis-2,6-dimethylmorpholino 30 phenyl)]benzoate (525 mg) as a pale yellow solid. IR (KBr) : 1720, 1603, 1497, 1446 cm-1 NMR (CDCl 3 , 5) : 1.28 (6H, d, J=6.3Hz), 2.46 (1H, d, J=10.6Hz), 2.49 (1H, d, J=10.6Hz), 3.46-3.62 (2H, m), 3.72-3.94 (2H, m), 3.93 (3H, s), 6.98 (2H, d, 35 J=8.9Hz), 7.51-7.70 (4H, m), 8.02-8.14 (2H, m) WO 99/40108 PCT/JP99/00538 115 MASS (m/z) : 326 (M+1) The following compound was obtained in a manner similar to that of Preparation 180. Preparation 181 5 Methyl 4-[4-(4-cyclohexylpiperazin-1 yl)phenyl] benzoate IR (KBr) : 2929, 2852, 2829, 1714, 1603, 1529, 1498, 1439 cm -1 NMR (CDCl 3 , 5) : 1.00-1.41 (5H, m), 1.51-2.05 (5H, m), 10 2.24-2.43 (1H, m), 2.69-2.84 (4H, m), 3.22-3.36 (4H, m), 3.93 (3H, s), 7.00 (2H, d, J=8.9Hz), 7.48-7.68 (4H, m), 8.00-8.12 (2H, m) MASS (m/z) : 379 (M+1) Preparation 182 15 To a suspension of 2-amino-5-(4-methoxyphenyl)-1,3,4 thiadiazole (7.2 g) in ethanol (50 ml) was added ethyl 4 bromoacetylbenzoate (11.3 g) and the mixture was stirred under refluxing for 2.5 hours. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by 20 filtration and dried. To a suspension of the powder in xylene (50 ml) was added trifluoroacetic acid (5 ml) and the mixture was stirred under refluxing for 3.5 hours. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration and dried to give 25 4-[2-(4-methoxyphenyl)imidazo[2,1-b] [1,3,4]thiadiazol-6 yl]benzoic acid ethyl ester trifluoroacetic acid salt (13.7 g). IR (KBr) : 2360.4, 1746.3, 1604.5, 1483.0 cm-1 MASS (m/z) : 380 ((M-TFA)+H +) 30 The following compounds [Preparations 183 to 190] were obtained in a manner similar to that of Preparation 182. Preparation 183 4-[2-(4-Piperidin-1-yl-phenyl)imidazo[2,1 b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester 35 trifluoroacetic acid salt WO 99/40108 PCT/JP99/00538 116 IR (KBr) :2940, 2584, 2474, 1702, 1608, 1523, 1471, 1409, 1367, 1280 cm

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1 MASS (m/z) : 433 ((M-TFA)+H +) Preparation 184 5 4-[2-(4-Morpholin-4-yl-phenyl)imidazo [2,1 b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) :2669, 1706, 1606, 1473, 1274, 1236, 1176, 1118, 1020, 929 cm

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1 10 MASS (m/z) : 435 ((M-TFA)+H ) Preparation 185 4-[2-(cis-2,6-Dimethylmorpholin-4-yl phenyl)imidazo[2,1-b] [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt 15 IR (KBr) :2979, 1710, 1606, 1473, 1371, 1278, 1241, 1176, 1106 cm

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1 MASS (m/z) : 463 ((M-TFA)+H +) Preparation 186 4-[2-(4-Thiomorpholin-4-yl-phenyl)imidazo[2,1 20 b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) : 2979, 1708, 1604, 1504, 1471, 1274, 1193, 1105 cm - 1 MASS (m/z) : 451 ((M-TFA)+H ) 25 Preparation 187 4-[2-[4-(4-Ethylpiperazin-1-yl)phenyl] imidazo[2,1 b] [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) : 2983, 2931, 2674, 2605, 1702, 1606, 1471, 30 1405, 1282, 1241, 1201 cm

-

1 NMR (DMSO-d 6 , 5) : 1.23-1.38(6H, m), 3.30-3.23 (6H, m), 3.61 (2H, d, J=8.2Hz), 4.12 (2H, d, J=8.2Hz), 4.33 (2H, q, J=7.2Hz), 7.20 (2H, d, J=8.8Hz), 7.85 (2H, d, J=8.8Hz), 8.02 (4H, s), 8.86 (1H, s) 35 MASS (m/z) : 462 ((M-TFA)+H ) WO 99/40108 PCT/JP99/00538 117 Preparation 188 4-[2-[4-(4-Cyclohexylpiperazin-1 yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt S IR (KBr) : 2935, 2586, 1708, 1604, 1571, 1488, 1409, 1367, 1278, 1199, 1106 cm-1 MASS (m/z) : 516 ((M-TFA)+H+) Preparation 189 4-[6-(4-Hydroxyphenyl)imidazo [2,1 10 b][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester trifluoroacetic acid salt IR (KBr) : 3214, 3027, 1720, 1629, 1610, 1513, 1434, 1284, 1187, 1112 cm-1 NMR (DMSO-d 6 , 5) : 3.91 (3H, s), 7.72 (2H, d, J=8.5Hz), 15 7.91 (2H, d, J=8.5Hz), 8.12 (4H, s), 8.61 (1H, s) MASS (m/z) : 352 ((M-TFA)+H ) Preparation 190 4-[6-(4-Pentyloxyphenyl)imidazo[2,1 b][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester 20 trifluoroacetic acid salt IR (KBr) :2952, 2869, 1720, 1612, 1494, 1471, 1436, 1405, 1280, 1251, 1182, 1110 cm-1 MASS (m/z) : 422 ((M-TFA)+H ) Preparation 191 25 A solution of methyl 4-[4-(4 bromobutoxy)phenyl]benzoate (1.40 g) in methanol (14 ml) was treated with 28% sodium methoxide in methanol (14 ml) and the solution was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was poured into cold 1N 30 hydrochloric acid (110 ml) and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a white solid. To a mixture of this solid in methanol (20 ml) was added concentrated sulfuric acid (0.5ml) and refluxed for 4 hours. After cooling to room temperature, 35 the reaction mixture was poured into cold water and the WO 99/40108 PCT/JP99/00538 118 resulting precipitate was collected by filtration, washed thoroughly with water and dried to give methyl 4-[4-(4 methoxybutoxy)phenyl]benzoate (1.16 g) as a white solid. IR (KBr) : 2949, 2873, 1720, 1603, 1529, 1498, 1439 cm-1 5 NMR (DMSO-d 6 , 6) : 1.54-1.85 (4H, m), 3.24 (3H, s), 3.38 (2H, t, J=6.2Hz), 3.87 (3H, s), 4.04 (2H, t, J=6.1Hz), 7.05 (2H, t, J=8.8Hz), 7.69 (2H, d, J=8.7Hz), 7.78 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.4Hz) MASS (m/z) : 315 (M +1) 10 The following compounds [Preparations 192 to 194] were obtained in a manner similar to that of Preparation 191. Preparation 192 Methyl 4-[4'-(3-methoxypropoxy)phenyl]benzoate IR (KBr) : 2953, 2875, 1724, 1603, 1529, 1495, 1435cm-1 15 NMR (DMSO-d 6 , 5) : 1.96 (2H, m), 3.26 (3H, s), 3.49 (2H, t, J=6.3Hz), 3.87 (3H, s), 4.08 (2H, t, J=6.4Hz), 6.98-7.14 (2H, m), 7.64-7.86 (4H, m), 7.96-8.10 (2H, m) MASS (m/z) : 301 (M'+1) 20 Preparation 193 1-Bromo-4-ethoxymethylbenzene NMR (DMSO-d 6 , 6) : 1.15 (3H, t, J=7.0Hz), 3.47 (2H, q, J=7.0Hz), 4.42 (2H, s), 7.28 (2H, d, J=8.5Hz), 7.46-7.61 (2H, m) 25 Preparation 194 Methyl 4-[4-(3-ethoxypropoxy)phenyl]benzoate NMR (DMSO-d 6 , 6) : 1.11 (3H, t, J=7.0Hz), 1.96 (2H, m), 3.43 (2H, q, J=7.0Hz), 3.52 (2H, t, J=6.3Hz), 3.87 (3H, s), 4.08 (2H, t, J=6.3Hz), 7.06 (2H, d, J=8.8Hz), 30 7.70 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.SHz) MASS (m/z) : 315 (M +1) Preparation 195 To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1 35 b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester (500 mg) WO 99/40108 PCT/JP99/00538 119 and potassium carbonate (2 g) inN,N-dimethylformamide (25ml) was added 1,4-dibromobutane (1 ml) and the mixture was stirred at room temperature for 22 hours. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected 5 by filtration and dried. To a suspension of the powder in N,N-dimethylformamide (25 ml) was added piperidine (2 ml) and the mixture was stirred at room temperature for 21 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration, washed with water, acetonitrile 10 and diisopropyl ether and dried to give 4-[2-[4-(4 piperidin-1-yl-butyloxy)phenyl] imidazo[2,1 b] [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester (479 mg) IR (KBr) : 2933.2, 1708.6, 1608.3, 1471.4, 1274.7, 1176.4, 1101.2 cm-1 15 MASS (m/z) : 505 (M+H +) The following compounds [Preparations 196 to 201] were obtained in a manner similar to that of Preparation-195. Preparation 196 4-[2-[4-(5-Piperidin-1-yl 20 pentyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6 yl]benzoic acid ethyl ester IR (KBr) : 2935, 1708, 1608, 1471, 1274, 1176, 1101cm

-

1 MASS (m/z) : 519 (M+H ) Preparation 197 25 4-[2-[4-(6-Piperidin-1-yl hexyloxy)phenyl]imidazo[2,1-b] [1,3,4]thiadiazol-6 yl]benzoic acid ethyl ester IR (KBr) : 2933, 1710, 1608, 1471, 1274, 1176, 1103 cm

-

1 MASS (m/z) : 533 (M+H ) 30 Preparation 198 4-[2-[4-(5-Morpholin-4-yl pentyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6 yl]benzoic acid ethyl ester IR (KBr) : 2940, 1708, 1608, 1471, 1276, 1176 35 1116cm-1 WO 99/40108 PCT/JP99/00538 120 MASS (m/z) : 521 (M+H ) Preparation 199 4-[2-[4-[5-(cis-2,6-Dimethylmorpholin-4 yl)pentyloxy]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6 5 yl]benzoic acid ethyl ester IR (KBr) :2937, 1708, 1608, 1471, 1409, 1369, 1307, 1278, 1176 cm-1 MASS (m/z) : 549 (M+H ) Preparation 200 10 4-[2-[4-[6-(cis-2,6-Dimethylmorpholin-4 yl)hexyloxy]phenyl]imidazo[2,1-b] [1,3,4]thiadiazol-6 yl]benzoic acid ethyl ester IR (KBr) :2937, 1710, 1606, 1544, 1471, 1403, 1305, 1270, 1257, 1176 cm-1 15 MASS (m/z) : 563 (M+H ) Preparation 201 4-[2-[4-(5-Thiomorpholin-4-yl pentyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6 yl]benzoic acid ethyl ester 20 IR (KBr) : 2939, 1706, 1608, 1471, 1274, 1176, 1108 cm-1 MASS (m/z) : 537 (M+H') Preparation 202 To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1 b] [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester (1 g) and 25 potassium carbonate (4 g) inN,N-dimethylformamide (50ml) was added 1,5-dibromopentane (2 ml) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, washed with water andmethanol. To a suspension 30 of the powder in methanol (10 ml) was added sodium methylate (28% in methanol) (20 ml) and the mixture was stirred at 80 0 C for 19 hours. The reaction mixture was pulverized with water. The precipitatewas collectedby filtration, washedwithwater, methanol and diisopropyl ether and dried to give 4-[2-[4 35 (5-methoxypentyloxy)phenyl] imidazo[2,1- WO 99/40108 PCT/JP99/00538 121 b] [1,3,4]thiadiazol-6-yl]benzoic acid methyl ester (479 mg) MASS (m/z) : 452 (M+H ) The following compounds [Preparations 203 to 205] were obtained in a manner similar to that of Preparation 202. 5 Preparation 203 4-[2-[4-(6-Methoxyhexyloxy)phenyl]imidazo[2,1 b] [1,3,4]thiadiazol-6-yl]benzoic acid methyl ester IR (KBr) : 2935, 2861, 1712, 1608, 1591, 1533, 1471, 1417, 1305, 1259, 1178, 1116 cm-1 10 MASS (m/z) : 466 (M+H +) Preparation 204 4-[2-[4-(7-Methoxyheptyloxy)phenyl]imidazo[2,1 b][1,3,4]thiadiazol-6-yl]benzoic acid methyl ester IR (KBr) : 2933, 2858, 1714, 1608, 1591, 1533, 1469, 15 1419, 1305, 1259, 1178, 1112 cm-1 MASS (m/z) : 480 (M+H +) Preparation 205 4-[2-[4-(8-Methoxyoctyloxy)phenyl]imidazo[2,1 b][1,3,4]thiadiazol-6-yl]benzoic acid methyl ester 20 IR (KBr) : 2931, 2856, 1712, 1610, 1591, 1533, 1471, 1419, 1305, 1259, 1178, 1112 cm-1 MASS (m/z) : 494 (M+H ) Preparation 206 A mixture of piperazin-1-carboxylic acid tert-butyl 25 ester (0.64 g), 4-bromo-4'-(5-methoxypentyloxy)biphenyl (1 g), tris(dibenzylideneacetone)(chloroform)dipalladium(0) (59 mg), (S)-(-)-2,2'-bis(diphenylphosphino)-1,1' binaphthyl (0.12 g) and sodium tert-butoxide (0.55 g) in toluene (10ml) was stirred for 54 hours at 90 0 C. The reaction 30 mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4'-(5 methoxypentyloxy)biphenyl-4-yl] piperazin-1-carboxylic 35 acid tert-butyl ester (1.19 g).

WO 99/40108 PCT/JP99/00538 122 IR (KBr) : 1691.3, 1504.2, 1232.3 cm

-

1 NMR (CDC1 3 , 5) : 1.49 (9H, s), 1.49-1.90 (6H, m), 3.14-3.19 (4H, m), 3.34 (3H, s), 3.41 (2H, t, J=6.2Hz), 3.57-3.62 (4H, m), 3.99 (2H, t, J=6.4Hz), 6.91-6.99 5 (4H, m), 7.44-7.49 (4H, m) MASS (m/z) : 455 (M+l) The following compound was obtained in a manner similar to that of Preparation 206. Preparation 207 10 4-[4-[4-(7-Methoxyheptylthio)phenyl]piperazin-1 yl]benzoic acid IR (KBr) : 1681.6, 1585.2, 1423.2, 1230.4 cm -1 NMR (DMSO-d 6 , 5) : 1.20-1.55 (10H, m), 2.80 (2H, t, J=6.7Hz), 3.20 (3H, s), 3.24-3.43 (10H, m), 15 6.82-6.86 (2H, m), 6.94-6.98 (2H, m), 7.23-7.27 (2H, m), 7.69-7.73 (2H, m) MASS (m/z) : 443.2 (M+1) Preparation 208 1-tert-Butoxycarbonyl-4-[4-(4 20 cyclohexylphenyl)piperazin-l-yl]piperidine (3.3 g) and trifluoroacetic acid (10 ml) were mixed and the mixture was stirred at ambient temperature for 1 hour. The solution was placed in water, adjusted to pH 8 with IN sodium hydroxide and extracted with ethyl acetate. The organic layer was 25 separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-(4 cyclohexylphenyl)-4-piperidylpiperazine (3.83 g). Preparation 209 To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1 30 b] [1,3,4]thiadiazol-6-yl]benzoic acid (4.0 g) in ethanol (50 ml) was added sulfuric acid (1.0 ml) and the mixture was stirred at 80 0 C for 9 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration, washed with water, acetonitrile and diisopropyl 35 ether and dried to give 4-[2-(4- WO 99/40108 PCT/JP99/00538 123 hydroxyphenyl)imidazo[2,1-b] [1,3,4]thiadiazol-6 yl]benzoic acid ethyl ester (2.09 g). IR (KBr) : 3215, 1679.7, 1608.3, 1473.3, 1288.2 cm-1 NMR (DMSO-d 6 , 5) : 1.34 (3H, t, J=7.1Hz), 4.32 (2H, q, 5 J=7.1Hz), 6.96 (2H, d, J=8.5Hz), 7.89 (2H, d, J=8.5Hz), 8.02 (4H, s), 8.84 (1H, s), 10.40 (1H, s) MASS (m/z) : 366 (M+H ) The following compound was obtained in a manner similar to that of Preparation 209. 10 Preparation 210 4-Cyclohexylbenzoic acid methyl ester NMR (CDCl 3 , 5) : 1.10-1.55 (5H, m), 1.65-1.95 (5H, m), 2.45-2.65 (1H, m), 3.89 (3H, s), 7.26 (2H, d, J=8.2Hz), 7.95 (2H, d, J=8.2Hz) 15 APCI MASS: 219 (M +1) The Object Compounds (211) to (457) obtained in-the following Preparations 211 to 457 are given in the tables as below.

WO 99/40108 PCT/JP99/00538 124 Preparation No. Formula N iN IIN, N-N 0 211 o 0 51 o OMe 212 0 213N8 O

,NO(CH

2

)

6

CH

3 213 s. SoI },O 0 ' ' N-N 2, 4N

.

II o . SN, N-N 214 0 1N-N N N, " /\J \/- WO 99/40108 PCT/JP99/00538 125 Preparation No. Formula O NV, N, - N- = ,-- X 217 o 0 2 1 8 9 N O 2 2I 0 N8 O -N 219 " cOo O ,N 0 S 220 0 -1 O 0 221 N 'O Q N N S(CH 2

)

7 0CH 3 O 222 N N' -- O(CH 2

)

6 0CH 3 WO 99/40108 PCT/JP99/00538 126 Preparation No. Formula 0 N 223 S O O (CH 2)4C H 3

H

3 C N N-N 224 NoN S -O(CH 2

)

6 0CH 3 O

CH

3 N-N 2 25-OO O(CH2)60CH3 225 0 N I N-N 226 0 0 o o O(CH2)2CH 3 227 NN' IO(CH260CH3 228

N

WO 99/40108 PCT/JP99/00538 127 Preparation No. Formula N o ~ - N-N 229 S 0 o 230 OEt O 0 231 , o p Me 0 232 -o o o 0 23 3OEt 234 O8'o o Me WO 99/40108 PCT/JP99/00538 128 Preparation No. Formula 0 N N oJ / N s 0-,_./ '= o

-

235 o O 2,3 N,. oIo I O(CH2) CHz N O 2 3-8- '. N., s % -% N. N N-NN 236 bOKY6Q/~ SNo 0 N237 S [HNN N N 238 N, ) 'j \, 239 0N/ N 0 .N~ 240\ 6

N-N

WO 99/40108 PCT/JP99/00538 129 Preparation No. Formula 0 .N. 0 N/=\ , N,14, Nl / -\ s I_ N-- ---O C 6

H

1 3 241 / s N/ N-N O 242o N 243 NN.A%./y :. 7 ) --CYN0 0 N NM0e 245 / o 0 N~ ~ ~ & N. . s = -X/" N-N O 2~ ~ 4N o 2 45 8'oS N o 24 6 r o N N WO 99/40108 PCT/JP99/00538 130 Preparation No. Formula O N Ni., 247 0o O~ NN , N, N -- N Ome 248 6 ' 0N Cl 0 N'

N

0 1 +0- 0 O 249 N- I 0NN N N 250 0 o SNjJ O 0 251 O N N -O(CH2)CH3 252 0 & o- WO 99/40108 PCT/JP99/00538 131 Preparation No. Formula O NN-N 2 53 '8'o S OHC 254 N O C0 2 Me O2NCO 2 , 255 < ) N a_-- CO2M e 256 NC-- N NC 0 257 258 NC N0 259 NCs WO 99/40108 PCT/JP99/00538 132 Preparation No. Formula 260 NC-O -NN-Et 261 EtOOC-Q-N -OH 262 EtOOC- -NQ- D 263 EtOOC--Q-N N 264 EtOOC- -ND-OH 265 Meooc 266 EtOOCN N WO 99/40108 PCT/JP99/00538 133 Preparation No. Formula OMe 267 EtOOC- NC Oe Cl c1 268 NC N N Q 269 NC N N N 270 0 271 Me 0 c OflC 6

H

13 272 MeO 2 C-O

-O-

273 Meo2C

O

Br WO 99/40108 PCT/JP99/00538 134 Preparation No. Formula 2 7 4 Meo2C-aOO--OMe 2 7 5 MeO 2 C-O -- O OEt 276 MeO 2 C-0 O OMe

N-

N 277 MeO 2 C

O(CH

2

)

3

CH

3 N. 278 MeO 2 C N O(CH 2

)

5

CH

3 279 EtO 2 C O( CH2)5CH3 N 280 H 2 NN /

'*

(CH

2

)

6

C

H 3 O 280 2H 0 WO 99/40108 PCT/JP99/00538 13 5 Preparation No. Formula N - 281 HNN 0 282 ~Y N

H

2 NHN 0 283

H

2 NHN NjJ-f1 0 285

H

2 NHNy a N\jr1N\ 0 285 H 2 NHNra ND/ 0 286

H

2 NN - a 0 WO 99/40108 PCT/JP99/00538 136 Preparation No. Formula 2 8 8 H 2 NHN (a 0 0 289

H

2 NHN 0 290 H O

H

2 NHN NN O 0 291

H

2 NHN-- -- Na---O o 292 .

2 NHN N 0 0 293 H2

H

2 NHN /N\~\j WO 99/40108 PCT/JP99/00538 137 Preparation No. Formula O 294 H 2 NHN N O 0 295 0 296

H

2 NHN O O 0 297 H2NHN 0 298 H 2 NHN O OMe 0 299

II

2 NHN \ /_

>_

WO 99/40108 PCT/JP99/00538 138 Preparation No. Formula 0 300 H 2 NHN N 0 301

H

2

NHN

J N NIII O o 3 04 H2NHN OpO/ OMe 0 302

H

2 NHNQt 0 303e H2NHN U--

-

- O/

\

/

O 0 304 H 2 NHN J /\ /O-- ---0Me 0 305 H 2 NHN & & - & WO 99/40108 PCT/JP99/00538 139 Preparation No. Formula O 0 306 H2NHN O O Et O 307

H

2 NHN //OO"OMe 0 38H 2 NH-N J- - 0Me 0 OMe 309 H 2 NHN \/N Cl O 0 310 Me H H N O ..- NN N \ / (CHACH 0 0 0 311 MeO I I " N N- NNN\/ N~ \ 0 0 WO 99/40108 PCT/JP99/00538 140 Preparation No. Formula O 312 MeO I H H o 0 0 0 313 MeO HH N & N ~- N N o o 0 314 MeO H H N O 3 J ,( yN-N ,_,-a o o 0 315 MeO I H H N/ZaO 1 N-N / o 0 0 316 MeO H Ha I N-N 0 0 0 0 317 MeO H H O N-N 0 0 WO 99/40108 PCT/JP99/00538 141 Preparation No. Formula 0 318 MeO H == 318 N-N 0 0 0 0 0 319 I/i MeO I H N 0 o o 320 MeO

H

N - N-N N N 0 O O 3 21MeO N -N -N O_ 322 MeO H H0N 3MeON-N N N 0 0 WO 99/40108 PCT/JP99/00538 142 Preparation No. Formula 0 324 MeO- HH N 0 o 0 o 0 0 325 M H\/ O 32 6 MeO HN NG o 0 0 0 327 ?. -N \ / \ / v 0 0 0329 0 0 329 MeOAO j N N N I - WO 99/40108 PCT/JP99/00538 143 Preparation No. Formula 330 MeO HH N N o o 331 MeO HN N NI Oo o o o 0 332 H H 3 of- _!Me- O O O O0 0 3350 5 -0O OE t 0 0 0 34 MeO L~~INN - -- \/\/OIOOt WO 99/40108 PCT/JP99/00538 144 Preparation No. Formula 0 - - N 0 OEt 3 3 6 -MeO N-N ~ /-\ / 00 0 0 0NH-N 337 MHN O OMe MOO 0 0 3380 MeO-- H HO O -Me 0 0 0 O OOe II/\J -/ O- Me 339 -MeOH~ ~ /N CI 340 H 3

CO

2 CCj -- N- /O(CH 2 )60CH 3 0 0C 341 H 3 CO HO(CH 2

)

4

CH

3 00 WO 99/40108 PCT/JP99/00538 145 Preparation No. Formula

H

3 C HN-NH 342 H 3

CO

2 C H- O(CH2)6CH3 OO

CH

3 H \ HN-NH 343 H3CO2C -0 a O(CH2)60CH 3 ~OO

H

3

CO

2 C _ N -NH__- O(CH 2

)

2

H

3 344 00 345

H

3

CO

2 C 345 [ I I r -,- = s N0C /

-

0(CH 2

)

6

CH

3 O 3 46 MeO O(CH2)6CH3 N-N O 347 N-NN O M-o / WO 99/40108 PCT/JP99/00538 146 Preparation No. Formula O 348 N-N MeOA / 0 - N-N 349MeO O 350 MeO S N OnCH3 N-N N-N 351

H

3

CO

2 C / -O(CH 2

)

6 0CH 3

H

3 C N-N 352 H 3

CO

2 S O(CH2)60CH3

CH

3 N-N 353

H

3

CO

2 C S O(CH2)6CH 3 S \ /O(CHA) 6

CH

3 WO 99/40108 PCT/JP99/00538 147 Preparation No. Formula

H

3

CO

2 C ) N-N 354 H3 S

O(CH

2

)

6 0CH 3 - N 355 Br - S \ -O(CH 2

)

6

CH

3 356 NMeOOC S - N--NO N-N 357 ,/ / MeOOC S N jN N-N OWOO - N-N 358 MeOOC N MeOOC S

N-N

WO 99/40108 PCT/JP99/00538 148 Preparation No. Formula 360 MeOOC1O S / (H)O(CH4CH 3 N-N N-N 361 MeOOC S/N Nf N-N 362 MeOOCiOf S N O N-N 3643 MeOOC \ N Ne N-N 364 MeOOC SyNDO N-N 365 MOC MeOOC C -S/'-\/_ INO J/

N

WO 99/40108 PCT/JP99/00538 149 Preparation No. Formula N-N 366 MeOOC -- s-oOMe 367 MeOOC/S N N -0 N-N 368 MeOOC S < N N N-N 369 MeOOC- -S N NI N-N 370 MeOOC O S\\Os N-N 371 MeOOC S _ O

N-N

WO 99/40108 PCT/JP99/00538 150 Preparation No. Formula 372 MeOOC-O S YN 0 N-N 373 MeOOC-- S \/\ / y Ot N-N 374 MeOOC / S SO N-N 375 MeC(C S \ -SVOEt '\ / N-N 37M6 eOOC_ S OOMe N-N 377 MeOOC - S O O 377 \ \/

N-N

WO 99/40108 PCT/JP99/00538 151 Preparation No. Formula 378 MeOOC - ( S \/ /O-' OEt N-N 379 MeOOC / /O---SO Et N-N 380 MeOOC - S SO OMe N-N 3 81 MeOOC _S O, OMe N-N N-N OMe 382 MeOOC-O S- O/ Cl 38 ,N 383 HOCS N / O(CHACH 3

N-N

WO 99/40108 PCT/JP99/00538 152 Preparation No. Formula HOOC ,N /-\ / 384 HOOC N N N Icl", \ / f N-N 385 HOOC , N N N-N 386 HOOCI " S N On H N-N HOO S N N N-N 386 N-N - N-N 38HMOOC-0N ,'\rO - WO 99/40108 PCT/JP99/00538 153 Preparation No. Formula N-N 390 MeOOC _ / O_ 391 MeOOC- 392

H

3

CO

2 C - --

O(CH

2 )4CH 3 N-N 393 H3CO2C 7 ' -O(CH22CH3 3 9 4 H O O N 395 HOOC

-

WO 99/40108 PCT/JP99/00538 154 Preparation No. Formula 3 9 6 HOOC O - N-N S 397 HOOC -- N& -N-N 398 HOOC-O--O 399 HON-N 40HOOC N N 400 N-N -0 * 2HCI 4 0 1 HSOH 41 HOOC-, sjx~ \/ sI O(CH 2

)

4

CH

3 N-N N-N WO 99/40108 PCT/JP99/00538 155 Preparation No. Formula HOOC S N-\ 402 N-N * 2HC1 40 3 HOOC N) sO~ O N-N * HCI 404 - sr/= / __ HOOC N N 0 N-N HC S, Me HOOC - N N .2HCI o-oo 406 HOOC N jO N-N * HCI 407 HOOC o 4 0 7 ".......

WO 99/40108 PCT/JP99/00538 156 Preparation No. Formula N-N HOOC NXC 408 N [ SHC1 4 0 9 HOOC O N-N - N-N 410 HOOC

O

411 HO 'N

N

411 N-N ' * 2HC1 412 HOOC - J----()I--Qf N N . 2HC1 413 HOOCN N NIn N-N * 2HC1 WO 99/40108 PCT/JP99/00538 157 Preparation No. Formula 414 HOOC .

. N-N 41 HOOC OEt 416 HOOC O OMe - N-N 417 HOOCO O Oe N-N 418 HOOC O Ot N-N 419 O C ( V lK II.............. j

N-N

WO 99/40108 PCT/JP99/00538 158 Preparation No. Formula 420 HOOC O O e N-N s 421 HOOC S o OMe N-N Oe 422 HOOC N O Cl HOOC N N

O(CH

2

)

5 0CH 3 423 . HCI 424 424 HOOC-- N *HCI 425 HOOC-O(CH2)6CH3 WO 99/40108 PCT/JP99/00538 159 Preparation No. Formula N-N 426 HO(CH2)4CH 3

HO

2 C S

H

3 C N-N 4 2 7 HO 2 C O(CH 2

)

6 0CH 3 -S CH3 N-N 4 2 8 2 S-O(CH2)6OCH3 N-N HO2C f 03-O(CH2 2

CH

3 429 430

HO

2 C 431 OO(CH2)OCH3 H02C O(H2Z WO 99/40108 PCT/JP99/00538 160 Preparation No. Formula 432 HO 2 C NZO(CH2)5'N 433 HO 2 C O(CH26N D 4 34 HO 2 C O(CH2)5-N O 4345N 436 HO 2 C--,O(CH2)-N O 4N - N 435 HO2C / ,O(CH2)6--N O 4362 OC H-N2' 0 H02 "-- __, s" - _ -o(CH ,,_- s WO 99/40108 PCT/JP99/00538 161 Preparation No. Formula

N

N 438 HO 2 C O(CH2)5OMe / NN 439 HO 2 C / /O(CH 2

)

6 OMe NS -N N 440 HO 2 C-"\ / N,) \/O(CH 2

)

7 OMe 441 HO 2 C - / N S O(CH 2

)

8 OMe NS 442 HO 2 443 2-N O

HO

2 C ItN\ ~ 1 NK / WO 99/40108 PCT/JP99/00538 162 Preparation No. Formula 444 HO 2 CN 0 -L_ .. _S-s- N> _- _ 445 HO 2 C -- /N S 446 HO 2 C N\N N-Et 447 HO 2 C N - N N-Ns 448 HO 2 C- \ / O(CH 2

)

3

CH

3 44/9 HO2C O(CH 2

)

4

CH

3 449 H02 ---- /\S 2)4CHN WO 99/40108 PCT/JP99/00538 163 Preparation No. Formula 450 O2C O(CH2

)

5

CH

3 450 - S N 451

HO

2 C

O(CH

2

)

5

CH

3 N K 0 N-N 452 N S \/O(CH2)4

CH

3 452 H

HO

2 C 4 5 3

H

3

CO

2 C CO 2 H

H

3 C 4 5 4

H

3

CO

2 C / CO 2 H

CH

3 4 5 5

H

3 CO2C COH

H

3

CO

2 C / CO 2 H 456 H3CO2C 457 C2H

CO

2

H

WO 99/40108 PCT/JP99/00538 164 The following compounds [Preparations 211 to 253] were obtained in a manner similar to that of Preparation 18. Preparation 211 NMR (CDCl 3 , 6) : 1.10-1.45 (6H, m), 1.45-2.10 (8H, m), 5 3.0-3.80 (6H, m), 6.97 (2H, d, J=9.0Hz), 7.40-7.65 (3H, m), 7.90 (2H, d, J=8.9Hz), 8.13 (2H, d, J=8.2Hz), 8.18 (2H, d, J=8.7Hz), 8.39 (2H, d, J=8.6Hz) APCI MASS : 581 (M

+

) Preparation 212 10 IR (KBr) : 3008, 2935, 1792, 1770, 1600 cm

-

1 NMR (CDCl 3 , 5) : 3.97 (3H, s), 7.07 (2H, d, J=8.5Hz), 7.43-7.56 (3H, m), 8.10 (1H, d, J=8.5Hz), 8.23 (2H, d, J=8.5Hz) MASS (m/z) : 270 (M+H') 15 Preparation 213 IR (KBr) : 1776, 1234, 1095 cm-i NMR (CDCl 3 , 5) : 0.89 (3H, m), 1.1-2.0 (10H, m), 3.52 (2H, t, J=6.6Hz), 4.57 (2H, s), 7.4-7.6 (4H, m), 7.75 (2H, d, J=8.5Hz), 8.14 (2H, d, J=8.1Hz), 20 8.22 (1H, s), 8.26 (2H, d, J=8.7Hz), 8.43 (2H, d, J=8.7Hz), 8.59 (1H, s) MASS (m/z) : 594 (M +l) Preparation 214 NMR (CDC1 3 , 5) : 1.20-1.60 (5H, m), 1.70-2.05 (5H, m), 25 2.50-2.75 (1H, m), 7.25-8.50 (12H, m) ESI MASS (positive) : 502.3 (M +Na) Preparation 215 NMR (CDCl 3 , 5) : 1.10-2.20 (10H, m), 4.30-4.50 (1H, m), 7.04 (2H, d, J=9.1Hz), 7.40-8.50 (10H, m) 30 APCI MASS (positive) : 518.3 (M +Na) Preparation 216 NMR (CDC1 3

+CD

3 OD, 5) : 1.70-2.15 (4H, m), 2.70-2.90 (1H, m), 2.90-3.20 (2H, m), 4.00-4.15 (2H, m), 7.08 (2H, d, J=9.1Hz), 7.10-7.40 (5H, m), 7.40-7.70 (3H, 35 m), 7.90-8.55 (7H, m) WO 99/40108 PCT/JP99/00538 165 APCI MASS : 543 (M +l) Preparation 217 NMR (CDC1 3

+CD

3 OD, 5) : 1.70-2.10 (4H, m), 2.60-3.15 (3H, m), 3.90-4.15 (2H, m), 6.90-7.15 (2H, m), 5 7.15-7.40 (6H, m), 7.40-8.45 (9H, m) Preparation 218 NMR (CDCl 3 , 5) : 1.20-2.15 (10H, m), 4.25-4.50 (1H, m), 7.05 (2H, d, J=6.9Hz), 7.35-7.65 (3H, m), 8.00-8.50 (7H, m) 10 APCI MASS (positive) : 502.2 (M +Na) Preparation 219 NMR (CDC1 3 , 5) : 1.15-2.00 (10H, m), 2.45-2.75 (1H, m), 7.30-8.50 (12H, m) APCI MASS (positive) : 466.2 (M 4 +1) 15 Preparation 220 IR (KBr) : 2978, 2937, 2873, 1772, 1599, 1498, 1439 cm-1 NMR (CDC1 3 , 5) : 1.27 (3H, t, J=7.0Hz), 3.65 (2H, q, J=7.0Hz), 3.84 (2H, t, J=4.8Hz), 4.20 (2H, t, 20 J=4.8Hz), 7.05 (2H, d, J=8.8Hz), 7.40-7.66 (5H, m), 7.60 (2H, d, J=8.8Hz),7.72 (2H, d, J=8.4Hz), 8.07-8.17 (1H, m), 8.28 (2H, d, J=8.6Hz), 8.43 (2H, d, J=8.7Hz) MASS (m/z) : 564 (M +1) 25 Preparation 221 IR (KBr) : 1778.0, 1600.6, 1230.4, 1182.2 cm

-

1 NMR (CDCl 3 , 6) : 1.10-1.74 (10H, m), 2.82 (2H, t, J=7.2Hz), 3.33 (3H, s), 3.33-3.65 (10H, m), 6.88-7.02 (4H, m), 7.32-7.58 (5H, m), 8.07-8.18 (3H, m) 30 Preparation 222 IR (KBr) : 1810.8, 1600.6, 1257.4, 1178.3 cm -1 NMR (DMSO-d 6 , 5) : 1.30-2.40 (18H, m), 3.21 (3H, s), 3.28-3.35 (2H, m), 4.05 (2H, t, J=6.6Hz), 7.05-7.10 (2H, m), 7.40-8.18 (6H, m) 35 MASS (m/z) : 536 (M+1) WO 99/40108 PCT/JP99/00538 166 Preparation 223 IR (KBr) : 1776.1, 1677.8, 1251.6, 1197.6 cm NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=6.9Hz), 1.23-1.55 (4H, m), 1.60-1.90 (2H, m), 4.00-4.10 (2H, m), 5 7.03-7.09 (2H, m), 7.39-8.17 (12H, m) MASS (m/z) : 552 Preparation 224 IR (KBr) : 1795.4, 1606.4, 1442.5, 1259.3, 1220.7 cm -1 10 NMR (DMSO-d 6 , 5) : 1.44-1.95 (8H, m), 2.71 (3H, s), 2.75 (3H, s), 3.35 (3H, s), 3.40 (2H, t, J=6.4Hz), 4.05 (2H, t, J=6.4Hz), 7.02 (2H, d, J=8.8Hz), 7.43-7.64 (3H, m), 7.84 (1H, s), 7.96-8.15 (3H, m), 8.34 (1H, s) 15 MASS (m/z) : 558 (M+1) Preparation 225 IR (KBr) : 1697.1, 1604.5, 1251.6 cm-I NMR (CDCl 3 , 5) : 1.40-2.00 (8H, m), 3.35 (3H, s), 3.40 (2H, t, J=6.4Hz), 4.04 (2H, t, J=6.4Hz), 20 6.97-7.02 (2H, m), 7.20-8.07 (9H, m), 8.50-8.54 (1H, m) MASS (m/z) : 506 (M+1) Preparation 226 IR (KBr) : 1778.0, 1602.6, 1238.1 cm 25 NMR (CDCl 3 , 5) : 1.07 (3H, t, J=7.4Hz), 1.77-1.94 (2H, m), 4.00 (2H, t, J=6.6Hz), 7.00-7.05 (2H, m), 7.46-9.56 (16H, m) MASS (m/z) : 568 (M+1) Preparation 227 30 IR (KBr) : 1778.0, 1604.5, 1257.4, 1172.5 cm NMR (CDC1 3 , 5) : 1.40-1.90 (8H, m), 3.35 (3H, s), 3.41 (2H, t, J=6.3Hz), 4.05 (2H, t, J=6.3Hz), 7.00-7.04 (2H, m), 7.44-9.04 (12H, m) MASS (m/z) : 580 (M+1) WO 99/40108 PCT/JP99/00538 167 Preparation 228 IR (KBr) : 2956, 2933, 2872, 1776, 1601, 1500, 1438 cm - 1 NMR (CDC1 3 , 5) : 1.00 (3H, t, J=7.3Hz), 1.40-1.96 5 (4H, m), 4.04 (2H, t, J=6.5Hz), 7.02 (2H, d, J=8.7Hz), 7.36-7.66 (5H, m), 7.73 (2H, d, J=8.4Hz), 8.00-8.21 (3H, m), 8.28 (2H, d, J=8.6Hz), 8.44 (2H, d, J=8.7Hz) MASS (m/z) : 548 (M +1) Preparation 229 10 IR (KBr) : 2870, 1778, 1649, 1601, 1529, 1500, 1471, 1439 cm-1 NMR (CDC1 3 , 5) : 1.70-2.00 (4H, m), 3.37 (3H, s), 3.47 (2H, t, J=6.1Hz), 4.06 (2H, t, J=6.1Hz), 7.01 (2H, d, J=8.7Hz), 7.42-7.68 (3H, m), 7.60 (2H, d, 15 J=8.8Hz), 7.72 (2H, d, J=8.5Hz),8.06-8.20 (1H, m), 8.28 (2H, d, J=8.7Hz), 8.43 (2H, d, J=8.6Hz) MASS (m/z) : 578 (M +1) Preparation 230 NMR (CDCl 3 , 5) : 1.29 (3H, t, J=7.0 Hz), 3.60 (2H, q, 20 J=7.0Hz), 4.58 (2H, s), 7.40-7.64 (5H, m), 7.65 (2H,d, J=8.2Hz), 7.76 (2H, d, J=8.4Hz), 8.09-8.20 (3H, m), 8.29 (2H, d, J=8.7Hz), 8.44 (2H, d, J=8.7Hz) MASS (m/z) : 534 (M +1) Preparation 231 25 IR (KBr) : 2978, 2937, 2873, 1772, 1599, 1498, 1439 cm

-

1 NMR (CDC1 3 , 5) : 3.42 (3H, m), 3.55-3.74 (4H, m), 4.65 (2H, s), 7.43-7.63 (5H, m), 7.65 (2H, d, J=8.2Hz), 7.76 (2H, d, J=8.5Hz), 8.08-8.17 (3H, m), 8.28 (2H, 30 d, J=8.7Hz), 8.43 (2H, d, J=8.6Hz) MASS (m/z) : 564 (M'+1) Preparation 232 NMR (CDCl 3 , 5) : 3.41 (3H, s) , 3.54-3.68 (2H, m) ,3.68-3.80 (2H, m), 3.90 (2H, t, J=4.9Hz), 4.22 (2H, t, J=4.9Hz), 35 7.04 (2H, d, J=8.8Hz), 7.44-7.68 (3H, m), 7.55 (2H, WO 99/40108 PCT/JP99/00538 168 d, J=9.1Hz), 7.72 (2H, d, J=8.5Hz), 8.05-8.20 (3H, m), 8.27 (2H, d, J=8.6Hz), 8.43 (2H, d, J=8.7Hz) MASS (m/z) : 594 (M+1) Preparation 233 5 IR (KBr) : 2976, 2868, 1778, 1601, 1527, 1500, 1471, 1439 cm-1 NMR (CDC1 3 , 5) : 1.22 (3H, t, J=7.0Hz), 2.10 (2H, m), 3.52 (2H, q, J=7.0Hz), 3.63 (2H, t, J=6.2Hz), 4.14 (2H, t, J=6.5Hz), 7.03 (2H, d, J=8.8Hz), 7.42-7.66 10 (5H, m), 7.72 (2H, d, J=8.5Hz), 8.04-8.20 (1H, m), 8.10 (2H, d, J=8.4Hz), 8.28 (2H, d, J=8.6Hz), 8.43 (2H, d, J=8.6Hz) Preparation 234 IR (KBr) : 2926, 2877, 1768, 1601, 1527, 1500, 1439, 15 1417 cm

-

1 NMR (CDC1 3 , 5) : 2.09 (2H, m), 3.38 (3H, s), 3.59 (2H, t, J=6.1Hz), 4.13 (2H, t, J=6.3Hz), 7.03 (2H, d, J=8.8Hz), 7.44-7.66 (5H, m), 7.72 (2H, d, J=8.5Hz), 8.08-8.18 (3H, m), 8.28 (2H, d, J=8.7Hz), 8.44 (2H, 20 d, J=8.7Hz) MASS (m/z) : 564 (M+1) Preparation 235 IR (KBr) : 1776, 1655, 1601, 1529, 1498, 1439 cm-1 NMR (CDCl 3 , 5) : 3.49 (3H, s), 3.80 (2H, m), 4.20 (2H, 25 m), 7.05 (2H, d, J=8.8Hz), 7.40-7.64 (4H, m), 7.72 (2H, d, J=8.4Hz), 7.98-8.18 (4H, m), 8.28 (2H, d, J=8.6Hz), 8.44 (2H, d, J=8.7Hz) MASS (m/z) : 550 (M +1) Preparation 236 30 IR (KBr) : 1776, 1603, 1527, 1497, 1439 cm

-

1 NMR (CDC1 3 , 5) : 1.19-2.14 (10H, m), 4.23-4.40 (1H, m), 7.02 (2H, d, J=8.8Hz), 7.41-7.67 (SH, m), 7.72 (2H, d, J=8.SHz), 8.02-8.21 (3H, m), 8.28 (2H, d, J=8.7Hz), 8.43 (2H, d, J=8.7Hz) 35 MASS (m/z) : 574 (M +1) WO 99/40108 PCT/JP99/00538 169 Preparation 237 IR (KBr) : 2929.3, 2856.1, 1774.2, 1602.6, 1253.5 cm-1 NMR (CDC13, 5) : 0.80-1.10 (3H, m), 1 10-1.60 (8H, m), 5 1.60-2.00 (2H, m), 4.03 (2H, t, J=6.5Hz), 6.98 (2H, d, J=8.8Hz), 7.40-7.70 (3H, m), 7.81 (2H, d, J=8.5Hz), 7.93 (2H, d, J=8.8Hz), 8.12 (2H, d, J=8.1Hz), 8.17 (1H, s), 8.31 (2H, d, J=8.5Hz) APCI MASS (m/z) : 513 10 Preparation 238 IR (KBr) : 1776, 1603, 1524, 1441, 1414 cm - 1 NMR (CDC1 3 , 6) : 1.03-1.43 (5H, m), 1.54-2.14 (5H, m), 2.24-2.50 (1H, m), 2.65-2.86 (4H, m), 3.23-3.47 (4H, m), 6.98 (2H, d, J=8.7Hz), 7.41-7.68 (3H, m), 7.92 15 (2H, d, J=8.5Hz), 8.13 (1H, d, J=8.2Hz),8.24 (2H, d, J=8.2Hz), 8.40 (2H, d, J=8.2Hz) MASS (m/z) : 566 (M+1) Preparation 239 IR (KBr) : 1772, 1574, 1234 cm

-

1 20 NMR (CDCl 3 , 5) : 2.6-2.75 (4H, m), 3.2-3.3 (4H, m), 3.65 (2H, s), 6.8-7.0 (3H, m), 7.1-7.3 (2H, m), 7.4-7.6 (4H, m), 7.74 (2H, d, J=8.5Hz), 8.14 (2H, d, J=8.1Hz), 8.21 (1H, s), 8.26 (2H, d, J=8.6Hz), 8.43 (2H, d, J=8.6Hz), 8.59 (1H, s) 25 MASS (m/z) : 640 (M+1) Preparation 240 IR (KBr) : 1780, 1520, 1236, 982 cm - 1 NMR (CDC1 3 , 5) : 1.5-1.8 (6H, m), 3.42 (4H, t, J=5.6Hz), 7.02 (2H, d, J=9.1Hz), 7.4-7.7 (5H, m), 8.14 (2H, 30 d, J=10.5Hz), 8.25 (2H, d, J=8.6Hz), 8.42 (2H, d, J=8.6Hz), 8.47 (1H, s) MASS (m/z) : 549 (M+1) Preparation 241 IR (KBr) : 1776, 1571, 1252 cm

-

1 35 NMR (CDC1 3 , 6) : 0.8-1.0 (3H, m), 1.2-1.8 (8H, m), WO 99/40108 PCT/JP99/00538 170 4.02 (2H, t, J=6.5Hz), 7.01 (2H, d, J=9.0Hz), 7.4-7.7 (5H, m), 8.1-8.3 (4H, m), 8.43 (2H, d, J=8.6Hz), 8.51 (1H, s) Preparation 242 5 IR (KBr) : 2927, 2854, 1599, 1531, 1498, 1444 cm -I 1 MASS (m/z) : 642 (M1+1) Preparation 243 IR (KBr) : 1782, 1597, 1533, 1502, 1444, 1421 cm NMR (CDCl 3 , 5) : 1.30 (6H, d, J=6.3Hz), 2.40-2.58 10 (2H, m), 3.49-3.63 (2H, m), 3.72-3.94 (2H, m), 7.01 (2H, d, J=8.8Hz), 7.42-7.65 (5H, m), 7.73 (2H, d, J=8.5Hz), 8.09 (2H, d, J=8.6Hz), 8.14 (1H, d, J=8.4Hz), 8.28 (2H, d, J=8.6Hz), 8.44 (2H, d, J=8.6Hz) 15 MASS (m/z) : 589 (M+1) Preparation 244 IR (KBr) : 1778, 1603, 1441, 1414 cm NMR (CDCl 3 , 5) : 0.92 (6H, s), 1.10-1.84 (8H, m), 2.16-2.35 (1H, m), 2.68-2.87 (4H, m), 3.30-3.46 (4H, 20 m), 6.98 (2H, d, J=9.0Hz), 7.40-7.65 (3H, m), 7.93 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.1Hz), 8.25 (2H, d, J=8.7Hz), 8.40 (2H, d, J=8.6Hz) MASS (m/z) : 594 (M +1) Preparation 245 25 IR (KBr) : 1784, 1603, 1520, 1441, 1414 cm NMR (CDC1 3 , 5) : 1.66-2.14 (4H, m), 3.07-3.28 (2H, m), 3.56-3.84 (3H, m), 4.60 (2H, s), 6.98 (2H, d, J=9.0Hz), 7.23-7.67 (8H, m), 7.91 (2H, d, J=8.9Hz), 8.13 (1H, d, J=8.2Hz), 8.23 (2H, d, J=8.6Hz), 8.40 30 (2H, d, J=8.6Hz) MASS (m/z) : 589 (M+1) Preparation 246 IR (KBr) : 1780, 1603, 1522, 1441, 1414 cm NMR (CDC1 3 , 5) : 0.95 (3H, d, J=6.9Hz), 35 1.37-2.15 (9H, m), 2.25-2.44 (1H, m), 2.68-2.92 WO 99/40108 PCT/JP99/00538 171 (4H, m), 3.27-3.50 (4H, m), 6.98 (2H, d, J=9.0Hz), 7.37-7.67 (3H, m), 7.93 (2H, d, J=8.9Hz), 8.08-8.18 (1H, m), 8.24 (2H, d, J=8.6Hz), 8.40 (2H, d, J=8.6Hz) Preparation 247 5 IR (KBr) : 1778, 1603, 1524, 1441, 1414 cm -1 NMR (CDC1 3 , 5) : 0.90 (3H, d, J=6.4Hz), 0.90-1.13 (2H, m), 1.13-2.05 (7H, m), 2.20-2.48 (1H, m),2.62-2.90 (4H, m), 3.23-3.53 (4H, m), 6.97 (2H, d,J=9.0Hz), 7.38-7.66 (3H, m), 7.92 (2H, d, J=8.8Hz), 8.06-8.17 10 (1H, m), 8.24 (2H, d, J=8.6Hz), 8.40 (2H, d, J=8.7Hz) Preparation 248 IR (Nujol) : 1782, 1603 cm -I NMR (CDC1 3 , 5) : 1.9-2.3 (4H, m), 3.03 (3H, s), 3.2-3.5 (2H, m), 3.6-3.9 (2H, m), 7.03 (2H, d, J=8.9Hz), 7.36 15 (4H, s), 7.4-7.7 (3H, m), 7.93 (2H, d, J=8.9Hz), 8.13 (1H, d, J=8.2Hz) (+)APCI MASS : 623 (M+H) Preparation 249 IR (KBr) : 2923, 2848, 2823, 1766, 1602, 1515, 1450, 20 1378, 1259, 1222, 1186, 1153, 1089, 1014, 971 cm-i NMR (CDC1 3 , 5) : 1.2-1.5 (5H, m), 1.6-1.9 (7H, m), 2.07 (2H, m), 2.43 (1H, m), 2.6-2.9 (5H, m), 3.02 (2H, t, J=8.5Hz), 3.26 (4H, m), 4.07 (2H, d, J=13Hz), 25 6.8-7.1 (4H, m), 7.12 (2H, d, J=8.6Hz),7.3-7.6 (3H, m), 8.0-8.2 (3H, m) MASS (m/z) : 462 (M+H') Preparation 250 IR (KBr) : 1780, 1682, 1655, 1601, 1549, 1498, 1429 cm - 1 30 NMR (CDC1 3 , 5) : 1.62-1.95 (2H, m), 2.01 (2H, m), 2.70-3.18 (3H, m), 4.64 (2H, m), 6.80 (1H, d, J=9.1Hz), 7.18-7.40 (5H, m), 7.40-7.65 (3H, m), 8.00-8.25 (2H, m), 8.25 (2H, d, J=8.6Hz), 8.41 (2H, d, J=8.6Hz), 8.76 (1H, d, J=2.3Hz) 35 MASS (m/z) : 560 (M +1) WO 99/40108 PCT/JP99/00538 172 Preparation 251 IR (KBr) : 1781.9, 1602.6, 1228.4 cm

-

1 NMR (CDCl 3 , 6) : 1.54-1.87 (6H, m), 3.35 (3H, s), 3.38-3.68 (10H,m), 4.00 (2H, t, J=6.4Hz), 6.93-7.05 5 (6H, m), 7.39-7.53 (7H, m), 8.08-8.18 (3H, m) Preparation 252 IR (KBr) : 1776.1, 1600.6, 1232.3 cm-1 NMR (CDC13, 6) : 2.73-2.78 (4H, m), 2.93-3.73 (9H, m), 6.94-6.98 (2H, m), 7.14-7.58 (7H, m), 8.07-8.15 (3H, 10 m) MASS (m/z) : 440 (M+1) Preparation 253 IR (KBr) : 1778, 1599, 1576, 1527, 1498, 1473, 1439 cm-1 NMR (CDCl 3 , 5) : 1.47 (3H, t, J=7.0Hz), 4.11 (2H, q, 15 J=7.0Hz), 7.02 (2H, d, J=8.9Hz), 7.42-7.80 (7H, m), 8.10-8.56 (7H, m) MASS (m/z) : 520 (M +1) The following compounds [Preparations 254 to 270] were obtained in a manner similar to that of Preparation 46. 20 Preparation 254 IR (KBr) : 1702.2, 1702.8 cm-1 NMR (DMSO-d 6 , 5) : 3.83 (3H, s), 8.06 (2H, d, J=8.7Hz), 8.20 (2H, d, J=8.7Hz), 8.24 (1H, s), 9.31 (1H, s), 10.04 (1H, s) 25 MASS (m/z) : 231 (M 4 +1) Preparation 255 IR (KBr) : 1722, 1562, 1514, 1346, 1279 cm-1 NMR (CDC1 3 , 6) : 3.90 (3H, s), 7.92 (2H, d, J=9.2Hz), 8.16 (1H, s), 8.38 (2H, d, J=9.2Hz), 8.86 (1H, s) 30 MASS (m/z) : 246 (M+1) Preparation 256 IR (KBr) : 2937, 2856, 2819, 2213, 1608, 1517, 1448, 1384, 1349, 1247, 1224, 1180, 1122 cm

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1 NMR (CDCl 3 , 5) : 1.66 (6H, m), 3.32 (4H, t, J=5.0Hz), 35 6.83 (2H, d, J=9.1Hz), 7.46 (2H, d, J=9.1Hz) WO 99/40108 PCT/JP99/00538 173 MASS (m/z) : 187 (M+H +) Preparation 257 NMR (CDCl 3 , 6) : 3.28 (4H, t, J=4.9Hz), 3.85 (2H, d, J=4.9Hz), 6.87 (2H, d, J=9.0Hz), 7.52 (2H, d, 5 J=9.0Hz) MASS (m/z) : 189 (M+H ) Preparation 258 NMR (CDC1 3 , 6) : 1.27 (6H, d, J=6.2Hz), 2.52 (2H, t, J=11.5Hz), 3.57 (2H, dd, J=2.2 and J=12.7Hz), 10 3.6-3.9 (2H, m), 6.85 (2H, d, J=9.0Hz), 7.50 (2H, d, J=9.0Hz) MASS (m/z) : 217 (M+H ) Preparation 259 NMR (CDCl 3 , 5) : 2.69 (2H, t, J=5.1Hz), 3.77 (2H, t, 15 J=5.1Hz), 6.81 (2H, d, J=9.0Hz), 7.49 (2H, d, J=9.0Hz) MASS (m/z) : 205 (M+H ) Preparation 260 NMR (CDCl 3 , 5) : 1.13 (3H, t, J=7.2Hz), 2.47 (2H, q, 20 J=7.2Hz), 2.58 (4H, t, J=5.1Hz), 3.35 (4H, t, J=5.1Hz), 7.22 (2H, d, J=8.8Hz), 7.49 (2H, d, J=8.8Hz) MASS (m/z) : 216 (M+H ) Preparation 261 25 NMR (CDCl 3 , 6) : 1.36 (3H, t, J=7.1Hz), 1.55-1.75 (2H, m), 1.80-2.10 (4H, m), 3.00-3.15 (2H, m), 3.60-4.00 (3H, m), 4.31 (2H, q, J=7.1Hz), 6.82 (2H, d, J=9.1Hz), 7.90 (2H, d, J=9.1Hz) APCI MASS (positive) : 250.3 (M+1) 30 Preparation 262 NMR (CDCl 3 , 5) : 1.37 (3H, t, J=7.1Hz), 1.60-2.10 (4H, m), 2.55-2.80 (1H, m), 2.95 (2H, dt, J=3.1Hz, J=12.3Hz), 3.90-4.05 (2H,m), 4.32 (2H, q, J=7.1Hz), 6.90 (2H, d, J=9.1Hz), 7.10-7.35 (4H, m), 7.93 (2H, 35 d, J=9.1Hz) WO 99/40108 PCT/JP99/00538 174 APCI MASS : 310.3 (M+1) Preparation 263 NMR (DMSO-d 6 , 5) : 1.29 (3H, t, J=7.1Hz), 3.21-3.34 (4H, m), 3.40-3.53 (4H, m), 4.24 (2H, q, J=7.1Hz), 6.81 5 (1H, t, J=7.2Hz), 7.00 (2H, d, J=7.9Hz), 7.05 (2H, d, J=9.0Hz), 7.25 (2H, t, J=7.9Hz), 7.81 (2H, d, J=8.9Hz) MASS (m/z) : 311 (M++I1) Preparation 264 10 NMR (DMSO-d 6 , 5) : 1.28 (3H, t, J=7.1Hz), 1.26-1.54 (2H, m), 1.64-1.90 (2H, m), 2.90-3.16 (2H, m), 3.58-3.84 (3H, m), 4.23 (2H, q, J=7.1Hz),4.75 (1H, brs), 6.95 (2H, d, J=9.1Hz), 7.76 (2H, d, J=9.0Hz) MASS (m/z) : 250 (M+1) 15 Preparation 265 IR (KBr) : 2939, 2843, 1703, 1601, 1552, 1497, 1439, 1414 cm

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1 NMR (DMSO-d 6 , 6) : 1.59 (2H, m), 1.87 (2H, m), 2.78-3.15 (3H, m), 3.79 (3H, s), 4.62 (2H, m), 6.92 (1H, d, 20 J=9.1Hz), 7.21 (5H, m), 7.94 (1H, dd, J=9.1 and 2.3Hz), 8.65 (1H, d, J=2.3Hz) MASS (m/z) : 297 (M+1) Preparation 266 IR (KBr) : 1707, 1610, 1516, 1444 cm

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1 25 NMR (DMSO-d 6 , 6) : 1.04-1.30 (5H, m), 1.28 (3H, t, J=7.1Hz), 1.47-1.86 (5H, m), 2.16-2.34 (1H, m), 2.52-2.64 (4H, m), 3.19-3.34 (4H, m),4.23 (2H, q, J=7.1Hz), 6.95 (2H, d, J=9.0Hz), 7.77 (2H, d, J=8.9Hz) 30 MASS (m/z) : 317 (M+1) Preparation 267 IR (Nujol) : 1699, 1606 cm

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1 MR (CDC1 3 , 5) : 1.37 (3H, t, J=7.1Hz), 1.9-2.2 (4H, m), 3.01 (3H, s), 3.2-3.4 (2H, m), 3.6-3.8 (2H, m), 4.33 35 (2H, q, J=7.1Hz) WO 99/40108 PCT/JP99/00538 175 (+)APCI MASS : 374 (M+H) Preparation 268 IR (KBr) :2927, 2850, 2212, 1602, 1517, 1442, 1394, 1253, 1178, 1143, 927, 823 cm

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1 5 NMR (CDCl 3 , 5) : 1.2 (5H, m), 1.65 (1H, m), 1.85 (4H, m), 2.30 (1H,m), 2.70 (4H, t, J=5.1Hz), 3.32 (4H, t, J=5.1Hz), 6.85 (2H, d, J=9.0Hz), 7.48 (2H, d, J=9.0Hz) MASS (m/z) : 270 (M+H ) 10 Preparation 269 Preparation 270 IR (KBr) : 1708.6, 1288.2, 1230.4 cm

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1 NMR (CDCl 3 , 5) : 1.38 (3H, t, J=7.1Hz), 1.50-1.87 (6H, m), 3.34 (3H, s), 3.37-3.53 (10H, m), 4.00 (2H, 15 t,J=6.4Hz), 4.34 (2H, q, J=7.1Hz), 6.90-7.04 (6H, m),7.45-7.51 (4H, m), 7.94-7.98 (2H, m) MASS (m/z) : 503 (M+1) The following compounds [Preparations 271 to 279] were obtained in a manner similar to that of Preparation 16. 20 Preparation 271 IR (KBr) : 1724, 1558, 1521, 1257 cm - I NMR (CDCl 3 , 5) : 0.91 (3H, t, J=6.9Hz), 1.3-1.9 (8H, m), 3.87 (3H, s), 3.99 (2H, t, J=6.5Hz), 6.98 (2H, d, J=9.0Hz), 7.58 (2H, d, J=9.0Hz), 8.30 (1H, s), 8.53 25 (1H, s) MASS (m/z) : 303 (M+1) Preparation 272 MR (CDCl 3 , 5) : 1.44 (3H, t, J=7.0Hz), 4.08 (2H, qt, J=7.0Hz), 6.98 (2H, d, J=8.8Hz), 7.56 (2H, d, 30 J=8.8Hz), 7.62 (2H, d, J=8.6Hz), 8.07 (2H, d, J=8.6Hz) MASS (m/z) : 257 (M'+1) Preparation 273 IR (KBr) : 2947, 2875, 1722, 1603, 1527, 1495, 35 1435 cm

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1 WO 99/40108 PCT/JP99/00538 176 NMR (CDC1 3 , 5) : 1.88-2.18 (4H, m), 3.51 (2H, m), 3.93 (3H, s), 4.05 (2H, m), 6.98 (2H, d, J=8.6Hz),7.50-7.70 (4H, m), 8.08 (2H, d, J=8.2Hz) MASS (m/z) : 363 (M++1), 365 (M++3) 5 Preparation 274 NMR (CDC1 3 , 5) : 3.40 (3H, s), 3.60 (2H, m), 3.73 (2H, m), 3.89 (2H, m), 3.93 (3H, s), 4.20 (2H, m), 7.01 (2H, d, J=8.8Hz), 7.56 (2H, d, J=8.8Hz), 7.62 (2H, d, J=8.6Hz), 8.08 (2H, d, J=8.6Hz) 10 MASS (m/z) : 331 (M +1) Preparation 275 NMR (CDC1 3 , 5) : 1.26 (3H, t, J=7.0Hz), 3.62 (2H, q, J=7.0Hz), 3.76-3.87 (2H, m), 3.93 (3H, s), 4.12 4.24 (2H, m), 6.96-7.08 (2H, m), 7.52-7.70 (4H, m), 15 8.02-8.14 (2H, m) MASS (m/z) : 301 (M +1) Preparation 276 IR (KBr) : 2949, 2877, 1722, 1695, 1603, 1529, 1497, 1435 cm - 1 20 NMR (CDC1 3 , 5) : 3.47 (3H, s), 3.78 (2H, m), 3.93 (3H, s), 4.18 (2H, m), 6.95-7.08 (2H, m), 7.48-7.68 (4H, m), 8.00-8.12 (2H, m) MASS (m/z) : 287 (M +1) Preparation 277 25 IR (KBr) : 2954, 2873, 1718, 1610, 1544, 1494, 1471, 1280, 1249, 1110 cm - 1 MASS (m/z) : 408 ((M-TFA)+H ) Preparation 278 IR (KBr) : 2935, 2867, 1720, 1610, 1544, 1494, 1471, 30 1436, 1405, 1332, 1280, 1249, 1176, 1110 cm

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1 MASS (m/z) : 436 (M+H ) Preparation 279 IR (KBr) : 2950, 2867, 1708, 1608, 1525, 1471, 1409, 1305, 1259, 1274, 1176, 1103 cm

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1 35 MASS (m/z) : 450 (M+H ) WO 99/40108 PCT/JP99/00538 177 The following compounds [Preparations 280 to 309] were obtained in a manner similar to that of Preparation 47. Preparation 280 IR (KBr) : 1653, 1626, 1574, 1524 cm

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1 5 NMR (DMSO-d 6 , 5) : 0.85 (3H, m), 1.1-1.6 (10H, m), 3.44 (2H, t, J=6.4Hz), 4.42 (2H, brs), 4.48 (2H, s), 7.44 (2H, d, J=8.6Hz), 7.82 (2H, d, J=8.6Hz), 8.12 (1H,s), 8.88 (1H, s), 9.48 (1H, brs) MASS (m/z) : 331 (M+1) 10 Preparation 281 IR (KBr) : 1657, 1603, 1570, 1516, 1313 cm-1 NMR (DMSO-d 6 , 5) : 2.4-2.6 (4H, m), 3.0-3.2 (4H, m), 3.57 (2H, s), 4.41 (2H, d, J=4.3Hz), 6.76 (1H, t, J=7.8Hz), 6.92 (2H, d, J=7.8Hz), 7.20 (2H, t, 15 J=7.8Hz), 7.47 (2H, t, J=8.5Hz), 7.81 (2H, d, J=8.5Hz), 8.12 (1H, s), 8.88 (1H, s),9.48 (1H, t, J=4.3Hz) MASS (m/z) : 377 (M+1) Preparation 282 20 IR (KBr) : 1632, 1562, 1516 cm

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1 NMR (DMSO-d 6 , 5) : 1.5-1.8 (6H, m), 3.0-3.3 (4H, m), 4.38 (2H, d, J=3.9Hz), 7.03 (2H, d, J=9.1Hz), 8.04 (1H, s), 8.70 (1H, s), 9.41 (1H, brs) MASS (m/z) : 286 (M+1) 25 Preparation 283 IR (KBr) : 1649, 1623, 1522 cm-1 NMR (DMSO-d 6 , 5) : 0.8-1.0 (3H, m), 1.2-1.8 (8H, m), 4.00 (2H, t, J=4.0Hz), 4.39 (2H, d, J=4.0Hz),7.05 (2H, d, J=9.0Hz), 7.72 (2H, d, J=9.0Hz),8.07 (1H, s), 30 8.76 (1H, s), 9.44 (1H, t, J=4.0Hz) MASS (m/z) : 303 (M 4 +1) Preparation 284 IR (KBr) : 1618, 1560, 1525 cm

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1 NMR (DMSO-d 6 , 5) : 1.9-2.1 (4H, m), 3.1-3.3 (4H, m), 35 4.38 (2H, brs), 6.62 (2H, d, J=9.0Hz), 7.58 (2H, d, WO 99/40108 PCT/JP99/00538 178 J=9.0Hz), 8.02 (1H, s), 8.64 (1H, s),9.40 (1H, brs) MASS (m/z) : 294 (M'+23) Preparation 285 NMR (CDC1 3 , 5) : 1.10-1.40 (5H, m), 1.40-2.10 (10H, m), 5 2.90-3.15 (2H, m), 3.25-3.50 (1H, m), 3.50-3.75 (3H, m), 4.05 (2H, d, J=3.9Hz), 6.88 (2H, d, J=9.0Hz), 7.63 (2H, dd, J=9.0 and 2.0Hz) APCI MASS (positive) : 318.3 (M +1) Preparation 286 10 NMR (CDC1 3 , 5) : 1.70-2.10 (4H, m), 2.60-2.85 (1H, m), 2.85-3.05 (2H, m), 3.05-3.50 (2H, m), 3.85-4.10 (2H, m), 6.85-7.00 (2H, m),7.10-7.40 (5H, m), 7.68 (2H, d, J=8.8Hz) APCI MASS : 296 (M+1) 15 Preparation 287 NMR (CDC1 3 , 5) : 1.20-2.10 (10H, m), 4.10 (2H, brs), 4.20-4.40 (1H, m), 6.91 (2H, d, J=8.9Hz), 7.49 (1H, brs), 7.78 (2H, d, J=8.9Hz) ESI MASS : 257.3 (M 4 +Na) 20 Preparation 288 NMR (CDC1 3 , 5) : 1.10-1.55 (5H, m), 1.60-2.00 (5H, m), 2.40-2.65 (1H, m), 7.25 (2H, d, J=8.2Hz), 7.67 (2H, d, J=8.2Hz) APCI MASS : 219 (M +1) 25 Preparation 289 IR (KBr) :2958, 2929, 2850, 2821, 1651, 1628, 1603, 1529, 1487, 1443 cm

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1 NMR (DMSO-d 6 , 5) : 1.00-1.36 (5H, m), 1.50-1.92 (5H, m), 2.16-2.38 (1H, m), 2.57-2.64 (4H, m), 3.10-3.28 (4H, 30 m), 4.48 (2H, s), 7.01 (2H, d, J=8.9Hz), 7.59 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.5Hz), 7.86 (2H, d, J=8.4Hz), 9.76 (1H, s) MASS (m/z) : 379 (M'+1) Preparation 290 35 NMR (DMSO-d 6 , 5) : 3.13-3.54 (8H, m), 4.38 (2H, s), 6.81 WO 99/40108 PCT/JP99/00538 179 (1H, t, J=7.2Hz), 7.00 (2H, d, J=6.9Hz), 7.01 (2H, d, J=8.8Hz), 7.24 (2H, t, J=7.9Hz), 7.74 (2H, d, J=8.8Hz), 9.51 (1H, s) MASS (m/z) : 297 (M+1) 5 Preparation 291 NMR (DMSO-d 6 , 5) : 0.87 (3H, t, J=7.4Hz), 1.37-1.60 (4H, m), 1.80-1.98 (2H, m), 2.90-3.10 (2H, m), 3.38 (2H, t, J=6.6Hz), 3.38-3.70 (3H, m), 4.34 and 4.35 (2H, s), 6.92 (2H, d, J=9.0Hz), 7.68 (2H, d, J=8.9Hz), 10 9.45 (1H, brs) MASS (m/z) : 278 (M +1) Preparation 292 IR (KBr) : 1666, 1605, 1545, 1495, 1448 cm

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1 NMR (DMSO-d 6 , 5) : 1.17 (6H, d, J=6.1Hz), 2.20-2.38 (2H, 15 m), 3.59-3.78 (4H, m), 4.49 (2H, s), 7.03 (2H, d, J=8.9Hz), 7.61 (2H, d, J=8.8Hz), 7.69 (2H, d, J=8.5Hz), 7.87 (2H, d, J=8.4Hz), 9.77 (1H,-s) MASS (m/z) : 326 (M+1) Preparation 293 20 NMR (DMSO-d 6 , 5) : 0.88 (6H, s), 1.05-1.52 (6H, m), 1.52-1.73 (2H, m), 2.08-2.26 (1H, m), 2.52-2.72 (4H, m), 3.10-3.31 (4H, m), 4.36 (2H, s), 6.91 (2H, d, J=8.9Hz), 7.69 (2H, d, J=8.8Hz), 9.46 (1H, s) MASS (m/z) : 331 (M +1) 25 Preparation 294 IR (KBr) : 1637, 1606, 1554, 1508, 1456 cm - 1 NMR (DMSO-d 6 , 5) : 1.46-1.70 (2H, m), 1.87-2.06 (2H, m), 2.92-3.12 (2H, m), 3.52-3.73 (3H, m), 4.35 (2H, s), 4.54 (2H, s), 6.94 (2H, d, J=8.9Hz), 7.20-7.42 (5H, 30 m), 7.69 (2H, d, J=8.8Hz), 9.45 (1H, s) MASS (m/z) : 326 (M +1) Preparation 295 NMR (DMSO-d 6 , 5) : 1.16-2.04 (10H, m), 4.29-4.51 (1H, m), 4.51 (2H, s), 7.03 (2H, d, J=8.8Hz), 7.64 (2H, d, 35 J=8.8Hz), 7.69 (2H, d, J=8.4Hz), 7.88 (2H, d, WO 99/40108 PCT/JP99/00538 180 J=8.4Hz), 9.79 (1H, s) MASS (m/z) : 311 (M +1) Preparation 296 IR (KBr) : 2912, 2870, 2846, 1608, 1597, 1533, 1493, 5 1423 cm

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1 NMR (CDC1 3 , 5) : 1.74 (2H, m), 1.97 (2H, m), 2.70-3.12 (3H, m), 3.31 (2H, brs), 4.58 (2H, m), 6.69 (1H, d, J=9.0Hz), 7.05-7.55 (6H, m), 7.88 (1H, dd, J=9.0 and 2.3Hz), 8.56 (1H, d, J=2.3Hz) 10 MASS (m/z) : 297 (M +1) Preparation 297 NMR (DMSO-d 6 , 5) :1.35 (3H, t, J=7.0Hz), 4.07 (2H, q, J=7.0Hz), 4.50 (2H, s), 7.02 (2H, d, J=8.8Hz), 7.66(2H, d, J=8.7Hz), 7.70 (2H, d, J=8.4Hz), 7.89 15 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS (m/z) : 257 (M +1) Preparation 298 IR (KBr) : 2956, 2916, 2870, 1612, 1535, 1514, 1493 cm-1 20 NMR (DMSO-d 6 , 5) : 1.55-1.87 (4H, m), 3.24 (3H, s), 3.38 (2H, t, J=6.2Hz), 4.03 (2H, t,, J=6.1Hz), 4.57 (2H, brs), 7.03 (2H, d, J=8.7 Hz), 7.58-7.78 (4H, m), 7.89 (2H, d, J=8.3Hz), 9.79 (1H, s) MASS (m/z) : 315 (M +1) 25 Preparation 299 IR (KBr) : 1626, 1606, 1566, 1524, 1498, 1454 cm - I NMR (DMSO-d 6 , 5) : 1.00-1.35 (5H, m), 1.35-1.90 (5H, m), 2.16-2.36 (1H, m), 2.54-2.69 (4H, m), 3.12-3.28 (4H, m), 4.35 (2H, s), 6.91 (2H, d, J=8.9Hz), 7.69 (2H, 30 d, J=8.8Hz), 9.46 (1H, s) MASS (m/z) : 303 (M +1) Preparation 300 IR (KBr) : 1659, 1626, 1606, 1531, 1498, 1446 cm-1 NMR (DMSO-d 6 , 5) : 0.89 (3H, d, J=6.8Hz), 1.32-1.80 35 (9H, m), 2.10-2.26 (1H, m), 2.50-2.65 (4H, m), WO 99/40108 PCT/JP99/00538 181 3.15-3.30 (4H, m), 4.36 (2H, s), 6.92 (2H, d, J=9.0Hz), 7.69 (2H, d, J=8.8Hz), 9.46 (1H, s) MASS (m/z) : 317 (M+1) Preparation 301 5 IR (KBr) : 1660, 1606, 1549, 1506, 1446 cm

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1 NMR (DMSO-d 6 , 5) : 0.86 (3H, d, J=6.4Hz), 0.84-1.05 (2H, m), 1.05-1.54 (3H, m), 1.60-1.90 (4H, m), 2.12-2.33 (1H, m), 2.54-2.65 (4H, m), 3.11-3.27 (4H, m), 4.36 (2H, s), 6.91 (2H, d, J=8.9Hz), 7.69 (2H, d, J=8.8Hz), 10 9.46 (1H, s) MASS (m/z) : 317 (M +1) Preparation 302 NMR (DMSO-d 6 , 5) : 1.17 (3H, t, J=7.0Hz), 3.51 (2H, q, J=7.0Hz), 4.50 (2H, m), 4.52 (2H, s), 7.42 (2H, d, 15 J=8.2Hz), 7.66-7.80 (4H, m), 7.92 (2H, d, J=8.9Hz), 9.83 (1H, s) MASS (m/z) : 271 (M+1) Preparation 303 MR (DMSO-d 6 , 5) : 3.27 (3H, m), 3.45-3.68 (4H, m), 20 4.54 (4H, s), 7.43 (2H, d, J=8.2Hz), 7.66-7.81 (4H, m), 7.92 (2H, d, J=8.4Hz), 9.83 (1H, s) MASS (m/z) : 301 (M+1) Preparation 304 NMR (DMSO-d 6 , 5) : 3.25 (3H, s), 3.44-3.55 (2H, m), 25 3.55-3.65 (2H, m), 3.73-3.86 (2H, m), 4.08-4.20 (2H, m), 4.52 (2H, s), 7.05 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.4Hz), 7.89 (2H, d, J=8.5Hz), 9.80 (1H, s) MASS (m/z) : 331 (M+1) 30 Preparation 305 NMR (DMSO-d 6 , 5) : 1.11 (3H, t, J=7.0Hz), 1.96 (2H, m), 3.43 (2H, q, J=7.0Hz), 3.52 (2H, t, J=6.4Hz), 4.07 (2H, t, J=6.4Hz), 4.50 (2H, s), 7.03 (2H, d, J=8.8Hz), 7.66 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.SHz), 7.89 35 (2H, d, J=8.4Hz), 9.79 (1H, s) WO 99/40108 PCT/JP99/00538 182 MASS (m/z) : 315 (M++1) Preparation 306 NMR (DMSO-d 6 , 6) : 1.14 (3H, t, J=7.0Hz), 3.51 (2H, q, J=7.0Hz), 3.66-3.80 (2H, m), 4.07-4.20 (2H, m), 4.51 5 (2H, s), 7.05 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.8Hz), 7.70 (2H, d, J=8.4Hz), 7.89 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS (m/z) : 301 (M +1) Preparation 307 10 IR (KBr) : 2933, 2873, 1608, 1531, 1491 cm

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1 NMR (DMSO-d 6 , 6) : 1.97 (2H, m), 3.26 (3H, s), 3.49 (2H, t, J=6.3Hz), 4.07 (2H, t, J=6.4Hz), 4.50 (2H, brs), 7.03 (2H, d, J=8.8Hz), 7.66 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.4Hz), 9.79 (1H, 15 s) MASS (m/z) : 301 (M +1) Preparation 308 IR (KBr) : 2927, 2881, 1630, 1606, 1533, 1489 cm -1 NMR (DMSO-d 6 , 5) : 3.32 (3H, s), 3.67 (2H, m), 4.14 (3H, 20 s), 4.52 (2H, s), 7.05 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.8Hz), 7.70 (2H, d, J=8.6Hz), 7.89 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS (m/z) : 287 (M++1) Preparation 309 25 IR (Nujol) : 3292, 1603 cm

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1 NMR (DMSO-d 6 , 6) : 1.8-2.2 (4H, m), 2.92 (3H, s), 3.0-3.2 (2H, m), 3.6-3.8 (2H, m), 4.36 (2H, s), 6.98 (2H, d, J=8.8Hz), 7.44 (4H, s), 7.71 (2H, d, J=8.8Hz), 9.46 (1H, s) 30 (+)APCI MASS : 360 (M+H) The following compounds [Preparations 310 to 345] were obtained in a manner similar to that of Preparation 7. Preparation 310 IR (KBr) : 1724, 1282 cm-1 35 NMR (DMSO-d 6 , 6) : 0.86 (3H, t, J=6.9Hz), 1.1-1.6 (10H, WO 99/40108 PCT/JP99/00538 183 m), 3.45 (2H, t, J=6.4Hz), 3.90 (3H, s), 4.50 (2H, s), 7.48 (2H, d, J=8.6Hz), 7.86 (2H, d, J=8.6Hz), 8.04 (2H, d, J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 8.26 (1H, s), 9.02 (1H, s), 10.37 (1H, s), 10.70 (1H, s) 5 MASS (m/z) : 493 (M++1) Preparation 311 IR (KBr) : 1718, 1614, 1279 cm

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1 NMR (DMSO-d 6 , 5) : 2.4-2.6 (4H, m), 3.0-3.2 (4H, m), 3.59 (2H, s), 3.90 (3H, s), 6.77 (1H, t, J=7.7Hz), 10 6.92 (2H, d, J=7.7Hz), 7.20 (2H, t, J=7.7Hz), 7.50 (2H, t, J=8.5Hz), 7.86 (2H, d, J=8.5Hz), 8.04 (2H, t, J=8.6Hz), 8.11 (2H, d, J=8.6Hz), 8.26 (1H, s), 9.02 (1H, s), 10.37 (1H, s), 10.70 (1H, s) MASS (m/z) : 539 (M +1) 15 Preparation 312 NMR (DMSO-d 6 , 5) : 1.10-2.00 (14H, m), 2.95-3.15 (2H, m), 3.40-3.75 (4H, m), 3.90 (3H, s), 7.00 (2H,- d, J=8.9Hz), 7.80 (2H, d, J=8.8Hz), 8.03 (2H, d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.25 (1H, s), 20 10.58 (1H, s) APCI MASS (positive) : 480.3 (M +1) Preparation 313 IR (KBr) : 1724, 1635, 1570, 1520, 1279 cm

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1 NMR (DMSO-d 6 , 5) : 1.5-1.7 (6H, m), 3.1-3.3 (4H, m), 25 3.90 (3H, s), 7.05 (2H, d, J=9.1Hz), 7.66 (2H, d, J=9.1Hz), 8.04 (2H, d, J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 8.85 (1H, s), 10.30 (1H, s), 10.68 (1H, s) MASS (m/z) : 448 (M'+1) 30 Preparation 314 IR (KBr) : 1716, 1603, 1552, 1521, 1470, 1284, 1257 cm - 1 NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.8Hz), 1.2-1.8 (8H, m), 3.90 (3H, s), 4.02 (2H, t, J=6.4Hz), 7.08 (2H, 35 d, J=9.0Hz), 7.77 (2H, d, J=9.0Hz), 8.04 (2H, d, WO 99/40108 PCT/JP99/00538 184 J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 8.91 (1H, s), 10.33 (1H, s), 10.69 (1H, s) MASS (m/z) : 465 (M+1) Preparation 315 5 NMR (DMSO-d 6 , 5) : 1.60-1.95 (4H, m), 2.65-3.00 (3H, m), 3.90 (3H, s), 4.04 (2H, m), 7.05 (2H, d, J=8.9Hz), 7.10-7.40 (5H, m), 7.83 (2H, d, J=8.9Hz), 8.00-8.15 (4H, m), 10.27 (1H, s), 10.59 (1H, s) APCI MASS : 458 (M+) 10 Preparation 316 IR (KBr) : 1720, 1645, 1560, 1525, 1281 cm

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1 NMR (DMSO-d 6 , 5) : 1.9-2.1 (4H, m), 3.2-3.4 (4H, m), 3.90 (3H, s), 6.64 (2H, d, J=9.0Hz), 7.63 (2H, d, J=9.0Hz), 8.04 (2H, d, J=8.7Hz), 8.11 (2H, d, 15 J=8.7Hz), 8.15 (1H, s), 8.78 (1H, s), 10.28 (1H, s), 10.67 (1H, s) MASS (m/z) : 456 (M++23) Preparation 317 NMR (DMSO-d 6 , 5) : 1.10-2.10 (10H, m), 3.90 (3H, s), 20 4.35-4.55 (1H, m), 7.04 (2H, d, J=8.8Hz), 7.88 (2H, d, J=8.8Hz), 8.00-8.15 (4H, m), 10.41 (1H, s), 10.64 (1H, s) APCI MASS (m/z) : 397 (M+1) Preparation 318 25 NMR (DMSO-d 6 , 5) : 1.15-1.60 (5H, m), 1.60-1.90 (5H, m), 2.50-2.70 (1H, m), 3.90 (3H, s), 7.37 (2H, d, J=8.3Hz), 7.85 (2H, d, J=8.2Hz), 8.00-8.15 (4H, m), 10.48 (1H, s), 10.68 (1H, s) APCI MASS : 381 (M +1) 30 Preparation 319 IR (KBr) : 2927, 2852, 1722, 1684, 1645, 1603, 1495, 1446 cm - 1 NMR (DMSO-d 6 , 5) : 1.00-1.36 (5H, m), 1.51-1.91 (5H, m), 2.20-2.38 (1H, m), 2.56-2.72 (4H, m), 3.12-3.28 35 (4H, m), 3.90 (3H, s), 7.03 (2H, d, J=8.9Hz), 7.64 WO 99/40108 PCT/JP99/00538 185 (2H, d, J=8.7Hz), 7.77 (2H, d, J=8.5Hz), 7.97 (2H, d, J=8.4Hz), 8.00-8.16 (4H, m), 10.57 (1H, s), 10.71 (1H, s) MASS (m/z) : 541 (M +1) 5 Preparation 320 NMR (DMSO-d 6 , 5) : 3.21-3.54 (8H, m), 3.90 (3H, s), 6.82 (1H, t, J=7.2Hz), 7.01 (2H, d, J=7.9Hz), 7.08 (2H, d, J=8.9Hz), 7.25 (2H, t, J=7.9Hz), 7.85 (2H, d, J=8.8Hz), 8.04 (2H, d, J=8.6Hz), 8.09 (2H, d, 10 J=8.6Hz), 10.31 (1H, s), 10.60 (1H, s) MASS (m/z) : 459 (M +1) Preparation 321 NMR (DMSO-d 6 , 5) : 0.88 (3H, t, J=7.4Hz), 1.41-1.63 (4H, m), 1.84-2.01 (2H, nm), 2.96-3.16 (2H, m), 3.40 (2H, 15 t, J=6.6Hz), 3.40-3.76 (3H, m), 3.90 (3H, s), 7.00 (2H, d, J=8.9Hz), 7.80 (2H, d, J=8.8Hz), 8.00-8.16 (4H, m), 10.25 (1H, s), 10.58 (1H, s) MASS (m/z) : 440 (M +1) Preparation 322 20 NMR (DMSO-d 6 , 5) : 1.18 (6H, d, J=6.1Hz), 2.18-2.43 (2H, m), 3.51-3.83 (4H, m), 3.90 (3H, s), 7.06 (2H, d, J=8.9Hz), 7.66 (2H, d, J=8.7Hz), 7.78 (2H, d, J=8.4Hz), 7.98 (2H, d, J=8.4Hz), 7.98-8.16 (4H, m), 10.58 (1H, s), 10.71 (1H, s) 25 MASS (m/z) : 488 (M +1) Preparation 323 NMR (DMSO-d 6 , 6) : 0.89 (6H, s), 1.05-1.72 (8H, m), 2.09-2.30 (1H, m), 2.54-2.73 (4H, m), 3.14-3.37 (4H, m), 3.90 (3H, s), 6.99 (2H, d, J=8.9Hz), 7.81 (2H, 30 d, J=8.8Hz), 8.03 (2H, d, J=8.6Hz), 8.09 (2H, d, J=8.7Hz), 10.26 (1H, s), 10.58 (1H, s) MASS (m/z) : 493 (M +1) Preparation 324 IR (KBr) : 1714, 1687, 1653, 1605, 1560, 1522, 1460, 35 1439 cm - 1 WO 99/40108 PCT/JP99/00538 186 NMR (DMSO-d 6 , 5) : 1.45-1.70 (2H, m), 1.87-2.10 (2H, m), 2.98-3.20 (2H, m), 3.56-3.78 (3H, m), 3.90 (3H, s), 4.56 (2H, s), 7.01 (2H, d, J=9.0Hz), 7.21-7.46 (5H, m), 7.80 (2H, d, J=8.8Hz), 8.04 (2H, d, J=8.7Hz), 5 8.09 (2H, d, J=8.7Hz), 10.26 (1H, s), 10.58 (1H, s) MASS (m/z) : 488 (M+1) Preparation 325 NMR (DMSO-d 6 , 6) : 1.18-2.05 (10H, m), 3.90 (3H, s), 4.34-4.50 (1H, m), 7.05 (2H, d, J=8.8Hz), 7.69 (2H, 10 d, J=8.7Hz), 7.78 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.4Hz), 8.06 (2H, d, J=8.6Hz), 8.11 (2H, d, J=8.6Hz), 10.60 (1H, s), 10.72 (1H, s) MASS (m/z) : 473 (M+1) Preparation 326 15 IR (KBr) : 2945, 2852, 1720, 1693, 1645, 1601, 1524, 1485 cm-1 NMR (DMSO-d 6 , 5) : 1.61 (2H, m), 1.87 (2H, m), 2.78-3.14 (3H, m), 3.90 (3H, s), 4.61 (2H, m), 6.96 (1H, d, J=9.2Hz), 7.27 (5H, m), 7.98-8.10 (1H, m), 8.03 (2H, 20 d, J=8.7Hz), 8.10 (2H, d, J=8.6Hz), 8.70 (1H, d, J=2.3Hz), 10.34 (1H, s), 10.62 (1H, s) MASS (m/z) : 459 (M +1) Preparation 327 NMR (DMSO-d 6 , 5) : 1.36 (3H, t, J=7.0Hz), 3.90 (3H, s), 25 4.09 (2H, q, J=6.9Hz), 7.04 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.8Hz), 7.79 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.5Hz), 8.06 (2H, d, J=8.8Hz), 8.10 (2H, d, J=8.7Hz), 10.60 (1H, s), 10.72 (1H, s) MASS (m/z) : 419 (M +1) 30 Preparation 328 IR (KBr) :2951, 2872, 1724, 1680, 1651, 1605, 1554, 1497, 1439 cm-1 NMR (DMSO-d 6 , 5) : 1.57-1.89 (4H, m), 3.25 (3H, s), 3.39 (2H, t, J=6.2Hz), 3.91 (3H, s), 4.05 (2H, t, J=6.1Hz), 35 7.05 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.7Hz), 7.79 WO 99/40108 PCT/JP99/00538 187 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.5Hz), 8.06 (2H, d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.61 (1H, s), 10.73 (1H, s) MASS (m/z) : 477 (M +1) 5 Preparation 329 IR (KBr) : 1720, 1678, 1643, 1608, 1564, 1525, 1502 cm - I 1 MMR (DMSO-d 6 , 5) : 0.96-1.36 (5H, m), 1.49-1.91 (5H, m), 2.16-2.35 (1H, m), 2.52-2.75 (4H, m), 3.10-3.35 (4H, 10 m), 3.90 (3H, s), 6.99 (2H, d, J=8.9Hz), 7.81 (2H, d, J=8.8Hz), 8.04 (2H, d, J=8.6Hz), 8.09 (2H, d, J=8.7Hz), 10.27 (1H, s), 10.59 (1H, s) MASS (m/z) : 465 (M +1) Preparation 330 15 IR (KBr) : 1722, 1676, 1641, 1608, 1500, 1446 cm - I 1 NMR (DMSO-d 6 , 5) : 0.90 (3H, d, J=6.8Hz), 1.30-1.85 (9H, m), 2.11-2.30 (1H, m), 2.63-2.69 (4H, m), 3.18-3.38 (4H, m), 3.90 (3H, s), 6.99 (2H, d, J=9.0Hz), 7.81 (2H, d, J=8.8Hz), 8.04 (2H, d, J=9.1Hz), 8.09 (2H, 20 d, J=8.7Hz), 10.27 (1H, s), 10.58 (1H, s) MASS (m/z) : 479 (M +1) Preparation 331 IR (KBr) : 1722, 1678, 1643, 1608, 1500, 1446 cm -1 NMR (DMSO-d 6 , 6) : 0.86 (3H, d, J=6.4Hz), 0.88-1.08 (2H, 25 m), 1.08-1.51 (3H, m), 1.60-1.90 (4H, m), 2.14-2.35 (1H, m), 2.54-2.66 (4H, m), 3.13-3.36 (4H, m), 3.90 (3H, s), 6.98 (2H, d, J=8.9Hz), 7.81 (2H, d, J=8.8Hz), 8.03 (2H, d, J=8.7Hz), 8.09 (2H, d, J=8.6Hz), 10.26 (1H, s), 10.58 (1H, s) 30 MASS (m/z) : 479 (M+1) Preparation 332 NMR (DMSO-d 6 , 5) : 1.18 (3H, t, J=7.0Hz), 3.52 (2H, q, J=7.0Hz), 3.90 (3H, m), 4.52 (2H, s), 7.45 (2H, d, J=8.2Hz), 7.75 (2H, d, J=8.2Hz), 7.84 (2H, d, 35 J=8.4Hz), 8.03 (2H, d, J=8.4Hz), 8.00-8.17 (4H, m), WO 99/40108 PCT/JP99/00538 188 10.64 (1H, s), 10.74 (1H, s) MASS (m/z) : 433 (M +1) Preparation 333 NMR (DMSO-d 6 , 5) : 3.28 (3H, m), 3.47-3.66 (4H, m), 3.91 5 (3H, s), 4.56 (2H, s), 7.46 (2H, d, J=8.3Hz), 7.76 (2H, d, J=8.2Hz), 7.85 (2H, d, J=8.4Hz), 7.98-8.16 (6H, m), 10.65 (1H, s), 10.74 (1H, s) MASS (m/z) : 463 (M +1) Preparation 334 10 NMR (DMSO-d 6 , 5) : 3.26 (3H, s), 3.39-3.55 (2H, m), 3.55-3.66 (2H, m), 3.77 (2H, t, J=4.5Hz), 3.90 (3H, s), 4.16 (2H, t, J=4.5Hz), 7.08 (2H, d, J=8.8Hz), 7.72 (2H, d, J=8.8Hz), 7.80 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.SHz), 8.06 (2H, d, J=8.7Hz), 8.10 (2H, 15 d, J=8.7Hz), 10.61 (1H, s), 10.73 (1H, s) MASS (m/z) : 493 (M+1) Preparation 335 NMR (DMSO-d 6 , 5) : 1.12 (3H, t, J=7.0Hz), 1.88-2.12 (2H, m), 3.44 (2H, q, J=7.0Hz), 3.53 (2H, t, J=6.4Hz), 20 3.91 (3H, s), 4.09 (2H, t, J=6.4Hz), 7.06 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.8Hz), 7.79 (2H, d, J=8.SHz), 8.00 (2H, d, J=8.5Hz), 8.06 (2H, d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.61 (1H, s), 10.72 (1H, s) 25 MASS (m/z) : 477 (M+1) Preparation 336 NMR (DMSO-d 6 , 5) : 1.14 (3H, t, J=7.0Hz), 3.52 (2H, q, J=7.0Hz), 3.68-3.78 (2H, m), 3.90 (3H, s), 4.14 4.22 (2H, m), 7.08 (2H, d, J=8.8Hz), 7.72 (2H, d, 30 J=8.8Hz), 7.80 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.4Hz), 8.06 (2H, d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.61 (1H, s), 10.73 (1H, s) MASS (m/z) : 463 (M+1) Preparation 337 35 IR (KBr) : 1724, 1680, 1655, 1605, 1495, 1437 cm - I WO 99/40108 PCT/JP99/00538 189 NMR (DMSO-d 6 , 5) : 1.98 (2H, m), 3.26 (3H, s), 3.49 (2H, t, J=6.3Hz), 3.90 (3H, s), 4.09 (2H, t, J=6.4Hz), 7.06 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.8Hz), 7.79 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.5Hz), 8.06 (2H, 5 d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.60 (1H, s), 10.72 (1H, s) MASS (m/z) : 463 (M+1) Preparation 338 IR (KBr) : 1724, 1682, 1645, 1605, 1495, 1439, 10 1404 cm

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1 NMR (DMSO-d 6 , 5) : 3.33 (3H, s), 3.69 (2H, m), 3.90 (3H, s), 4.16 (2H, m), 7.07 (2H, d, J=8.9Hz), 7.72 (2H, d, J=8.7Hz), 7.72 (2H, d, J=8.7Hz), 7.80 (2H, d, J=8.6Hz), 9.79 (1H, s) 15 MASS (m/z) : 287 (M+1) Preparation 339 IR (Nujol) : 3259, 1724, 1672, 1626, 1605 cm

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1 NMR (DMSO-d 6 , 6) : 1.9-2.2 (4H, m), 2.93 (3H, s), 3.0-3.4 (2H, m), 3.7-3.8 (2H, m), 3.90 (3H, s), 7.06 (2H, 20 d, J=8.9Hz), 7.45 (4H, s), 7.82 (2H, d, J=8.9Hz), 8.0-8.2 (4H, m), 10.27 (1H, s), 10.59 (1H, s) (+)APCI MASS : 522 (M+H) + Preparation 340 IR (KBr) : 3247.5, 1727.9, 1687.4, 1255.4 cm

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1 25 NMR (DMSO-d 6 , 5) : 1.23-1.99 (16H, m), 2.15-2.45 (2H, m), 3.21 (3H, s), 3.27-3.35 (2H, m), 3.60 (3H, s), 4.02 (2H, t, J=6.4Hz), 7.00 (2H, d, J=8.6Hz), 7.83 (2H, d, J=8.6Hz), 9.74 (1H, s), 10.12 (1H, s) MASS (m/z) : 435 (M+1) 30 Preparation 341 IR (KBr) : 3236.0, 1724.0, 1677.8, 1255.4 cm

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1 NMR (DMSO-d 6 , 6) : 0.91 (3H, t, J=7.0Hz), 1.30-1.50 (4H, m), 1.70-1.80 (2H, m), 3.87 (3H, s), 4.03 (2H, t, J=6.4Hz), 7.03-7.07 (2H, m), 7.68-8.00 (8H,m), 35 10.50-11.00 (2H, m) WO 99/40108 PCT/JP99/00538 190 MASS (m/z) : 467 (M+1) Preparation 342 IR (KBr) : 3201.3, 1714.4, 1594.8, 1253.5 cm-1 NMR (DMSO-d 6 , 5) : 1.30-1.80 (8H, m), 2.42 (3H, s), 3.21 5 (3H, s), 3.28-3.34 (2H, m), 3.34 (3H, s), 3.85 (3H, s), 4.04 (2H, t, J=6.4Hz), 7.04 (2H, d, J=8.8Hz), 7.36 (1H, s), 7.73 (1H, s), 7.95 (2H, d, J=9Hz), 10.22 (1H, s), 10.39 (1H, s) MASS (m/z) : 457 (M+1) 10 Preparation 343 IR (KBr) : 3199.3, 1716.3, 1608.3, 1253.5 cm-1 NMR (DMSO-d 6 , 5) : 1.37-1.80 (8H, m), 3.21 (3H, s), 3.28-3.33 (2H, m), 3.71 (3H, s), 4.03 (2H, t, J=6.4Hz), 6.39-6.59 (2H, m), 7.00-7.04 (2H, m), 15 7.24-7.47 (2H, m), 7.83-7.88 (2H, m), 10.35 (2H, d, J=6.9Hz) MASS (m/z) : 405 (M+1) Preparation 344 IR (KBr) : 3193.5, 1718.3, 1606.4, 1249.6 cm- 1 20 NMR (DMSO-d 6 , 6) : 1.00 (3H, t, J=7.4Hz), 1.75-1.85 (2H, m), 3.97-4.03 (5H, m), 7.06-8.78 (12H, m), 10.64 (1H, s), 10.72 (1H, s) MASS (m/z) : 483 (M+1) Preparation 345 25 IR (KBr) : 3220.5, 1720.2, 1685.5, 1290.1, 1251.6 cm

-

1 NMR (DMSO-d 6 , 5) : 1.30-1.80 (8H, m), 3.22 (3H, s), 3.28-3.34 (2H, m), 3.94 (3H, s), 4.05 (2H, t, J=6.3Hz), 7.04-7.08 (2H, m), 7.91-8.71 (8H, m), 30 10.47 (1H, bs), 10.70 (1H, bs) MASS (m/z) : 479 (M+1) The following compounds [Preparations 346 to 1355] were obtained in a manner similar to that of Preparation 41. Preparation 346 35 IR (KBr) : 1726, 1284 cm

-

1 WO 99/40108 PCT/JP99/00538 191 NMR (CDCl 3 , 5) : 0.89 (3H, t, J=6.8Hz), 1.2-1.8 (10H, m), 3.51 (2H, t, J=6.6Hz), 3.97 (3H, s), 4.56 (2H, s), 7.48 (2H, d, J=8.6Hz), 7.74 (2H, d, J=8.6Hz), 8.07 (2H, d, J=8.6Hz), 8.17 (2H, d, J=8.6Hz), 8.18 (1H, 5 s), 8.55 (1H, s) MASS (m/z) : 491 (M'+1) Preparation 347 NMR (CDC1 3

-CD

3 OD, 5) : 1.15-1.40 (6H, m), 1.40-2.30 (12H, m), 2.80-3.55 (4H, m), 3.65-3.80 (4H, m), 3.97 (3H, 10 s), 4.00-4.25 (1H, m), 7.20 (2H, d, J=8.6Hz), 7.93 (2H, d, J=8.6Hz), 8.06 (2H, d, J=8.6Hz), 8.16 (2H, d, J=8.6Hz) ESI MASS (positive) : 478 (M +1) Preparation 348 15 NMR (CDC1 3

+CD

3 OD, 5) : 1.20-1.60 (5H, m), 1.65-2.05 (5H, m), 2.50-2.70 (1H, m), 3.97 (3H, s), 7.36 (2H, d, J=8.2Hz), 7.92 (2H, d, J=8.3Hz), 8.05-8.20 t4H, m) APCI MASS (positive) : 379.2 (M+1) Preparation 349 20 NMR (CDC1 3 , 5) : 1.20-2.15 (10H, m), 3.97 (3H, s), 4.30-4.50 (1H, m), 7.01 (2H, d, J=8.9Hz), 7.92 (2H, d, J=8.9Hz), 8.00-8.30 (4H, m) APCI MASS (positive) : 395.2 (M +1) Preparation 350 25 IR (KBr) : 1722, 1651, 1574, 1522, 1279 cm

-

1 NMR (CDC1 3 , 5) : 0.92 (3H, t, J=6.7Hz), 1.2-1.9 (8H, m), 3.97 (3H, s), 4.01 (2H, t, J=6.5Hz), 7.01 (2H, d, J=9.0Hz), 7.64 (2H, d, J=9.0Hz), 8.07 (2H, d, J=8.6Hz), 8.15 (1H, s), 8.17 (2H, d, J=8.6Hz), 8.46 30 (1H, s) MASS (m/z) : 465 (M +1) Preparation 351 IR (KBr) : 1727.9, 1249.6, 1180.2 cm

-

1 NMR (DMSO-d 6 , 5) : 1.30-2.30 (18H, m), 3.21 (3H, s), 35 3.28-3.35 (2H, m), 3.62 (3H, s), 4.04 (2H, t, WO 99/40108 PCT/JP99/00538 192 J=6.4Hz), 7.07 (2H, d, J=8.7Hz), 7.85 (2H, d, J=8.7Hz) MASS (m/z) : 433 (M+1) Preparation 352 5 IR (KBr) : 1724.0, 1604.5, 1261.2, 1182.2 cm -1 NMR (DMSO-d 6 , 5) : 1.23-1.80 (8H, m), 2.48 (3H, s), 3.22 (3H, s), 3.22-3.33 (2H, m), 3.33 (3H, s), 3.87 (3H, s), 4.07 (2H, t, J=6.4Hz), 7.13 (2H, d, J=8.9Hz), 7.76-8.00 (4H, m) 10 MASS (m/z) : 455 (M+1) Preparation 353 IR (KBr) : 1718.3, 1629.6, 1257.4, 1226.5 cm -1 NMR (DMSO-d 6 , 5) : 1.25-1.75 (8H, m), 3.21 (3H, s), 3.28-3.34 (2H, m), 3.72 (3H, s), 4.06 (2H, t, 15 J=6.4Hz), 6.33-6.41 (2H, m), 7.09-7.13 (2H, m), 7.27-7.60 (2H, m), 7.90-7.95 (2H, m) MASS (m/z) : 403 (M+1) Preparation 354 IR (KBr) : 1716.3, 1297.9, 1255.4 cm - 1 20 NMR (DMSO-d 6 , 5) : 1.20-1.80 (8H, m), 3.22 (3H, s), 3.28-3.33 (2H, m), 3.95 (3H, s), 4.08 (2H, t, J=6.4Hz), 7.12-7.17 (2H, m), 7.97-8.73 (8H, m) MASS (m/z) : 477 (M+1) Preparation 355 25 IR (KBr) : 2935.1, 2854.1, 1257.4, 827.3 cm

-

1 NMR (CDCl 3 , 5) : 0.80-1.10 (3H, m), 1.20-1.60 (8H, m), 1.70-2.00 (2H, m), 4.01 (2H, t, J=6.5Hz), 6.96 (2H, d, J=8.8Hz), 7.44 (2H, d, J=8.7Hz), 7.54 (2H, d, J=8.7Hz), 7.89 (2H, d, J=8.8Hz), 7.95 (1H, s) 30 APCI MASS (m/z) : 430, 432 The following compounds [Preparations 356 to 382] were obtained in a manner similar to that of Preparation 48. Preparation 356 IR (KBr) : 1714, 1514, 1277 cm-1 35 NMR (CDC1 3 , 5) : 2.66 (4H, brs), 3.23 (4H, brs), 3.64 (2H, WO 99/40108 PCT/JP99/00538 193 s), 3.90 (3H, s), 6.92 (3H, m), 7.26 (2H, m), 7.52 (2H, d, J=8.0Hz), 7.73 (2H, d, J=8.0Hz), 8.0-8.3 (5H, m), 8.56 (1H, s) MASS (m/z) : 537 (M+1) 5 Preparation 357 IR (KBr) : 1718, 1520, 1275, 1242 cm -1 NMR (CDC1 3 , 5) : 1.5-1.8 (6H, m), 3.24 (4H, t, J=5.3Hz), 3.97 (3H, s), 7.02 (2H, d, J=9.1Hz), 7.59 (2H, d, J=9.1Hz), 8.07 (2H, d, J=8.7Hz), 8.14 (1H, s), 8.17 10 (2H, d, J=8.7Hz), 8.44 (1H, s) MASS (m/z) : 446 (M+1) Preparation 358 NMR (DMSO-d 6 , 5) : 1.50-1.95 (4H, m), 2.60-3.05 (3H, m), 3.90 (3H, s), 3.95-4.10 (2H, m), 6.90-7.35 (7H, m), 15 7.65-8.15 (6H, m) APCI MASS (m/z) : 456 (M +) Preparation 359 NMR (CDC1 3 , 5) : 2.0-2.2 (4H, m), 3.2-3.4 (4H, m), 3.97 (3H, s), 6.62 (2H, d, J=8.8Hz), 7.56 (2H, d, J=8.8Hz), 20 8.07 (2H, d, J=8.4Hz), 8.13 (1H, s), 8.17 (2H, d, J=8.4Hz), 8.40 (1H, s) MASS (m/z) : 432 (M+1) Preparation 360 NMR (CDC1 3 , 5) : 0.95 (3H, t, J=6.6Hz), 1.33-1.94 (6H, 25 m), 3.99 (3H, s), 4.05 (2H, t, J=6.5Hz), 7.02 (2H, d, J=8.8Hz), 7.98 (2H, d, J=8.7Hz), 8.05-8.33 (8H, m) MASS (m/z) : 543 (M+1) Preparation 361 30 IR (KBr) : 1722, 1603, 1500, 1439, 1417 cm

-

1 NMR (CDC1 3 , 5) : 3.30-3.69 (8H, m), 3.93 (3H, s), 6.88-7.17 (3H,n m), 7.03 (2H, d, J=9.0Hz), 7.34 (2H, t, J=7.7Hz), 7.94 (2H, d, J=8.8Hz), 8.08 (2H, d, J=8.6Hz), 8.16 (2H, d, J=8.6Hz) 35 MASS (m/z) : 457 (M+1) WO 99/40108 PCT/JP99/00538 194 Preparation 362 NMR (CDC1 3 , 5) : 0.95 (3H, t, J=7.4Hz), 1.40-2.16 (6H, m), 3.03-3.30 (2H, m), 3.45 (2H, t, J=6.7Hz), 3.44-3.95 (3H, m), 3.96 (3H, s), 6.85-7.12 (2H, m), 5 7.80-7.97 (2H, m), 8.07 (2H, d, J=8.6Hz), 8.15 (2H, d, J=8.6Hz) MASS (m/z) : 438 (M+1) Preparation 363 IR (KBr) : 1722, 1605, 1520, 1439, 1414 cm

-

1 10 NMR (CDC1 3 , 5) : 0.92 (6H, s), 1.12-1.90 (8H, m), 2.18-2.24 (1H, m), 2.68-2.86 (4H, m), 3.27-3.46 (4H, m), 3.96 (3H, s), 6.97 (2H, d, J=9.0Hz), 7.90 (2H, d, J=8.9Hz), 8.07 (2H, d, J=8.6Hz), 8.15 (2H, d, J=8.6Hz) MASS (m/z) : 491 (M+1) 15 Preparation 364 IR (KBr) : 1716, 1606, 1520, 1441, 1417 cm-1 NMR (CDC1 3 , 6) : 1.70-2.26 (4H, m), 3.10-3.31 (2H, m), 3.60-3.84 (3H, m), 3.96 (3H, s), 4.60 (2H, s), 6.90-7.20 (2H, nm), 7.26-7.46 (5H, m), 7.91 (2H, d, 20 J=8.8Hz), 8.09 (2H, d, J=8.7Hz), 8.15 (2H, d, J=8.7Hz) MASS (m/z) : 486 (M+1) Preparation 365 IR (KBr) : 2941, 2845, 1713, 1601, 1549, 1504, 1431, 25 1404 cm

-

1 NMR (CDCl 3 , 5) : 1.79 (2H, m), 2.01 (2H, m), 2.84 (1H, m), 3.08 (2H, m), 3.96 (3H, s), 4.64 (2H, m), 6.80 (1H, d, J=9.1Hz), 7.18-7.40 (5H, m), 8.03-8.23 (5H, m), 8.73 (1H, d, J=2.3Hz) 30 MASS (m/z) : 457 (M'+1) Preparation 366 IR (KBr) : 2949, 2870, 1722, 1605, 1504, 1437 cm - 1 NMR (CDCl 3 , 5) : 1.66-2.00 (4H, m), 3.27 (3H, s), 3.47 (2H, t, J=6.0Hz), 3.97 (3H, s), 4.05 (2H, t, J=6.1Hz), 35 7.00 (2H, d, J=8.6Hz), 7.59 (2H, d, J=8.6Hz), 7.70 WO 99/40108 PCT/JP99/00538 195 (2H, d, J=8.2Hz), 8.00-8.14 (4H, m), 8.17 (2H, d, J=8.5Hz) MASS (m/z) : 475 (M+1) Preparation 367 5 IR (KBr) : 1720, 1605, 1522, 1439, 1416 cm - I NMR (CDC1 3 , 5) : 1.00-1.41 (5H, m), 1.56-2.14 (5H, m), 2.24-2.41 (1H, m), 2.66-2.82 (4H, m), 3.27-3.43 (4H, m), 3.96 (3H, s), 6.96 (2H, d, J=9.0Hz), 7.89 (2H, d, J=8.9Hz), 8.06 (2H, d, J=8.6Hz), 8.14 (2H, d, 10 J=8.6Hz) MASS (m/z) : 463 (M+1) Preparation 368 IR (KBr) : 1718, 1605, 1520, 1439, 1414 cm -1 NMR (CDC1 3 , 5) : 0.95 (3H, d, J=6.9Hz), 1.38-1.90 (9H, 15 nm), 2.24-2.47 (1H, m), 2.66-2.92 (4H, m), 3.28-3.53 (4H, m), 3.96 (3H, s), 6.97 (2H, d, J=9.0Hz), 7.90 (2H, d, J=8.9Hz), 8.07 (2H, d, J=8.7Hz), 8.15 (2H, d, J=8.7Hz) MASS (m/z) : 477 (M+1) 20 Preparation 369 IR (KBr) : 1724, 1605, 1520, 1437, 1412 cm-1 NMR (CDC1 3 , 6) : 0.89 (3H, d, J=6.4Hz), 0.89-1.13 (2H, m), 1.13-2.07 (7H, m), 2.24-2.50 (1H, m), 2.68-2.93 (4H, m), 3.30-3.52 (4H, m), 3.96 (3H, s), 6.97 (2H, 25 d, J=8.9Hz), 7.90 (2H, d, J=8.9Hz), 8.07 (2H, d, J=8.6Hz), 8.15 (2H, d, J=8.6Hz) MASS (m/z) : 477 (M +1) Preparation 370 IR (KBr) : 2976, 1716, 1601, 1531, 1500, 1479, 30 1437 cm-1 NMR (CDC1 3 , 5) : 1.46 (3H, t, J=7.0Hz), 3.97 (3H, s), 4.10 (2H, q, J=7.0Hz), 7.00 (2H, d, J=8.7Hz), 7.59 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.4Hz), 8.07 (2H, d, J=8.3Hz), 8.10-8.30 (4H, m) 35 MASS (m/z) : 417 (M +1) WO 99/40108 PCT/JP99/00538 196 Preparation 371 IR (KBr) : 2926, 2852, 1722, 1599, 1529, 1498, 1437 cm - 1 NMR (CDC1 3 , 6) : 1.00-1.41 (5H, m), 1.51-2.05 (5H, m), 5 2.24-2.43 (1H, m), 2.69-2.84 (4H, m), 3.22-3.36 (4H, m), 3.97 (3H, s), 7.02 (2H, d, J=8.8Hz), 7.59 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.4Hz), 8.06 (2H, d, J=8.5Hz), 8.09-8.15 (4H, m) MASS (m/z) : 539 (M+1) 10 Preparation 372 IR (KBr) : 1718, 1601, 1429 cm-1 NMR (CDC1 3 , 5) : 1.29 (6H, d, J=6.3Hz), 2.36-2.56 (2H, m), 3.44-3.63 (2H, m), 3.74-3.93 (2H, m), 3.96 (3H, s), 6.99 (2H, d, J=8.9Hz), 7.58 (2H, d, J=8.8Hz), 15 7.69 (2H, d, J=8.5Hz), 8.05 (2H, d, J=8.4Hz), 8.09 (2H, d, J=8.6Hz), 8.16 (2H, d, J=8.6Hz) MASS (m/z) : 486 (M+1) Preparation 373 IR (KBr) : 1707, 1603, 1529, 1498, 1433, 1414 cm -1 20 NMR (CDC1 3 , 5) : 1.23-2.12 (10H, m), 3.97 (3H, s), 4.18-4.38 (1H, m), 7.00 (2H, d, J=8.8Hz), 7.57 (2H, d, J=8.8Hz), 7.69 (2H, d, J=8.4Hz), 8.10 (2H, d, J=8.5Hz), 8.06-8.25 (4H, m) MASS (m/z) : 471 (M+1) 25 Preparation 374 IR (KBr) : 2956, 2933, 2872, 1722, 1605, 1502, 1435 cm-1 NMR (CDC1 3 , 6) : 1.00 (3H, t, J=7.2Hz), 1.52 (2H, m), 1.79 (2H, m), 3.97 (3H, s), 4.03 (2H, m), 7.00 (2H, m), 30 7.45-7.78 (4H, m), 7.96-8.29 (6H, m) MASS (m/z) : 445 (M'+1) Preparation 375 IR (KBr) : 1716, 1435 cm

-

1 NMR (CDC1 3 , 6) : 1.28 (3H, t, J=7.0Hz), 3.60 (2H, q, 35 J=7.0Hz), 3.97 (3H, m), 4.58 (2H, s), 7.47 (2H, d, WO 99/40108 PCT/JP99/00538 197 J=8.3Hz), 7.56-7.78 (4H, m), 8.04-8.29 (6H, m) MASS (m/z) : 431 (M +1) Preparation 376 IR (KBr) : 1720, 1651, 1606, 1560, 1504, 1435 cm

-

1 5 NMR (CDCl 3 , 5) : 3.42 (3H, m), 3.55-3.71 (4H, m), 3.97 (3H, s), 4.64 (2H, s), 7.47 (2H, d, J=8.2Hz), 7.64 (2H, d, J=8.2Hz), 7.68-7.80 (2H, m), 8.04-8.26 (6H, m) MASS (m/z) : 461 (M +1) 10 Preparation 377 IR (KBr) : 2926, 2877, 1720, 1605, 1504, 1437 cm

-

1 NMR (CDC1 3 , 5) : 3.41 (3H, s), 3.54-3.64 (2H, m), 3.69-3.78 (2H, m), 3.86-3.96 (2H, m), 3.97 (3H, s), 4.14-4.28 (2H, m), 6.95-7.18 (2H, m), 7.51-5.64 (2H, m), 15 5.64-6.77 (2H, m), 8.00-8.26 (6H ,m) MASS (m/z) : 491 (M+1) Preparation 378 NMR (CDC1 3 , 5) : 1.22 (3H, t, J=7.0Hz), 2.09 (2H, m), 3.52 (2H, q, J=7.0Hz), 3.63 (2H, t, J=6.2Hz), 3.97 (3H, 20 s), 4.13 (2H, t, J=6.2Hz), 7.02 (2H, d, J=8.8Hz), 7.59 (2H, d, J=8.8Hz), 7.70 (2H, d, J=8.5Hz), 8.07 (2H, d, J=8.4Hz), 8.08-8.26 (4H, m) MASS (m/z) : 475 (M +1) Preparation 379 25 NMR (CDC1 3 , 5) : 1.27 (3H, t, J=7.0Hz), 3.63 (2H, q, J=7.0Hz), 3.74-3.90 (2H, m), 3.97 (3H, s), 4.14 4.28 (2H, m), 7.04 (2H, d, J=8.7Hz), 7.59 (2H, d, J=8.7Hz), 7.69 (2H, d, J=8.3Hz), 8.06 (2H, d, J=8.2Hz), 8.10 (2H, d, J=8.SHz), 30 8.16 (2H, d, J=8.5Hz) MASS (m/z) : 461 (M+1) Preparation 380 IR (KBr) : 1722, 1605, 1531, 1500, 1435 cm

-

1 NMR (CDC1 3 , 5) : 2.09 (2H, m), 3.38 (3H, s), 3.59 (2H, 35 t, J=6.1Hz), 3.97 (3H, s), 4.13 (2H, t, J=6.3Hz), WO 99/40108 PCT/JP99/00538 198 7.02 (2H, d, J=8.8Hz), 7.50-7.64 (2H, m), 7.70 (2H, d, J=8.5Hz), 8.07 (2H, d, J=8.4Hz), 8.08-8.25 (4H, m) MASS (m/z) : 461 (M+1) 5 Preparation 381 IR (KBr) : 1720, 1643, 1603, 1531, 1500, 1435 cm

-

1 NMR (CDCl 3 , 5) : 3.48 (3H, s), 3.80 (2H, m), 3.97 (3H, s), 4.18 (2H, m), 7.04 (2H, d, J=8.8Hz), 7.51-7.77 (4H, m), 8.03-8.23 (6H, m) 10 MASS (m/z) : 447 (M+1) Preparation 382 IR (Nujol) : 1714, 1601 cm - 1 NMR (CDC1 3 , 5) : 1.7-2.0 (4H, m), 2.75 (3H, s), 3.0-3.2 (2H, m), 3.4-3.6 (2H, m), 3.69 (3H, s), 6.77 (2H, 15 d, J=8.8Hz), 7.08 (4H, s), 7.60 (2H, d, J=8.8Hz), 7.7-8.0 (4H, m) (+)APCI MASS : 520 (M+H)* The following compounds [Preparations 383 to 388] were obtained in a manner similar to that of Preparation 33. 20 Preparation 383 IR (KBr) : 1699, 1684 cm -1 NMR (DMSO-d 6 , 5) : 0.86 (3H, t, J=6.6Hz), 1.2-1.7 (10H, m), 3.46 (2H, t, J=6.6Hz), 4.51 (2H, s), 7.50 (2H, d, J=8.6Hz), 7.95 (2H, d, J=8.6Hz), 8.13 (4H, s), 25 8.42 (1H, s), 9.36 (1H, s) MASS (m/z) : 477 (M+1) Preparation 384 IR (KBr) : 1583, 1543, 1516, 1396 cm - 1 NMR (DMSO-d 6 , 5) : 2.4-2.6 (4H, m), 3.1-3.3 (4H, m), 3.60 30 (2H, s), 6.77 (1H, t, J=7.4Hz), 6.93 (2H, d, J=7.4Hz), 7.20 (2H, t, J=7.4Hz), 7.9-8.1 (6H, m), 8.39 (1H, s), 9.32 (1H, s) MASS (m/z) : 523 (M+1) Preparation 385 35 IR (KBr) : 1716, 1520, 1277, 1109 cm

-

1 WO 99/40108 PCT/JP99/00538 199 MASS (m/z) : 432 (M +1) Preparation 386 IR (KBr) : 1684, 1518, 1252 cm

-

1 Preparation 387 5 NMR (DMSO-d 6 , 5) : 1.60-2.10 (4H, m), 2.70-3.10 (3H, m), 4.08 (2H, m), 7.10-7.40 (7H, m), 7.95 (2H, d, J=8.5Hz), 8.18 (4H, AB-q, J=8.3Hz, J=16.1Hz) APCI MASS : 426 (M +1) Preparation 388 10 IR (KBr) : 1687, 1610, 1568, 1527 cm

-

1 MASS (m/z) : 418 (M++1) The following compounds [Preparations 389 to 393] were obtained in a manner similar to that of Preparation 57. Preparation 389 15 NMR (CDC1 3

-CD

3 OD, 5) : 2.10-2.25 (2H, m), 2.65-3.15 (3H, m), 3.45-3.70 (2H, m), 3.99 (3H, s), 7.30-7.40 (5H, m), 7.90-8.40 (8H, m) APCI MASS : 440 (M+) Preparation 390 20 NMR (DMSO-d 6 , 5) : 1.10-2.10 (10H, m), 3.91 (3H, s), 4.40-4.60 (1H, m), 7.17 (2H, d, J=8.9Hz), 8.00-8.30 (6H, m) APCI MASS (positive) : 379.2 (M +1) Preparation 391 25 NMR (DMSO-d 6 , 5) : 1.20-1.60 (5H, m), 1.60-1.95 (5H, m), 2.50-2.75 (1H, m), 3.92 (3H ,s), 7.50 (2H, d, J=8.3Hz), 8.07 (2H, d, J=8.3Hz), 8.18 (2H, d, J=8.7Hz), 8.28 (2H, d, J=8.7Hz) APCI MASS (positive) : 363.3 (M +1) 30 Preparation 392 IR (KBr) : 1724.0, 1253.5, 1199.5 cm -1 NMR (CDCl 3 , 5) : 0.95 (3H, t, J=7.0Hz), 1.35-1.60 (4H, m), 1.70-1.95 (2H, m), 3.88-4.05 (5H, m), 6.98-7.03 (2H, m), 7.57-8.17 (8H, m) 35 MASS (m/z) : 449 (M+1) WO 99/40108 PCT/JP99/00538 200 Preparation 393 IR (KBr) : 1718.3, 1602.6, 1249.6 cm-1 NMR (CDC1 3 , 5) : 1.01 (3H, t, J=7.4Hz), 1.50-1.80 (2H, m), 3.97-4.05 (5H, m), 7.06-7.10 (2H, nm), 7.70-9.35 5 (12H, m) MASS (m/z) : 465 (M+1) The following compounds [Preparations 394 to 457] were obtained in a manner similar to that of Preparation 49. Preparation 394 10 NMR (DMSO-d 6 , 5) : 1.10-1.95 (12H, m), 3.55-3.80 (4H, m), 7.08 (2H, d, J=8.9Hz), 7.83 (2H, d, J=8.8Hz), 8.07 (4H, s) APCI MASS : 464 (M+) Preparation 395 15 NMR (DMSO-d 6 , 5) : 1.10-1.60 (5H, m), 1.60-1.95 (5H, m), 2.50-2.70 (1H, m), 7.45 (2H, d, J=8.3Hz), 7.96 (2H, d, J=8.3Hz), 8.14 (4H, s) Preparation 396 NMR (DMSO-d 6 , 5) : 1.20-2.10 (10H, m), 4.35-4.60 (1H, m), 20 7.13 (2H, d, J=8.9Hz), 7.95 (2H, d, J=8.9Hz), 8.12 (4H, s) APCI MASS (negative) : 379.2 (M -1) Preparation 397 NMR (DMSO-d 6 , 5) : 1.50-2.00 (4H, m), 2.65-3.10 (3H, m), 25 3.95-4.15 (2H, m), 6.90-7.35 (7H, m), 7.70-8.30 (6H ,m) APCI MASS : 442 (M ) Preparation 398 NMR (DMSO-d 6 , 5) : 1.20-2.10 (10H, m), 4.40-4.60 (1H, m), 30 7.17 (2H, d, J=8.9Hz), 7.95-8.30 (6H, m), 13.0-13.5 (1H, m) APCI MASS (positive) : 365.2 (M++1) Preparation 399 NMR (CDCl 3 , 5) : 1.15-1.60 (5H, m), 1.65-2.05 (5H, m), 35 2.50-2.70 (1H, m), 7.41 (2H, d, J=8.3Hz), 8.05 (2H, WO 99/40108 PCT/JP99/00538 201 d, J=8.4Hz), 8.23 (4H, s) APCI MASS (positive) : 349.2 (M++I1) Preparation 400 IR (KBr) : 2935, 2858, 1705, 1649, 1601, 1531, 1500, 5 1441, 1400 cm

-

1 MASS (m/z) : 523 (M+-1) Preparation 401 MASS (m/z) : 527 (M -1) Preparation 402 10 NMR (DMSO-d 6 , 5) : 3.30-3.64 (8H, m), 6.75-7.33 (7H, m), 7.70-8.29 (6H, m) MASS (m/z) : 443 (M+-2HC1+1) Preparation 403 NMR (DMSO-d 6 , 5) : 0.88 (3H, t, J=7.4Hz), 15 1.35-1.63 (4H ,m), 1.82-2.03 (2H, m), 2.99-3.20 (2H ,m), 3.40 (2H, t, J=6.6Hz), 3.40-3.80 (3H, m), 7.09 (2H, d, J=9.0Hz), 7.84 (2H, d, J=8.9Hz), 8.11 (4H, s), 13.22 (1H, brs) MASS (m/z) : 424 (M+-HC1+1) 20 Preparation 404 IR (KBr) : 1686, 1601, 1531, 1500, 1421 cm

-

1 NMR (DMSO-d 6 , 5) : 1.18 (6H, d, J=6.1Hz), 2.24-2.45 (2H, m), 3.63-3.82 (4H, m), 7.08 (2H, d, J=8.6Hz), 7.68 (2H, d, J=8.8Hz), 7.90 (2H, d, J=8.5Hz), 8.08 (2H, 25 d, J=8.3Hz), 8.13 (2H, d, J=8.7Hz), 8.16 (2H, d, J=8.7Hz) MASS (m/z) : 472 (M +1) Preparation 405 IR (KBr) : 1705, 1606, 1524, 1441, 1412 cm - 1 30 MASS (m/z) : 477 (M+1) Preparation 406 IR (KBr) : 1686, 1603, 1568, 1520, 1416 cm

-

1 NMR (DMSO-d 6 , 6) : 1.49-1.71 (2H, m), 1.90-2.10 (2H, m), 3.06-3.24 (2H, m), 3.58-3.80 (3H, m), 4.56 (2H, s), 35 7.10 (2H, d, J=9.0Hz), 7.23-7.46 (5H, m), 7.85 (2H, WO 99/40108 PCT/JP99/00538 202 d, J=8.9Hz), 8.10 (4H, m) MASS (m/z) : 472 (M+1) Preparation 407 IR (KBr) : 1682, 1606, 1572, 1524, 1498, 1427 cm - I 5 NMR (DMSO-d 6 , 5) : 1.25-2.05 (10H, m), 4.35-4.50 (1H, m), 7.07 (2H, d, J=8.8Hz), 7.64-7.94 (4H, m), 7.99-8.26 (6H, m) MASS (m/z) : 457 (M+1) Preparation 408 10 IR (KBr) : 2933, 2846, 1686, 1599, 1552, 1500, 1429 cm - I NMR (DMSO-d 6 , 5) : 1.56-2.00 (4H, m), 2.74-3.18 (3H, m), 4.62 (2H, m), 7.00-7.40 (6H, m), 7.99-8.26 (5H, m), 8.74 (1H, s), 13.20 (1H, brs) 15 MASS (m/z) : 443 (M+1) Preparation 409 IR (KBr) : 1686, 1603, 1574, 1527, 1500, 1427 cm - 1 NMR (DMSO-d 6 , 6) : 1.36 (3H, t, J=7.0Hz), 4.10 (2H, q, J=7.1Hz), 7.00-7.13 (2H, m), 7.65-8.25 (10H, m) 20 MASS (m/z) : 403 (M+1) Preparation 410 IR (KBr) : 1693, 1603, 1572, 1527, 1500, 1471, 1425 cm - I NMR (DMSO-d 6 , 5) : 1.60-1.84 (4H, m), 3.25 (3H, s), 25 3.30-3.50 (2H, m), 4.00-4.16 (2H, m), 7.07 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.6Hz), 7.87 (2H, d, J=8.SHz), 8.04-8.20 (6H, m) MASS (m/z) : 461 (M 4 +1) Preparation 411 30 IR (KBr) : 1705, 1606, 1524, 1441, 1412 cm -I 1 NMR (DMSO-d 6 , 5) : 1.00-2.20 (10H, m), 3.00-3.35 (9H, m), 7.18 (2H, d, J=9.1Hz), 7.92 (2H, d, J=8.7Hz), 8.11 (4H, s) MASS (m/z) : 447 (M+-1) WO 99/40108 PCT/JP99/00538 203 Preparation 412 IR (KBr) : 1703, 1605, 1524, 1441, 1412 cm - I 1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.8Hz), 1.43-2.00 (9H, m), 3.16-3.48 (9H, m), 7.17 (2H, d, J=8.4Hz), 7.92 5 (2H, d, J=8.3Hz), 8.12 (4H, s) Preparation 413 IR (KBr) : 1705, 1605, 1524, 1443, 1414 cm NMR (DMSO-d 6 , 5) : 0.88 (3H, d, J=6.4Hz), 0.86-1.60 (5H, m), 1.74-1.92 (2H, m), 2.00-2.20 (2H, m), 2.97-3.35 10 (9H, m), 7.18 (2H, d, J=8.9Hz), 7.92 (2H, d, J=8.8Hz), 8.12 (4H, s) Preparation 414 IR (KBr) : 2956, 2935, 2872, 1686, 1605, 1500, 1427 cm -1 15 NMR (DMSO-d 6 , 5) : 0.95 (3H, t, J=7.2Hz), 1.44 (2H, m), 1.74 (2H, m), 4.05 (2H, m), 7.02-7.14 (2H, m), 7.66-8.30 (10H, m) MASS (m/z) : 431 (M +1) Preparation 415 20 IR (KBr) : 1686, 1606, 1425 cm -1 NMR (DMSO-d 6 , 5) : 1.18 (3H, t, J=7.0Hz), 3.52 (2H, q, J=6.9Hz), 4.53 (2H, s), 7.46 (2H, d, J=8.5Hz), 7.77 (2H, d, J=8.3Hz), 7.92 (2H, d, J=8.4Hz), 8.10-8.24 (6H, m) 25 MASS (m/z) : 417 (M +1) Preparation 416 IR (KBr) : 1682, 1605, 1566, 1425 cm - I NMR (DMSO-d 6 , 5) : 3.28 (3H, m), 3.46-3.64 (4H, m), 4.56 (2H, s), 7.47 (2H, d, J=8.2Hz), 7.78 (2H, d, J=8.2Hz), 30 7.92 (2H, d, J=8.4Hz), 8.07-8.25 (6H, m) MASS (m/z) : 447 (M+1) Preparation 417 IR (KBr) : 1684, 1603, 1500, 1423 cm - I 1 NMR (DMSO-d 6 , 5) : 3.26 (3H, s), 3.35-3.54 (2H, m), 35 3.54-3.68 (2H, m), 3.77 (2H, t, J=4.5Hz), 4.17 (2H, WO 99/40108 PCT/JP99/00538 204 t, J=4.5Hz), 7.09 (2H, d, J=8.8Hz), 7.74 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 8.10 (2H, d, J=8.4Hz), 8.09-8.20 (4H, m) MASS (m/z) : 477 (M +1) 5 Preparation 418 NMR (DMSO-d 6 , 5) : 1.12 (3H, t, J=7.0Hz), 1.97 (2H, m), 3.39 (2H, q, J=7.0Hz), 3.53 (2H, t, J=6.3Hz), 4.09 (2H, t, J=6.3Hz), 7.07 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.7Hz), 7.87 (2H, d, J=8.5Hz), 8.10 (2H, d, 10 J=8.4Hz), 8.10-8.25 (4H, m) Preparation 419 IR (KBr) : 1686, 1603, 1529, 1498, 1470, 1427 cm-1 NMR (DMSO-d 6 , 5) : 1.15 (3H, t, J=7.0Hz), 3.52 (2H, q, J=7.0Hz), 3.68-3.80 (2H, m), 4.13-4.24 (2H, m), 7.08 15 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.8Hz), 7.86 (2H, d, J=8.5Hz), 8.09 (2H, d, J=8.4Hz), 8.10-8.21 (4H, m) MASS (m/z) : 447 (M +1) Preparation 420 20 IR (KBr) : 1686, 1603, 1529, 1498, 1470, 1427 cm-1 NMR (DMSO-d 6 , 5) : 1.98 (2H, m), 3.27 (3H, s), 3.50 (2H, t, J=6.2Hz), 4.09 (2H, m), 7.07 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 8.10 (2H, d, J=8.5Hz), 8.10-8.21 (4H, m) 25 MASS (m/z) : 447 (M+1) Preparation 421 IR (KBr) : 1684, 1603, 1525, 1500, 1421 cm

-

1 NMR (DMSO-d 6 , 5) : 3.32 (3H, s), 3.69 (2H, m), 4.17 (2H, m), 7.09 (2H, d, J=8.9Hz), 7.73 (2H, d, J=8.8Hz), 30 7.87 (2H, d, J=8.6Hz), 8.03-8.20 (6H, m) MASS (m/z) : 433 (M+1) Preparation 422 IR (Nujol) : 1684, 1601 cm

-

1 NMR (DMSO-d 6 , 5) : 1.8-2.2 (4H, m), 2.94 (3H, s), 3.1-3.3 35 (2H, m), 3.7-3.9 (2H, m), 7.14 (2H, d, J=8.9Hz), 7.45 WO 99/40108 PCT/JP99/00538 205 (4H, s), 7.86 (2H, d, J=8.9Hz), 8.0-8.2 (4H, m) (+)APCI MASS : 506 (M+H) + Preparation 423 IR (KBr) : 1664.3, 1602.6, 1230.4 cm

-

1 5 Preparation 424 IR (KBr) : 1685.5, 1608.3, 1238.1 cm - 1 NMR (DMSO-d 6 , 5) : 2.79-4.42 (13H, m), 6.92-7.14 (2H, m), 7.21-7.30 (4H, m), 7.81-7.96 (2H, m), 11.60 (1H, bs), 12.55 (1H, bs) 10 MASS (m/z) : 323 (M+1) Preparation 425 IR (KBr) : 1726.0, 1251.6, 1180.2 cm-1 NMR (DMSO-d 6 , 5) : 1.30-2.40 (18H, m), 3.21 (3H, s), 3.28-3.35 (2H, m), 4.04 (2H, t, J=6.4Hz), 7.07 (2H, 15 d, J=8.8Hz), 7.86 (2H, d, J=8.8Hz), 12.14 (1H, s) MASS (m/z) : 419 (M+1) Preparation 426 IR (KBr) : 1683.6, 1251.6, 825.4 cm-1 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=6.9Hz), 1.24-1.55 (4H, 20 nm), 1.60-1.90 (2H, nm), 4.00-4.10 (2H, m), 7.02-7.08 (2H, m), 7.63-8.36 (8H, m) MASS (m/z) : 435 (M+1) Preparation 427 IR (KBr) : 1693.2, 1305.6, 1259.3, 1178.3 cm

-

1 25 NMR (DMSO-d 6 , 5) : 1.38-1.80 (8H, m), 2.56 (3H, s), 3.22 (3H, s), 3.28-3.34 (5H, nm), 4.06 (2H, t, J=6.4Hz), 7.12 (2H, d, J=8.9Hz), 7.72 (1H, s), 7.86 (1H, s), 7.97 (2H, d, J=8.8Hz), 13.12 (1H, bs) MASS (m/z) : 441 (M+1) 30 Preparation 428 IR (KBr) : 1675.8, 1606.4, 1259.3 cm

-

1 NMR (DMSO-d 6 , 5) : 1.40-2.00 (8H, m), 3.35 (3H, s), 3.40 (2H, t, J=6.3Hz), 4.03 (2H, t, J=6.3Hz), 6.13-6.20 (2H, m), 6.96-7.94 (6H, m) 35 MASS (m/z) : 389 (M+1) WO 99/40108 PCT/JP99/00538 206 Preparation 429 IR (KBr) : 1699.0, 1604.5, 1249.6, 1193.7 cm - 1 NMR (DMSO-d 6 , 5) : 1.00 (3H, t, J=7.4Hz), 1.67-1.85 (2H, m), 3.99 (2H, t, J=6.5Hz), 7.04-7.09 (2H, m), 5 7.65-9.32 (12H, m) MASS (m/z) : 451 (M+1) Preparation 430 IR (KBr) : 1685.5, 1253.5, 1174.4 cm

-

1 NMR (DMSO-d 6 , 6) : 1.20-1.80 (8H, m), 3.22 (3H, s), 10 3.29-3.35 (2H, m), 4.00-4.15 (2H, m), 7.12-7.17 (2H, m), 7.97-8.68 (8H, m) MASS (m/z) : 463 (M+1) Preparation 431 IR (KBr) : 2950.6, 1708.6, 1608.3, 1473.3, 1419.4, 15 1367.3, 1259.3, 1211.1, 1174.4 cm

-

1 MASS (m/z) : 477 (M+H) Preparation 432 IR (KBr) :2946, 1710, 1608, 1469, 1413, 1369, 1307, 1263, 1218, 1176 cm - 1 20 MASS (m/z) : 491 (M+H) Preparation 433 IR (KBr) : 2944, 1706, 1606, 1469, 1417, 1375, 1259, 1176 cm

-

1 MASS (m/z) : 505 (M+H) 25 Preparation 434 IR (KBr) :3396, 2948, 2871, 1608, 1542, 1471, 1382, 1263, 1180, 1110 cm

-

1 MASS (m/z) : 493 (M+H) Preparation 435 30 IR (KBr) : 2942, 1687, 1608, 1471, 1309, 1261, 1176 cm

-

1 MASS (m/z) : 521 (M+H) Preparation 436 IR (KBr) : 2937, 1706, 1683, 1606, 1469, 1417, 1307, 35 1255, 1174, 1110 cm

-

1 WO 99/40108 PCT/JP99/00538 207 MASS (m/z) : 535 (M+H +) Preparation 437 IR (KBr) : 2946, 2570, 1706, 1608, 1469, 1415, 1371, 1309, 1259, 1216, 1174, 1108 cm-1 5 MASS (m/z) : 509 (M+H +) Preparation 438 IR (KBr) :2940, 2867, 2665, 2547, 1681, 1606, 1469, 1421, 1311, 1290, 1255, 1176, 1116 cm - 1 MASS (m/z) : 438 (M+H +) 10 Preparation 439 IR (KBr) :2939, 2861, 1681, 1606, 1469, 1421, 1311, 1253, 1174, 1114, 1016, 833 cm

-

1 MASS (m/z) : 452 (M+H +) Preparation 440 15 IR (KBr) :2935, 2858, 1681, 1606, 1571, 1467, 1419, 1311, 1253, 1174, 1112 cm-1 MASS (m/z) : 466 (M+H) Preparation 441 IR (KBr) :2931, 2854, 2663, 1679, 1606, 1467, 1421, 1311, 20 1290, 1253, 1174, 1116 cm

-

1 MASS (m/z) : 480 (M+H ) Preparation 442 IR (KBr) :2935, 2850, 2819, 1608, 1589, 1537, 1473, 1417, 1240 cm - 1 25 MASS (m/z) : 405 (M+H ) Preparation 443 IR (KBr) : 3361, 2969, 2848, 1606, 1585, 1535, 1475, 1402, 1238, 1180, 1114, 927 cm-1 Preparation 444 30 IR (KBr) : 2975, 2873, 2829, 2665, 1681, 1606, 1469, 1423, 1315, 1288, 1240, 1176 cm - 1 MASS (m/z) : 435 (M+H') Preparation 445 IR (KBr) : 2969, 2530, 1672, 1604, 1467, 1423, 1288, 1267, 35 1228, 1191 cm

-

1 WO 99/40108 PCT/JP99/00538 208 MASS (m/z) : 423 (M+H ) Preparation 446 IR (KBr) :2937, 1702, 1606, 1473, 1405, 1369, 1268, 1241, 1176 cm - 1 5 MASS (m/z) : 434 (M+H ) Preparation 447 MASS (m/z) : 488 (M+H ) Preparation 448 IR (KBr) :2956, 2869, 2665, 2543, 1681, 1608, 1544, 1492, 10 1469, 1423, 1332, 1292, 1245, 1172 cm

-

1 MASS (m/z) : 394 (M+H ) Preparation 449 IR (KBr) :2954, 2865, 2665, 2545, 1681, 1608, 1544, 1492, 1423, 1332, 1292, 1247, 1172 cm-1 15 NMR (DMSO-d 6 , 6) : 0.91 (3H, t, J=6.8Hz), 1.3-1.5 (4H, m), 1.6-1.8 (2H, m), 4.00 (2H, t, J=6.8Hz), 6.99 (2H, d, J=8.8Hz), 7.82 (2H, d, J=8.8Hz), 8.11 (4H, s), 8.69 (1H, s) MASS (m/z) : 408 (M+H +) 20 Preparation 450 IR (KBr) :2933, 2865, 2667, 2545, 1681, 1608, 1544, 1492, 1469, 1423, 1332 cm

-

1 MASS (m/z) : 422 (M+H + ) Preparation 451 25 IR (KBr) :2933, 2863, 1677, 1606, 1469, 1421, 1313, 1292, 1255, 1174 cm

-

1 MASS (m/z) : 422 (M+H +) Preparation 452 IR (KBr) :2935, 2871, 2667, 2545, 1683, 1608, 1542, 1525, 30 1461, 1421, 1319, 1294, 1257, 1176 cm-1 NMR (DMSO-d 6 , 6) : 0.91 (3H, t, J=7.0Hz), 1.2-1.5 (4H, m), 1.6-1.9 (2H, m), 4.05 (2H, t, J=6.5Hz), 7.09 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.8Hz), 8.09 (2H, d, J=8.5Hz), 8.22 (2H, d, J=8.5Hz), 13.3 (1H, s) 35 MASS (m/z) : 412 (M+H

+)

WO 99/40108 PCT/JP99/00538 209 Preparation 453 IR (KBr) : 1726.0, 1687.4, 1259.3, 1176.4 cm-1 NMR (DMSO-d 6 , 5) : 1.23-1.44 (4H, m), 1.85-1.96 (4H, m), 2.10-2.40 (2H, m), 3.58 (3H, s), 12.08 (1H, s) 5 MASS (m/z) : 187 (M+1) Preparation 454 IR (KBr) : 1724.0, 1702.8, 1309.4, 1265.1 cm-1 NMR (DMSO-d 6 , 6) : 2.49 (6H, s), 3.84 (3H, s), 7.70-7.72 (2H, m), 13.14 (1H, bs) 10 Preparation 455 IR (KBr) : 1727.9, 1675.8, 1232.3 cm-1 NMR (DMSO-d 6 , 5) : 3.70 (3H, s), 6.24-6.51 (2H, m), 7.24-7.46 (2H, m), 12.66 (1H, bs) MASS (m/z) : 157 (M+1) 15 Preparation 456 IR (KBr) : 1726.0, 1685.5, 1286.3, 1251.6 cm-1 NMR (DMSO-d 6 , 5) : 3.98 (3H, s), 7.68-7.77 (2H, m), 8.11 (2H, s), 8.64-8.82 (2H, m), 13.58 (1H, bs) MASS (m/z) : 231 (M+1) 20 Preparation 457 IR (KBr) : 1724.0, 1697.1, 1290.1 cm - 1 NMR (DMSO-d 6 , 6) : 3.95 (3H, s), 8.04-8.08 (2H, m), 8.20-8.27 (2H, m), 8.68-8.71 (2H, m) MASS (m/z) : 231 (M+1) 25 Preparation 458 To a solution of 1-hydroxybenzotriazole (244 mg) and 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (528 mg) in dichloromethane (10 ml) was added 1-ethyl-3-(3' dimethylaminopropyl)carbodiimide hydrochloride (WSCD*HCl) 30 (430 mg) and the mixture was stirred for 4.5 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[5-(4 35 pentyloxyphenyl)isooxazol-3-yl]benzoic acid benzotriazol- WO 99/40108 PCT/JP99/00538 210 l-yl ester (640 mg) IR (KBr) : 1776.1, 1253.5, 1234.2, 1002.8 cm-1 NMR (CDC1 3 , 5) : 0.95 (3H, t, J=7.0Hz), 1.2-1.6 (4H, m), 1.6-1.9 (2H, m), 4.03 (2H, t, J=6.5Hz), 6.81 (1H, 5 s), 7.01 (2H, d, J=8.3Hz), 7.3-7.6 (3H, m), 7.79 (2H, d, J=8.3Hz), 8.11 (2H, d, J=8.0Hz), 8.12 (1H, d, J=8.2Hz), 8.39 (2H, d, J=8.0Hz) The Starting Compounds (459) to (461) used and the Object 10 Compounds (459) to (461) obtained in the following Preparations 459 to 461 are given in the table as below, in which the formula of the starting compounds are in the upper column and the formula of the object compounds are in the lower column, respectively.

WO 99/40108 PCT/JP99/00538 211 Preparation No. Formula HO OH o OHO

H

3 C r O

(CH

2 1 4

CH

3

H

2 N N >H:o O HN OH HO NH O CH 3 0 H N O /H HO6 OH *O OH 0// NaO 3 SO_ " HO 459 OHOOH O H3C/ 1 - N (CH 2

)

14

CH

3

H

2 N N \ H O ON OH HO NH 0= CH3 0 H o

TO

H H---O NaO 3 SO /

°

O

HO

WO 99/40108 PCT/JP99/00538 212 Preparation No. Formula HO OH HO O

H

3 C/1

N%

7 H2

H

2 N N o Oo OHN OH HO NH O OCH 3 O H 0 H04, N°/0

HO

3 SO O HO 460 HO OH O HHO H2 / O 0

H

2 N N ;Ho O0O HN OH HO NH 0 . CH 3 HO, N iO 0 H OH 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 213 Preparation No. Formula OHO OH

H

3 C/ NH2

H

2 N O O O HN OH HO NH O. ICH 3 HO, OH H *MOH 00 NaO3SO HO 461 OH O OHO H 3 C ,,/ N o

H

2 N O O O HN OH HO NH 0 = CH3 0=(' HN HO0 H /OH _OH 0 NaO 3 SO

HO

WO99/40108 PCT/JP99/00538 214 Preparation 459 To a suspension of Starting Compound (459) (5.0 g) and triethylsilane (6.67 ml) in dichloromethane (125 ml) was dropwise added trifluoroacetic acid (32.2 ml) with stirring 5 under ice-cooling. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was slowly poured into pH6.86 standard buffer solution (1.2 L) with stirring under ice-cooling adjusting pH to 8.5-10 with 1N sodium hydroxide. The mixture was evaporated in vacuo to 10 remove the organic solvent and chromatographed on nonionic adsorption resin, Diaion SP-205 (Trademark, prepared by Mitsubishi Chemical Industries) (400 ml) eluting in turn with water (2 L), 10% aqueous methanol (2 L), 20% aqueous methanol (2 L), 30% aqueous methanol (2 L), 50% aqueous methanol (2 L), 15 60% aqueous methanol (2 L) and 90% aqueous methanol (2 L). The fractions containing the desired compound were collected and evaporated in vacuo. The resulting residue was lyophilized to give Object Compound (459) (3.13 g). NMR (DMSO-d 6 , 5) : 0.85 (3H, t, J=7.0Hz), 0.96 (3H, d, 20 J=6.7Hz), 1.02 (3H, d, J=6.1Hz), 1.24 (26H, m), 1.35-1.50 (2H,m), 1.55-2.50 (11H,m), 2.80-3.30 (2H, m), 3.60-5.40 (20H, m), 6.60-6.80 (3H, m), 6.85 7.75 (5H, m), 8.00-8.15 (2H, m), 8.71 (1H, broad S) APCI MASS (m/z) : 1141.1 (M -Na) 25 Preparation 460 Asolution of Starting Compound (460) (100 g) in a mixture of tetrahydrofuran (1 L) and pH6.86 standard buffer solution (1 L) was dropwise added benzyloxycarbonyl chloride (16.8 ml) at 5-10 0 C adjusting pH to 7.0-8.0 with saturated aqueous sodium 30 hydrogen carbonate. The solution was stirred at the same conditions for 3 hours and adjusted pH to 6.0 with 1N hydrochloride. The mixture was evaporated in vacuo to remove organic solvent. The residue was passed ion exchange resin, DOWEX 50WX4 Na+ type (prepared byDowChemical) (1 L) and washed 35 with water (3 L). The eluate was chromatographed on reversed WO 99/40108 PCT/JP99/00538 215 phase silica gel (ODS SP-120, preparedbyDaiso Co., Ltd.) (2.5 L) withwater (12 L), 10% aqueous methanol (12L) and20% aqueous methanol (12 L) successively. The fractions containing the object compound were collected, concentrated by evaporation 5 in vacuo and lyophilized to give Object Compound (460) (76 g, yield 65%) NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.05 (3H, d, J=5.7Hz), 1.60-2.50 (7H, m), 3.10-5.20 (29H, m), 6.73 (1H, d, J=8.2Hz), 6.75-6.90 (2H, m), 6.90-7.10 10 (2H, m), 7.20-7.40 (7H, m), 7.63 (1H, d, J=7.8Hz), 8.00-8.15 (2H, m) ESI MASS (Negative) : 1069.3 (Me-Na) Preparation 461 To a solution of Starting Compound (461) (30 g) and sodium 15 cyanoborohydride (3.45 g) in dichloromethane (300 ml) was dropwise added trifluoroacetic acid (150 ml) with stirring under in ice-cooling. The mixture was stirred at the same condition for 3 hours. The reaction mixture was slowly poured into pH6.86 standard buffer solution (1.2 L) with stirring on 20 ice-sodium chloride bath adjusting pH to 8.5-10 with IN sodium hydroxide. An aqueous layer was separated and cooled at refrigerator overnight. The aqueous solution was evaporated in vacuo to remove organic solvent and chromatographed on reversed phase silica gel (ODS SP-120, prepared by Daiso Co., 25 Ltd.) (700ml) elutingwithwater (5 L) and 5% aqueous methanol (6 L) successively. The fractions containing the object compound were collected, concentrated by evaporation in vacuo and lyophilized to give Object Compound (461) (17.3 g) NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.07 (3H, d, 30 J=5.7Hz), 1.40-2.45 (7H, m), 2.85-3.30 (2H, m), 3.60-4.50 (13H, m), 4.60-5.35 (10H, m), 6.65-7.10 (5H, m), 7.20-7.75 (8H, m), 7.92 (1H, broad d, J=8.4Hz), 8.84 (1H, s) ESI MASS (Negative) : 1053.3 (M -Na) 35 WO 99/40108 PCT/JP99/00538 216 The Starting Compounds (1) to (169) used and the Object Compounds (1) to (169) obtained in the following Examples 1 to 169 are given in the table as below, in which the formulas of the starting compounds are in the upper column and the 5 formulas of the object compounds are in the lower column, respectively.

WO 99/40108 PCT/JP99/00538 217 Example Formula No. HO OH HO-N .S...,'O NaO3 S HO HO

OHH

2 N N 0 OH OH 0 HO NH 0 CH 3 0 H HO O N "'OH -OH NaO 3 S 4 HO OH HO 00 H=C NH-C (CH 2 ) 6

CH

3

H

2 N NH: O3 0 HO NH 0 CH 3 0 H HO- N 'oH - H NaO 3 S

HO

WO 99/40108 PCT/JP99/00538 218 Example Formula No. HO OH HO O H 3 C',-. > H - NH 2

H

2 N N O O H5 0 OH O OO H H6 NH 0 CH 3 0 H HO N NaO 3 S

O

: H HO 2 OH

H

0 HO O H NH 2

H

2 N OH O o H OH 0 Hd NH 0 CH 3 0 H HO -N - OH 0 NaO 3 S C /

HO

WO 99/40108 PCT/JP99/00538 219 Example Formula No. HO OH HO 0 H C.... N

H

2 N >=O O N OH 0 HO H 0 CH 3 0 H Ho, N- °' o--(.. YO C NaO 3S / HO 3 OH HO H

H

3 c.... ~ N

H

2 N N H' O*

N

0 HO NH 0 CH 3 H J HON H. OOH NaO 3 S

HO

WO 99/40108 PCT/JP99/00538 220 Example Formula No. HO OH HO 0 0 o H JN

H

3 ...... o-CH2

H

2 N N O o H OH HO --- N - 4. ... 'OH NaO3S H6 NH 0= c CH 3 0N HHO HO N O - H 0 NaO 3 S4~ HO 4 OH HO 0 0 H30..Y H N O-CH HO HO N.."O

H

3 0. / ~O H O NaO3S

HO

WO 99/40108 PCT/JP99/00538 221 Example No. Formula No. OH HO 0 O 0== epo H-C

H

2 N 0 2 O H OH 0 H> H 0

CH

3 0 H HO- N., HQ N O **OH - OH NaO 3 S HO 5 OH HO O

H

3 0.

H

2 N N 0 OH 0 HO NH 0

CH

3 0 H HO N ""'OH OHOO

-

H 0 NaO 3 S /

HO

WO 99/40108 PCT/JP99/00538 222 Example Formula No. HO OH HO 0 0 HNC 1H O-CH 2 / N 0 HO NH 0 3 OH O NaO 3 S / HO 6 OH HQ3 000 HgC.... NK H O-CH 2 CO

H

2 N OHI OH O HO H O CH 3 60 OO S OH NaO 3 S /

HO

WO 99/40108 PCT/JP99/00538 223 Example Formula Fo rmul a No. OH HQ 0 0 HO O N

H

3 C ...... H O-CH 2

-

HOO H2 O H OH HO NH 0 CH 3 0 HOH -D OH NaO 3 S 0_ HO 7 OH HOO H 0.... H 2 N3 H oH H 2 OH NaO 3 S H

HO

WO 99/40108 PCT/JP99/00538 224 Example Formula Formula No. OH HO 0 8N -ONH H 3C ....... N H 2

H

2 N N 0 0 H OH 0 HO NH 0 CH 3 HO, N .. "'OH NaO 3 Sa HO 8 OH HO OO 0

NH

H 3 C ... / N OH O

H

2 N N 0 HN OH HO NH 0 3 H f HO,. Ny .,O - .OH 0 NaO 3 S C, /

HO

WO 99/40108 PCT/JP99/00538 225 Example Formula Formula No. OH HO 0 - NC H -..... .1 NH 2

H

2 N 0 0 H OH 0 HO H o CH 3 0HH HO, N ... ," OH OH NaO 3 S HO 9 OH

H

2 N .... HNN HO NH \ CH 3 NaO 3 S H //

HO

WO 99/40108 PCT/JP99/00538 226 Example Formula Formula No. OH HO 0 NC H 3C... H 2 H2 N p-I O==

H

2 N N H OH O H OH HO H 0 CH 3 0 HO .

Ny .... "'OH H NaO 3 S / HO 10 OH

H

3 HO N 4 CH HO N NH OH 00 HO- H OH NaO 3 S e

HO

WO 99/40108 PCT/JP99/00538 227 Example Formula No. OH HO O N H ..... NH 2 NO

H

2 - 0 H OH 0 HO NH O0 3 OH NaO 3 S N HO 11 OH HO O

H

2

"

1 OH H0 N / ,N' H6 NH CH 3 O (CH 2

)

7 0CH 3 0 " H OHN "OH OH N a O 3 S o HO WO 99/40108 PCT/JP99/00538 228 Example Formula No. HO OH HO 0 H

NH

2

H

2 N N 0 o H OH 0 HG NH 0 CH 3 HO- -N"O - H 0 NaO 3 S HO 12 OH f H2H3C--H N -- -O (CH 2 ) 6 0CH 3 O O O HH0

H

3 C..... H

H

2 N N H OH 0 Hd NH 0 CH 3 0 H HO- N OH NaO 3 s o - '

HO

WO 99/40108 PCT/JP99/00538 229 Example Ex e Formula No. OH HO 0 N H 3 0....... N NH 2 OH

H

2 N N 0 0 OH 0 NNaOS ~ /O HO 13 OH HO 0 d NC 2H 3 ~ H N 1

O(CH

2 ) OCH

H

2 N H H CH 3 -OH __ OH NaO 3 S

HO

WO 99/40108 PCT/JP99/00538 230 Example Formula No. OH HO N1 H 3C... NH 2 ON H

H

2 N NH 0 OH OH Na03S 0 HO 2aO 3 / 14 OH oo OCH OH HO

H

2 OH

HOH

WO 99/40108 PCT/JP99/00538 231 Example Formula No. OH HQ 0 N H 3 .....- F/ NH 2 N IH 2 O H N O H H 15

H

2 H HO NH 0 H3 0 H OH- N - H 0H NaO 3 S HO 15 OH HO 0N \ C%..,.NH

(CR

2 )6 6

CH

3 H N N 0 C HO NH 0H 3 0N H HO," Ny 0 1-X OH - OH NaO 3 So_

HO

WO 99/40108 PCT/JP99/00538 232 Example Formula Fo rmulia No. OH O 0K HO -Y 0

H

2 N O H OH 0 HO NH 0 3 O OH

-N

OH NaO 3 S a HO 16 OH HO O O N-N HQ

H

3 C...... N S

H

2 N N O HN OH 0 H N'O OH NaO 3 S 0_

HO

WO 99/40108 PCT/JP99/00538 233 Example Formula No. OH Nf H 3 .... / NH 2 0 H2 N _' =o O- %=o H oH HO NH 0 3 00H f HO N OH.."OH OH NaO 3 S HO HO 17 OH H O - 0C H 3 H3 H NkZ - NNH- (CH 2 ) 3H H O -f N-

H

2 N N H ( 3 HO NH H 3 0 O HO HO N .... OH NaO 3 S )_ /

HO

WO 99/40108 PCT/JP99/00538 234 Example Formula No. HO OH H O OH HN O (C H CH H 3 cf.. H OH

H

2 N O N 0 O HC OH 0 Hd NH 0 CH 3 H HO- N"O - OH NaO3S HO 18 OH OO O HO HOH H/ N 0 '/ O(C H9CH 3

H

3 C."

H

2 N N 0 0 H OH 0 Hd NH CH 3 H - OH NaO 3 S 0_

HO

WO 99/40108 PCT/JP99/00538 235 Example Formula No. HO OH HO '- k--NH : I = ,-N N HHN C .... NH 'LO (CH2) 3CH3 OH NaO 3S 0 HO 19 OH HO 0 NC\ o H2HN3H (CH 2 ) 3

CH

3

H

2 N HO 0H 0 HC HO NaO 3 So_

HO

WO 99/40108 PCT/JP99/00538 236 Example Formula No. HO OH HO N\ 0-- N H32 H (CH 2 ) 4

CH

3

H

2 N N O

-

H 020 HO2 NH o(H CH 3 HO NOH -OH NaO 3 S e HO 20 OH

H

3 0,, (CH) 4

CH

3

H

2 N Nz 0 HO -0NH 0 - CH 3 OD 'O - OH 0 NaO 3 So_

HO

WO 99/40108 PCT/JP99/00538 237 Example Formula Fo rmul a No. HO OH H H o,, H, HO- -oC 2 ) 7 H

H

2 N N 0 o H OH 0 HO NH 0 CH 3 H HO N ....... OH \ OH NaO 3 SO HO 21 OH HO 0 o

H

3 C..,,,. H HC\OH273

H

2 N N H=0 0 H OH 0 H6 NH 0===* CH 3 o N- -. i)...o H HO,, N ~ OH __ OH NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 238 Example Formula No. HO OH HO 0 O N / \, /1

H

3 C . H NH-C-

(CH

2 ) 6

CH

3

H

2 N 0 o H OH 0 o HO NH 0 CH 3 HH HO N ..H OOH NaO 3 SO- / HO 22 OH HO 0 O

H

3 C.,,N NH-C

(CH

2 ) 6

CH

3 HH

H

2 N 0 OH 0c HO NH 0 CH 3 O H HQ, N ... O NaO 3 SO - /

HO

WO 99/40108 PCT/JP99/00538 239 Example Formula No. HO OH HO 0 H3C., H /\ (CH 2

)

4

CH

3

H

2 N N =0 o HN OH 0 HO NH CH 3 H HQ N s0N OH NaO 3 S e HO 23 OH HO 0 H3C,-,. H O NH C (CH2)4CH3

H

2 N 0 O O HN OH 0 HO NH OE H 3 o N - OH O NaO3 S /

HO

WO 99/40108 PCT/JP99/00538 240 Example Formula No. HO OH HO 0 0 H fNH-C (CH 2 )5CH3

H

2 N N 0 O HN OH 0 O H C0 NH 0 CH 3 0 H HO N'O - OHO0 NaO 3 S OH HO 24 OH HO 0 0

H

3 C.... HO NH- (CH2) 5CH3

H

2 N N 0 O H OH 0HO H 0 CH 3 N H HO N .... ' OH O H O NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 241 Example Formula No. HO OH HC.,H H-C-I \O (CH2) SCH3

H

2 N 0 HOO H OH 0 HO H 0 CH 3 NaO 3 SO H ' ''O HHO HO N **'O HO 25 OH HO 0 OH 0

H

3 C... H NH-C- N- - CO (CH 2 )5CH 3

H

2 N N 0 o H OH 0 Y5 HO NH O H 3 0N H OH .. , O OH/ 'O NaO 3 SO %/-H

HO

WO 99/40108 PCT/JP99/00538 242 Example Formula No. HO OH HO 0 N N I H NH-C H 2 N N o O HN OH

(CH

2

)

6

CH

3 HO NH 0 CH 3 HO N .-... 'OH O N OH NaO 3 SO-5 / HO 26 OH HO 0 o N II

H

3 C,,,H /NH-C

H

2 N 3 N... 0 HO - N=o HN OH

(CH

2

)

6

CH

3 HO NH H 3 oN S OH 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 243 Example Formula No. HO OH HO O 0

H

3 C,,. H NH-C

H

2 N N O O HN OH (CH 2

)

5

CH

3 HO NH 0 CH 3 HO N N OH H HQ N OHH NaO 3 SO HO 27 OH o'o HO H NH- C

H

2 N N 0 O HN OH (CH 2 )5CH 3 HO NH 0OH 3 0 N H HO N -H 0 NaO 3 SO---/

HO

WO 99/40108 PCT/JP99/00538 244 Example Formula No. HO OH HO 0 0

H

3 C. H NH-C \\m- / O (CH 2 ) 80CH 3

H

2 N V0 O H O H 0 H HO N OH O OH NaO 3 SO HO 28 OH

H

3 C.,, H- (CH2) 8CH3

H

2 N y 0 O H5 OH 0 SHO H 0 CH 3 0 H HO-- N "OH OH 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 245 Example Formula No. HO OH HO 0 0 H3C, H H- \ -O (CH 2 ) 7 0CH 3

H

2 N 0 OH OH N NaO3SO HHO 29 OH HO N -..

"O OH 0 NaO 3SO_5 HO 29 ~OH HO 0 o H !N 4 ~C9D~GCH2) 7CH3

H

2 N Y0 O H5 OH 0 H O H 0 H 3 0 H HQ- N O YH NaO 3 SO -5

HO

WO 99/40108 PCT/JP99/00538 246 Example Formula No. OH HOQ

H

3 C. H

NH

2

H

2 N N 0 0 HN OH H0 NH 0 CH 3 o N H HO N .. OH - OH 0 NaO 3 SO HO 30 OH HO 0 N N-N

H

3 C-,, H / O"' ' / \ 0(CH 2 ) 5

CH

3

H

2 N 0 O O H OH 0 HO H 0 CH 3 0 H HO. N_ o OH OH 0 NaO 3 SO -5

HO

WO 99/40108 PCT/JP99/00538 247 Example Formula No. OH HQ 0 N

H

3 C, H NH 2

H

2 N 0 O HN OH H O CH 3 O H N HO N OH OOH OH NaO 3 SO HO 31 OH // HO 0 H / \ ' /\0H 2

)

5

CH

3

H

2 N y0 0 Hi OH 0 H O H 0 CH 3 0 H HO N O -OH 0 NaO 3 SD HO WO 99/40108 PCT/JP99/00538 248 Example Formula No. OH HO 0 H 3 C,,H .NH 2

H

2 N O 0 HN OH OH H O CH 3 3 N H HO N OOH OH Y NaO 3 SO / HO 32 OH HO 0 0 N N H 3 C .H / N O(CH 2

)

7

CH

3

H

2 N N0 O O H OH 0 HO NH 0 CH 3 0 H HO NOH OH NaO 3 SO - /

HO

WO 99/40108 PCT/JP99/00538 249 Example Formula No. OH HO 0 - N H 3C...H

NH

2

H

2 N N =O 0 HN OH HO NH 0= CH 3 0 N H HO N O.."OH - OH NaO 3 SO O HO 33 OH HO 0 H3C,-... H - O (CH 2 ) 5

CH

3

H

2 N 0 0 H OH 0 HO NH 0 CH 3 0 H HO N 'OH OH NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 250 Example Formula Fo rmulIa No. OH H2HN3C.,gH HO HO 0 H3

C

...... H NH 2

H

2 N N C==0 0 HN OH HO NH O 1H 3 0 N H HO N .. 'OH OH O NaO 3 SO HO 34 OH HO 0 OH 0 /O H2HN 3 C NH O (CH 2 ) 8 0CH 3 Ho OO o< 'H3

H

2 N 0 HO N .H OH HO NH 0. CH 3 0N H HO N ***O OH NaO 3 SO5

HO

WO 99/40108 PCT/JP99/00538 251 Example Formula Fo rmul a No. OH HO 0

H

3 C,.... H NH 2

H

2 N N O 0 HN OH HO NH O CH 3 O N H HO N ..""OH S OH NaO 3 SO HO 35 OH HO 0 0 *N

H

2 N N 0 O HN OH HO NH O OH 3 0 N H HO N ... "OH OH 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 252 Example Formula No. OH HO 0 N H3 C.. H -NH 2

H

2 N 0 0 HN OH H/ H 0 OH 3 O H N HO- N HQ N*'OH OH NaO 3 SO - / HO 36 OH HO 0O H2HN3-N .\ / OCH 3

H

3 C H O H 3

H

2 N N /i 0 HO HN

'

"OH 0 H C6 NH 0= H 3 0 H N HO- N O OH 0 NaO 3 SO-/

HO

WO 99/40108 PCT/JP99/00538 253 Example Formula No. OH HO 0 ON

H

3 C.,,. H NH 2

H

2 N 0 S0 HN OH 0HH OHO H 0 CH 3 0 N HQ O N "OH OH NaO 3 SO / HO 37 OH / O HH3C H j N 'O (CH2 ) 2CH3 O O= o H H OH 0 '.. HO H

H

2 N0 O H OH O H 0- CH 3 0N HO b H 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 254 Example Formula No. OH HO 0 N

H

3 C.,,.. H NH 2

H

2 N N 0 o HN OH HO NH 0 CH 3 0 N H HO N ... "OH S OH 0 NaO 3 SO / HO 38 OH H2HW HO (CH2 3CH3

H

2 N 0 O0 H OH 0 H O H 0NCH 3 0N * H HO N-OH

-

OH 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 255 Example Formula Formula No. OH HO O N H 3 C,. H NH 2

H

2 N N 0 H HN OH 0 HO NH 0- H 3 0O H N HO N .O..H..o - OH N aO 3 SO HO 39 OH ./ O 00 HH O(CH2)4CH ON O O H 0 H HO O 'OH OH 0 NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 256 Example Formula No. OH HQ.., HO 0 N N H 3 c... H - NH 2

H

2 N N 0 O0 HN OH 40 OH 70 H2HN3C", N O (CH2) 5CH OO N O OH OH HH O H 3 NaO3SO----

HO

WO 99/40108 PCT/JP99/00538 257 Example Formula No. OH HO N N

H

3 C-,, o H -NH 2

H

2 N 0 o HN OH HO H O CH 3 O N H HO -N o .. '.OH - OH NaO 3 SO / HO 41 OH HO o0 NN-N ---- I.. -. - -,J v~ HH2 C..NO (CH2) 6CH O H OH 0 HO OH o NaOg3SO-- __ . HHO HO -N *~'O OHO0 NaO 3 SO HO WO 99/40108 PCT/JP99/00538 258 Example Formula No. OH HO N H

H

2 N 0__ 0 0 HN OH H0 H 0== CH 3 0 N H HO N .. "OH OH NaO 3 SO / HO 42 OH 0

H

2 HN3C..H N (CH 2 ) 3-ND O HN OH 0 HO NH 0 .C"OH - N H HO N OHH NaO 3

SO

HO

WO 99/40108 PCT/JP99/00538 259 Example Formula Fo rmulia No. OH HO 0 H3C.H ..

NH

2

H

2 N N O HN OH H0 NH O CH 3 HO - N -o.,"'OH OH O NaO 3 SO HO 43 OH HO H23C,, H -(CH 2 ) 9

CH

3

H

2 N 0 O0 H OH 0 H NaO 3 H 0 CH 3 HO H HQ- N ... "OH YO NaO 3 SO -5

HO

WO 99/40108 PCT/JP99/00538 260 Example Formula No. OH HO O 0 N H 3 C..... H NH 2

H

2 N N 0 O HN OH OH O NaO3SO HO- NH O= CH 3 0 N HHO 44 HO N O OH O NaN 3SOa HO 44 Ho 0 HQ. N-N N H3C,,,,,. H H - -(CH 2

)

9

CH

3

H

2 N 0 io o H OH 0 HO H o CH 3 0 H HO- N **"O OHH NaO 3 SO " ' /

HO

WO 99/40108 PCT/JP99/00538 261 Example Formula No. OH HO 0 N

H

3 C,, H NH 2

H

2 N N 0 o HN OH O NH O H 3 O N H HO - N ... 'OH OH O NaO 3 SO HO 45 OH 0

HN

H

3 C H HO

H

2 N 0 o H OH H6 H 0 %-CH 3 H HOO N OH OH

-O

H

YO

NaO 3 S O /

HO

WO 99/40108 PCT/JP99/00538 262 Example Formula No. OH HO 0 H2NH ON H

H

2 N N 0 0 HN OH HGH 0- CH 3 0 N H HO- N O - OH Y NaO 3 SO / HO 46 OH 0 HO NH 0 H 3 0 N HO O H HO N H O H OH - OH 0 Na03SO

HO

WO 99/40108 PCT/JP99/00538 263 Example Formula No. OH HO 0 -N

H

3 C.,,, H NH 2

H

2 N 0 0 HN OH HG N- H 0= OH 3 O N H HO N O OOH OH NaO 3 SO-_' HO 47 OH H2 3 C ., (CH2) 4-0 H 2 N O HH 0 H OH HNa 3SOCH 3 HO H HO N OHH NaO 3 SO HO WO 99/40108 PCT/JP99/00538 264 Example Formula No. OH HON N H3....H NH 2

H

2 N N o H No OH HO NH 0- CH 3 o N H HO N .. "OH - OH 0 NaO 3 SO HO 48 OH 0O

H

3 C,,,... H _ -- o(CHf)oCH 3

H

2 N HN 0O OH H O H 0

CH

3 0 H HO N "'OH OH NaO 3 SO_

HO

WO 99/40108 PCT/JP99/00538 265 Example Formula No. OH HO N 3C..H

NH

2

H

2 N N 0O o HN OH H NH 0- CH 3 O N HO N .. OH S H o NaO 3 SO HO 49 OH HO 0\ H2 3 C,, H 2)3 HO H 0 H 3 0 H HO N - , OH Y NaO 3 So_

HO

WO 99/40108 PCT/JP99/00538 266 Example Formula Formula No. OH HO 0 N H 3 C..H NH 2

H

2 N N0 O N N ... OH H - OH NaO 3

SO

HO 50 OH HO 0 OH0 H2HN3C... N O (oCH2) 4-0

H

3 C, H HH 3

H

2 N N 0 H 0 HN OH HO NH 0 = CH 3 0 H HO -N baO3SO OH NaO 3 SO_

HO

WO 99/40108 PCT/JP99/00538 267 Example Formula No. OH HO H 3 C,.. H 7 NH 2

H

2 N 0 0 HN OH H 0 OH 3 0 N H HO NO OH NaO 3 SO / HO 51 OH H H3 O. 0 0H ) H 2 N N N O HO NH O= CH 3 0 -/ H HO N'O OH 0 Na03SO /

HO

WO 99/40108 PCT/JP99/00538 268 Example Formula No. OH HO 0 N H 3 C,,, H NH 2

H

2 N 0 O O HN OH 0H6 H 0- CH 3 O N H HO- N HOH OH NaO 3 SO - / HO 52 OH

HO

0 /0 HC,,~ H NN O (CH2) 3-0 O.O-H 3 H3C,,... -/ N ,) s .,,o

H

2 N 0 0 H OH NaHo H 0 CH 3 HO H HO- -N ... O OH NaO 3 SO HO WO 99/40108 PCT/JP99/00538 269 Example Formula No. OH HO 0 H 3 C.,. H NH 2

H

2 N N 0 S0 HN OH HO N 0 ,OH 0 N H H O-- N .OH - OH 0 NaO 3 SO / HO 53 OH / O

HH

3 C,, HO~/ " (CH2)5 0CH 3 HO H 0H OH NaO 3 SO / HO I4 a C2 0H WO 99/40108 PCT/JP99/00538 270 Example Formula No. OH HO 0 N H3C... H

NH

2

H

2 N N 0 O HN OH HO NH 0 CH 3 O N H HO N .... "OH OH 0 NaO 3 SO yo HO 54 OH * 0 H. 0 HN2HN -CoN-.N

H

2 N N 0 O H OH H O N ... O H 0 -o OH 0 NaO3S

HO

WO 99/40108 PCT/JP99/00538 271 Example Formula Fo rmulia No. OH HO O 0 N H3C..... H . NH 2

H

2 N N 0 HO N ... OH H NH 0 H 3 SNaONSO HHO 55 HQ--. N '..,,OH - 0 OH NaO 3SO HO 55 OH HO 0 .(CH 2

)

4

CH

3

H

3 C,,,,,,. H H O H OH 0 Hd H 0 H 3 0 H HNO N .. ",OH bH NaO 3 SO -5

HO

WO 99/40108 PCT/JP99/00538 272 Example Formua Formula No. OH HO 0 N H 3 C.,. H NH 2

H

2 N y O HN OH H = NH 0 OH 3 OH N H{ HO N - N.o OOH NaO 3 SO / HO 56 OH O O O HHO HO O 0O 3S HO NH 0l OH 3 o N HQ N 0OH 0H 0 NaO 3 SO -5

HO

WO 99/40108 PCT/JP99/00538 273 Example Formula No. HO OH HQQ O HO 0 N H 3 C,. H N / O(CH2) 7

CH

3 0

H

2 N N 0 0 HN OH 00 O O0 CH 3 oN OH O NaO 3 SO / HO 57 OH HO 0 H 3 H /.H O (CH 2) 7

CH

3

H

2 N 0 H OH 0 HO H 0 CH 3 0 H N N O "'OH T) H NaO 3 S O

HO

WO 99/40108 PCT/JP99/00538 274 Example Formula No. HO OH HH O : N N H3CN HNy o(CH2) 6

CH

3 0

H

2 N N 0 0 HN OH 0 HO NH 0 CH 3 HO N ....... OH 0 N NaO3SO HHO H58 N OOH H C.,, =O , N CH 2 ) 6CH3 OY OH NaO 3SO ', HO 58 0 H HO HA NI -H CH C H H - 2 ) 6

C

3 H N H OH 0 HO H 0 H 3 0 H - OH NaO0 3 S - 7

HO

WO 99/40108 PCT/JP99/00538 275 Example Formula No. HO OH HO 0 " H3C./.. H/ O (CH 2 ) 4

CH

3

H

2 N0 H HN OH 0 HO H 0 OH 3 O HH O N H HO N - 0 - OH NaO 3 SO HO 59 OH OH O0 H--R .H / \ ~C~H, CH 3 H3C HO. C H 2 ) 4C3

H

2 N H§ OH 0 H C H 0 OH 3 0 H N ..... OH

-

OH NaO 3 SO_ /

HO

WO 99/40108 PCT/JP99/00538 276 Example Formula No. HO OH HO %N.. NO N OH--,, O . ;'( 7 NaO3SO HO H3C.H , . H

O(CH?)

5

CH

3 60

H

2 N N 0 S HN OH 0 HO NH 0 H 3 O N H HO-. -N Y O ."'OH bH 0 NaO 3 S -O HO 60 OH HO 0 N -N NT H (C C

H

2 N 5jO 0 HO H 0 CH 3 0 H N O OH Y NaO 3 S C_

HO

WO 99/40108 PCT/JP99/00538 277 Example Formula Formula No. OH HO H C...H NH

H

2 N SH OH (0 3 HO H O0 H 3 0 H N .. -"OH TH NaO 3 S 0_ HO 61 OH HO O N-N

H

3 Cn H H - O

H

2 N 6

"(CH

2 ) 9

CH

3 H OH 0 HO H 0 H 3 H N N OH - OH NaO 3 So~o

HO

WO 99/40108 PCT/JP99/00538 278 Example Formula No. OH HO 0

H

3 H / NH 2

H

2 N O H OH 0 H 0 H 0 CH 0 H N ..OH - OH NaO 3 S 0 HO 62 OH HO 0N H3C. HOOH

H

2 N HiOH \CH 2 ) 9

CH

3 0 HO H 0 H 3 H N N'OH -OH NaO 3 S C_

HO

WO 99/40108 PCT/JP99/00538 279 Example Formula No. OH HO 0

H

3 Co.... H F H 2

H

2 N O HN OH 0O H0 H 0 OH 3 0 H N . N "'OH - OH NaO 3 S _ HO 63 OH HO 0 N O (CH2) 3-00 O3 .. O H 3 )

H

2 N OHH 0 HO 0 H 0= OCH 3 H N O - OH Y NaO 3 So__

HO

WO 99/40108 PCT/JP99/00538 280 Example Formula No. OH

H

2 N O o 0 64 OH HO H O CH 3 O H N N OH f OH NaO 3 S / HO OH

H

3 ,, H ON

H

2 N O=o ON OH 00 /H0 H 0 CH 3 H OHO NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 281 Example Formula Formula No. OH HO 0 H ,, H H 2

H

2 , 0 H OH 0 HO HO H 0 CH 3 H N O -"'OH NaO3S _ 65 OH 3CH2 .... H - (CH 2 ) 4

-

0 O HH

H

2 N N HI OH 0 HOH 03 O 0 HCH 3 H N '.OH Nao 3 S C /

HO

WO 99/40108 PCT/JP99/00538 282 Example No. Formula OH OH 0 N

H

3 C/h,. H

H

2 N N 0o HN OH HO NH O "CH3 O N H N *.,viO H NaO3SO_ HO 66 <H N-N OHOOH , N -N H2N N HH3C/f, H S LA sXO(CH2yp-O O 0 HN OH HO NH 0 CH 3 H N OH OH NaO 3 SO- O

HO

WO 99/40108 PCT/JP99/00538 283 Example Formula Formula No. OH HO 0

H

3 C3 H

H

2 N I H O H OH 0 H H 0 CH 3 O H N .. "OH - OH ,,,,...C ~~- H'.- - ° NaO 3 S O HO 67 OH HO 0 O N-N H3C H H -1 /(CH2) 5-0

H

2 N H OH 0 H O H 0H 3 H N '..OH NaO 3

S(D-

HO

WO 99/40108 PCT/JP99/00538 284 Example Formula No. OH HO O H C H H 2

H

2 N Hd H 0 CH 3 0 H N '... H OOH NaO 3 So / HO 68 OH

H

3 C H N 2)3-0 O N (CH

-

OH SHO 0 H 0

FH

3 0 H N O NaO 3 So_

HO

WO 99/40108 PCT/JP99/00538 285 Example Formula No. OH HO 0 H. C,-H H 2

H

2 N SH OH 0 HO H 0 CH 3 0 H N .O -"'OH ' --- 0 H -O NaO 3 S H / HO 69 OH HO 0 N~ NN

H

3 C 2) 50CH HN 2 O OH 0 HO H 0 CH 3 H N "O OH NaO 3 S 0_

HO

WO 99/40108 PCT/JP99/00538 286 Example Formula No. OH HO 0f HH 0 CH 3 0H N OH -H OH HO HO H O3~ 70 H N. T) H Na 3S OH HO 70 OH H3.HO N (CH2 80CH H2 OH 0 OH NaO 3 S /

HO

WO 99/40108 PCT/JP99/00538 287 Example Formula Fo rmulia No. OH HO O Hg C3 H H 2

H

2 N HN OH HO H O CH 03 H N ... ".OH O H NaO 3 S _ / HO 71 OH HC H 0 (CH 2 ) 2

CH

3 O OH 0 H0 H 0 H 3 0 H N OHO NaO 3 SO_

HO

WO 99/40108 PCT/JP99/00538 288 Example Formula No. OH HO O H ,, H H 2

H

2 N O 0, 0 0 H N ...'OH H OH HO 72 OH HO 0

H

3 C-.-. H j- - (CH 2

)

4

CH

3 ON-0

H

2 NH H OH 0 NHO H 0 H 3 0 H N OH -N-O H2NH NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 289 Example Formul Formula No. OH HO O H. C,. H /NH 2 H NNHY

H

2 N 0 H OH 0 HO H 0 CH 3 O H N OH -"'OH DH NaO 3 S HO 73 OH

H

3 C, H (CH2 4CH3 H H 0 Hc(d H 0- H 3 OH NaO 3 So__

HO

WO 99/40108 PCT/JP99/00538 290 Example Formula No. OH HO O

H

3 C..... H H 2

H

2 N O~ 0 S H0 H OH O H G H O, CH 3 H N .. "OH NaO 3 S 0 / HO 74 OH HHO O

H

2 N H OH 0 HG H 0 CH 3 O H N ."OH -"'OH Nao 3 S

HO

WO 99/40108 PCT/JP99/00538 291 Example No. Formula OH OH 0

H

3 Ci,,. H

--

N H2 H O H O CH3 H NN H 0N * ./OH 6H O NaO3SO 75 OH O O

H

2 N34/ S N OC7H 15 O HN H N-N 0 HO NH CH3 O H -)"/OH H O NaO 3 SO _ OH

HO

WO 99/40108 PCT/JP99/00538 292 Example No. Formula OH OH 0 OH N/

H

3 C/h,. H

H

2 N N 0 HN OH o OOi- H3 O N H N **F/OH OH O H03SO _; HO 76 OOH OHO H3C/Io~y H N ,N,/ H-N \LII H I I S -~/ -O61 HO H O /CH0 Na HO

HO

WO 99/40108 PCT/JP99/00538 293 Example No. Formula OH OH O

H

3 Cis,,. H H2

H

2 N NO 0 HN OH 77

-H

3 C/I y

'

NH'T 0l / H2SNNN 0 HO NH 0 H3 O NN-" HH HO N **NitOH bOH O Na3OSO HOHO 77 OH 0 OH H2N SN N O O O HN OH HO NH O CH3 HO H)H#//OH Na03SO

HO

WO 99/40108 PCT/JP99/00538 294 Example No. Formula OH H3C/b. H H2

H

2 N N 0 HN OH O N H °0.. 0 .NN ' /O H HO N -re OH b H O NaO3S0 HO 78 OHO OH H2 , H S HOH H /OH H2N & N H>O- N-N G-O 0HN Q Na3S 0 HO H %5HN NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 295 Example No. Formula OH OHO0 N/ H3C,. H NH2 H2N N O oO HN OH 00 HO H O CH3 0 N H N **----/OH b6H O NaO3SO HO 79 OH H3Cfle H S O OO O OH N-N HO NH 0 1CH 3 0 %OH 0 NaO 3 SO/e

HO

WO 99/40108 PCT/JP99/00538 296 Example No. Formula OH H3Cher,. H

H

2 N N o O OH H6 NH O== 1H3 O N H HO N**O OH OH NaO3SO 80 ,OH OH o OH

H

3 C/, H O(CH 2

)

4 0CH 3 ONN 2 N N N-N HO N O CH 3 0 H N%%% 1 f /P<~ OH NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 297 Example No. Formula OH OH OOH N H zC/h<,. 6 'H

H

2 N NO 0 HN OH O d OO H3 O N H N **sq "IOH OH O NaO3SO HO 81 OH O H2H -H o OH)40CH O N N-- N O HN H 0 HONH O - CH3 0 H NaO 3 S O HH

HO

WO 99/40108 PCT/JP99/00538 298 Example No. Formula OH OH 0 0 HN OH 0ON HO H H N 8NH2 OH NaO3S_ HO 82 OH 0

H

3 CIf y H O S N N

H

2 OHN _ N-N HO NH 0 # CH 3 NaO 3 S /O

HO

WO 99/40108 PCT/JP99/00538 299 Example No. Formula OH OHO N/

H

2 N N 0 HN OH 0 N H N **;;-"/OH

O

H O NaO3S_ HO 83 OH O H

H

3 CI/,o H *-H'-N

H

2 N N O S 0 O HN ZOH N -N HO NH 0 CH 0N H N NIP /OH % H 0 NaO 3 SOO

HO

WO 99/40108 PCT/JP99/00538 300 Example No. Formula OH OHO N H3 C/Is,. H

H

2 N NO 0 HN OH 84 HO NH O CH3 bH O ~O HN

'

HNN-N NaO H S HO 84 %%.(%IOH .2_OH 0 H2H3C sf H sOOt O O QH N-N HO NH o = CH3 HO NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 301 Example No. Formula OHOH OH H301It8. H

H

2 N N 0 0 HN OH HO NH O0H 0 N 85 H N Hsti ' N O /OH bH O NaO3SO HHO 85 H \ OH 0 N7aO'SN HHO

HOH

WO 99/40108 PCT/JP99/00538 302 Example No. Formula OH OH O N

H

3 0/it. H

NH

2

H

2 N N 0 EN OH 0 H O OO H I H3 O = N H N **//OH bH 0 HO3SO HO 86 NH N0 3 SOH O O HONH O = CHz H N Y0,11/0HO(CR1)5OCHi3 Na;zS OH O

HO

WO 99/40108 PCT/JP99/00538 303 Example No. Formula OH OH 0 OH 'N H30I 1 H

H

2 N N O HN OH 0* O N OCH 3 0 N H N .**/OH bH O Y 0

HO

3 SO HO 87 OH OH O

H

3 C/Is H O

H

2 N O H O O HO NH OCH 3 O H N / H

S(CH

2

)

7 0CH 3 N 9/O.H OH 0 NaO 3 SO /0

HO

WO 99/40108 PCT/JP99/00538 304 Example No. Formula OH OH 0 N/ H30/Is,. H HH

H

2 N N 0 I-N OH OOO CH3 0 N H N **Mr #'/OH H03SObH O HOzSO-- +H HO 88 OH O OH NH N H3C//, --- 1 2H N'O 01O NaO 3 S H

HO

WO 99/40108 PCT/JP99/00538 305 Example No. Formula OH HOH 'N/

H

2 N No ON OH O N H N **#/OH bH O HO3SO HO 89 OHH NIC O.H o

H

2 N Ot O - N H O HO N H0 NH O k4x H3 I Ia H (C2)4CH3 N efl/OH NaO 3 SO/ H

HO

WO 99/40108 PCT/JP99/00538 306 Example No. Formula OH OH OOH N

H

3 CI ,. H

H

2 N N O HO N OH N H"/OH bH O

HO

3 SO HO 90 HO OH O O H HC/, O:H

H

2 N 0 OO 2SOH O HO NH 0 CH 3 H N -YflOH O 1 NaO 3 S /0

HO

WO 99/40108 PCT/JP99/00538 307 Example No. Formula OH OH OH N H3 C/I, H

H

2 N N 0 HN .OH OO N 0CH 3 0 N H N ***//OH HO HO3SO _? HO 91 OH OHO H3C/b<'IN

H

2 N -Nf O O H OH HNH 0 - CH 3 I, NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 308 Example No. Formula OH N H3Chen, H NH

H

2 N N 0 HN 1O H 0 H NH

OCH

3 O N H HO N O bH 0 00 NaO3SO HO 92 .OH H2H3CII>Z O N ..- N OH H 2 \ /'---N vo, HO NH o H CH 3 QC260H OH O HO H "/oH O(CH 2)6OCH 3 NaO3SO

HO

WO 99/40108 PCT/JP99/00538 309 Example No. Formula OH OH 0 N N H3Ckts,. H HN OHO H2 N OH O OO H3, H HO NO 93 OH 0 HO O H OH J OH O CO(CH24CH3 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 310 Example No. Formula N/ H3Cks1,. H H2NH2 H OH 001 O OO H3 H HON N O 0~ 0HN -OH 0H O NaO3Se HO 94 _OH H3C H OH3C/ O H 3 C H o O OO CH3S HO NH o= SH 03 " O(CH 2

)

6 0CH 3 H O-H 0' Na 3 HO

HO

WO 99/40108 PCT/JP99/00538 311 Example No. Formula O OH -N

H

2 N N 0 HN OH O OO

CH

3 O N HO N *iO b OH O NaO3SO-e HO 95 OOH .OH H3C/lt. H : N "oop N O HN OH HO NH O

CH

3 O(CH 2

)

6 0OCH 3 HO H 'k N H OH 0OH NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 312 Example No. Formula OH N H30 //i,. H H2

H

2 N N o0 HN OH O == CH 3 O N OH HH O 0 H Na3SO~ HO 96 N N. H . H.l~e N 2 =0 0

H

2 N0 HN HX 0 OH O O4 6 HO NH O

CH

3 O H N

O(CH

2

)

2

CH

3 H N '/OH NaO 3 SO OH O

HO

WO 99/40108 PCT/JP99/00538 313 Example No. Formula OH OH 0 N

H

3 Chs,. H

H

2 N NO O- 0 H N OH ON HH HO N sO bH O NaO3S9 HO 97 OH 0 HN H2N NC/Is H HO N N OH 0 HO~ H O(C 2)0CH 3 N /-YO) #/OH NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 314 Example No. Formula OH OH N/

H

2 N N H 98 NaOSO.0 HN_ 0 OH,10 O O OH 0H 3 S-CH4CH3 OH HO 0 0~ OH K H9 0 NaO3SO / H

HO

WO 99/40108 PCT/JP99/00538 315 Example No. Formula OH OH 0 N

H

3 il. H"O

H

2 N N O HN OH 0 O N 99 OH HO N N b6H O NaO3S HO 99

H

2 N H OHN OOH S '

O(CH

2

)

5

CH

3 0 NH 0=4H HO H Na03SOe0

HO

WO 99/40108 PCT/JP99/00538 316 Example No. Formula OH OH 0 N 0HH /NH010 H

H

2 N N O I-IN OH OO --CH 3 100 Od NH 0 H HO N -bH HO NHt 0 CH 3 O(CH )CH 3 NaO3SOe HO 100 ~~#H H H 3 , H O0 HN HS 00 HO0 NH O CHz O(CH2g H3 HO HON 1 flOH %HO NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 317 Example No. Formula OH OH 0 N H3011,s. H

H

2 N NO O HN OH O N H N **11OH OH O NaO3SO._ HO 101 oH O H3C/fy, H O

H

2 N - N O HN OH S HlO NHo = ' H 3 NO H O "IH

O(CH

2

)

2

CH

3 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 318 Example No. Formula OH OH 0• N H13 It,.H

H

2 N N oO H OH 0 N H N -- -OH *OH O N aO 3S

I

O HO 102

H

3 C/1t, H N ,gjoN

H

2 HO N S o N OH S HO0 NH O = CH3 0 H :3 O(CH 2

)

4

CH

3 OHN 't OH NaO3SO / OH

HO

WO 99/40108 PCT/JP99/00538 319 Example No. Formula OH H 3 011,. H NNH

H

2 N NO O0 HN OH O N HHO N --- p W'OH bH O NaO3S_ HO 103 OH === H3C//#o. H~ - -N; N -- N Ho NH o CH3 O(CH2)5CH3 H

HO

WO 99/40108 PCT/JP99/00538 320 Example No. Formula H2OH O " H

N-

NaO3SO- , l O OHHO 104 H3 Iu,. H H •2

H

2 N N 0 HN OH Of N OL CH 3 0 N OH ~. 0 HO

H

3 C/It H H2AN O HN OeH HO NH 0 CH O(CH 2

)

5

CH

3 0 O OH H NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 321 Example No. Formula OH OHO

H

3 Ch4. H H2

H

2 N N 0 HN OH HO NH O

CH

3 O N H N **W/OH OH O HO3SO HO 105

H

3 C/11 H OH OHCHO O0O N.% sH NaO 3 S /

HO

WO 99/40108 PCT/JP99/00538 322 Example No. Formula OH OH O H3C/sIt. H

H

2 N O HN OH 0 HO NH O CH 3 O N H N o-op /OH bH O

HO

3 SO HO 106 OH OH O O -NO I 0 HN OH S HO NH 0 CH 3 0 H O H 'llOH O(CH2)20(CH 2

)

2 OMe oH 0 NaO 3 SO_

HO

WO 99/40108 PCT/JP99/00538 323 Example No. Formula OH OH 0 H HO NH O=: CH 3 O N/ H

H

2 N N O 0 HN OH NaO3S HOO 107 OH H2N z~O N Q HO HO OH HQ0 N I,. H OHH H NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 3 24 Example No. Formula OH OH O

H

3 0O1. H -NH2 HO NH O CH3

OH

H N H ON O * ' " / OH OH O NaO3S_ HO 108 HO 0/ [N-xmNO NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 325 Example No. Formula OH OH O H3C//,. H "1 aT

H

2 N N o O H N .O.H HO NH CH3 O N H N oft #'/OH OH O

HO

3 SO HO 109

H

2 N N O s HN ' /OH 0 N-N HO Nil o- CH 3 NaO3S N HHO NH N>IP)OH Na0 3 SG_?

HO

WO 99/40108 PCT/JP99/00538 3 2 6 Example No. Formula OH OH O N

H

3 C1,.H

H

2 N N O0 HN OH 0 HO NH

CH

3 O N H N "'/OH bHH H03SO _? HO 0HN OH N 0 OH O OH O s N a 3

S

HO

WO 99/40108 PCT/JP99/00538 327 Example No. Formula OH OH 0.P H3Cli,. H H2

H

2 N N O oO HN .. OH HO NH O CH 3 0 N H N *.;;/OH OH 0

HO

3 SO HO 111 OH OH 0

H

3 C/, -- N

H

2 N N H1 0N OH O OH OH N-N HO 0 0 H N *;~h/OH OH NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 328 Example No. Formula OH OH 0 N

H

3 C/is,. H NH 2

H

2 N N oO N OH H0 NH CH3 O N H N *"'/OH bHO H3SO _ HO 112 OH OH 0O N H2H3// H HOS OO HN ZOH 0 ° X._ . N-N HO NH O- 4CH 3 OH 0 OH NaO 3 S / O

HO

WO 99/40108 PCT/JP99/00538 329 Example No. Formula OH OH 0 O N H30/hl,. H

H

2 N N 0 HN OH HO' NH O

CH

3 O N H HO N *iO bH O

HO

3 SO HO 113 HOH

H

2 N 3 s\ S *~ 2 N O C 6 Hl 3 o RNN-N ON 00 HH H2 .- 0 " "S N'\ / -O c 6H 13 HO N 1 \OH O -' N -- HO -. NE 0 C,,o % 'H 0 NaO 3 S O

HO

WO 99/40108 PCT/JP99/00538 330 Example No. Formula OH 0

H

N0 N H3C/Is H

~NH

2

H

2 N N O HN OH HO NH O CH3 O N HO N .**/OH bH O HO3SO HO 114 H-O SNN H3C/1, H NOT/ 2O 0NHN -O H O ON-N HO NH o CH3 0 H N H 0 NaO 3 SO ? OHO

HO

WO 99/40108 PCT/JP99/00538 331 Example No. Formula OH N H3/t,. H

H

2 N N 0 HN OH 0 o O H N .O H H NH O CH 3 0 N H N **P""/OH OH O

HO

3 SO HO 115 OH OHO OH HH3C/he H ON

H

2 N NH rO O O HN -OHNN sN-N OH NH N N N H -) /OH -'OH 0 NaO 3 S OH O

HO

WO 99/40108 PCT/JP99/00538 332 Example No. Formula OH OH O N

H

3 Cl-,. H

H

2 N N O HN OH 0 H NH

-CH

3 O N H N **FI/OH OH O

HO

3 SO HO 116 OH OH 0 H OH O

H

2 N C H HOO O O HN OH N C)- N-N HO NH O CH3 0 OH N H N #1/OH NaO 3 S OH O

HO

WO 99/40108 PCT/JP99/00538 333 Example No. Formula OH OH 0' N H3C/11,. H N2 O=H 0CH3

H

2 N N O N H""OH bH O HO3SO HO 117 OH OH 0 O

H

2 N=o 0 00 HMOH NN " -- _ O- 0N HO HO NH O

CH

3 O N H• NaO3SO-OHO

HO

WO 99/40108 PCT/JP99/00538 334 Example No. Formula OH OOH

H

2 N N oO HN OH HO NH CH3 0 N H N *#- /OH H

HO

3 SO HO 118 OH O H

H

2 N H3f O O O O H p3 O N OHH NaOO HO

HO:

WO 99/40108 PCT/JP99/00538 335 Example No. Formula OH ON HO3SO -- ") HO 01191 2H3C1," H O-N

H

2 N No O0 HN OH 0 HO NH O CH o NN OH N 'I/OH"/O NaOS-- OH O 119HO OHOH

H

2 N 6 0 HN Z- ,H N- N HO NH 0 4H 0 H NaO 3 S / 6 _

HO

WO 99/40108 PCT/JP99/00538 336 Example No. Formula OH OHO N H3Clis,. H H2

H

2 N N O O H N OH HO NH O CH3 O N H N .11/OH bHO

HO

3 SO OH OH N 0 0 HN Z9H N-N HO NH = CH 3 0 H N NaO3 S / OH

HO

WO 99/40108 PCT/JP99/00538 337 Example No. Formula OH OHO O o3O ... 6oH -N O OO CH3 0 N H N **lOH OH"OH

HO

3 SO HO 121 HOH OH O 0 H3CI. ,, Nl N INf

H

2 N~ H0lN O& CH, O 60 H "N N-N CH 3 HO NH O CH 3 NH O 0 H

HO

3 SO

HO

WO 99/40108 PCT/JP99/00538 338 Example No. Formula OH N H3Cksl,. H

NH

2

H

2 N N OO HN OH HO NH O CH3 O N H N -- '"i/OH bH O HO3SO HO 122

--

o OH

N

H3CH OH O HO NH O H 3 O H =H 0H H O NaO 3 S

HO

WO 99/40108 PCT/JP99/00538 339 Example No. Formula OH OHH H30/s. H

-

N H2

H

2 N O0 HN OH HO NH 0

CH

3 O N H HO N *iO 5O0' 0 - HO3S bHO HO 123 OH OHO0 0 HH3c//sH H OCH2CH3 0 HN OH HO NH O

CH

3 0 HO N OH Nao 3 SO

HO

WO 99/40108 PCT/JP99/00538 340 Example No. Formula OH OH 0 N

H

3 C1 1 ,. H

H

2 N N 0 HN OH O NN HOH HO N

H

2 0 -NW O HO 3S H NaO 3 SO__ O 0o HHO 124 OH OH 0 O H H3C/1, N

-

N N O0 HN OH HO NH O = CH3 H O HNH'?O NaO3SO

HO

WO 99/40108 PCT/JP99/00538 341 Example No. Formula OH OH 0 O N H30h1. H H2

H

2 N N O HN OH 125 HO NH O CH3 O N HH N *"/OH OH O H03S HO 125 OH OH OH O C NaO 3 S O H

HO

WO 99/40108 PCT/JP99/00538 342 Example No. Formula OH OH 0 N H3C/hC,. H

H

2 N N O0 HN OH HO NH O

CH

3 O N H N **,;/WOH HO3SH HO 126 OHOH OHO .. OH H3C/flN

H

2 N 'N 0 N N /=I/ 0 HN .QH C ".0-N HO NH 0- CH 3 N ,/N2~OH 6H O Nao 3 SO

HO

WO 99/40108 PCT/JP99/00538 343 Example No. Formula OH OH O N

H

3 0ts. H H2

H

2 N N oO BIHN OH HO NH 0

CH

3 O N H N **p N,"/OH OH O

HO

3 SO HO 127 OH OH O O

H

3 CI O/ CH20Et

H

2 N

CH

2 OEIO OHN H N-N HO NH 0 CH 3 6 H ON N -'- /O NaO 3 S /0

HO

WO 99/40108 PCT/JP99/00538 344 Example No. Formula OH OH 0 HC N HNH

H

2 N N O HN OH HOO NH 0

CH

3 O N H N *-I *;; / H OH 0 HO3SSO HO 128 O OH OH O

H

3 C/I >N 0

H

2 N O s H Y,/O CH 2 H2) 2 Me HN OH H NNN NH 0

CH

3 0 -1 N%7%DI/OH OH O NaO 3 S O

HO

WO 99/40108 PCT/JP99/00538 345 Example No. Formula OH OH N

H

2 N N H~O NH CH3 O N H N

.*/*O

H OH O HO3SO HO 129 OH OH 0 0

H

2 N NO sHO(CH 2

)

3 0Et HN OH N-N 0 NH 0= H 0 N H N &/OH NaO 3 SO / %oH o

HO

WO 99/40108 PCT/JP99/00538 346 Example No. Formula OH OHO N

H

2 N N 0 HN OH HO NH O

CH

3 O N H N stifOH HO3SO_ H 0 HO 130 OH OH 0 HO NH O CH O H H sl%.~ /OH NaO 3

SO

HO

WO 99/40108 PCT/JP99/00538 347 Example No. Formula OH OH 0 OH N H30I,. H

NF

2 HO NH O

CH

3 O N H N **#/OH NaO3SOo O HO 131 OH -H3C/ NH N OMe 0 HN OH HO NH O 4CH Cl 0 iIH O NaO3SO O?

HO

WO 99/40108 PCT/JP99/00538 348 Example No. Formula OH OHO Z \N/

H

3 CI,,,. H 132H2 H2N N O0 O HN OH HOI NH OCH3 O N H oHO N*,,O HNHOH HO OH 0 NaO3SO HO 132 OH\OH N-N H2H3C/ is H NJ OMe HO N O CH3( O2 N H HO N If/OH NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 349 Example No. Formula OH OH O H -N H2NH2 OO HN O H HO NH 0 CH3 H HON N O HN O H NaO3Se HO 133 OH H -C/, H O(CH 2) HO" NH O CHz Oii N-

H

2 N olN 0 : HO N OH HO' NH 0 0 HO H /N N\ %H ,/IOH Na0 3 SO

HO

WO 99/40108 PCT/JP99/00538 350 Example No. Formula OH OH 0 OH H30/I4-. H

H

2 N N 0 HN OUH HO NH O CH3 H HO N* ;OH O Na3SO~ HO 134 H .2H O 0 3ChH H O(CH 2 )-N H >- !NN- S

H

2 N N 0 HN OH H0 NH 0 CH 3 0N HO / - II / \ OH 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 3 5 1 Example No. Formula OH OH 0 N H3Cks,. H

H

2 N N O O- -0 H N OH HO NH O CH3 O N HO 135 OHH

H

3 C/- H O(CH- 2

)

6 H2N N O OL O l H N HC 2 ) - N HH 0 O CH 3 HO O H s H H NaO 3 SO /

HO

WO 99/40108 PCT/JP99/00538 352 Example No. Formula OH O , OH OH N

H

3 Cits.H

H

2 NN 0 HN O 0N H2O O 136 OH OH OO z H (CH)-N

H

2 N N O O 0 HN Q H O NH O CH 3 0 N HO HO NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 353 Example No. Formula OH OH OH0 H3C/os.. H N/ H2

H

2 N N O0 HN OH HO NH O

CH

3 0 N H H~q N ""/OH NaO3S 'OH 0 HO 137 H2 H3C/le

O(CH

2

)

5

H

2 N : 0 HN OH HO NH 0 =: CH 0 H NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 354 Example No. Formula OH HO NH O CH3 O H

N--

H

H

2 N N 0 N OH NNaO3SO HO 138 OH OH 0 NH -N' H 3 cN N H O ( C H ) 5 - NO 0 HN OH HO NH O CH 3 0 H N OOH NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 355 Example No. Formula OH OH0 N

H

3 Chs. H H2

H

2 N NO 0 HN OH HO NH O CH3 O N 139 OH HO Ni HOH 0 N 0bH NN ,/I N OHH26 N Na 3 SO O HO O S O N - /H H; NH O0~ NaSO HO WO 99/40108 PCT/JP99/00538 356 Example No. Formula N H3C/h1,. H H2OO

H

2 N N 0 HN OH 0 HO NH O CH3 O N 140 OH HO N 0 HN OH"IO HO NH0 CH 3 0H O NaO3Se HHO 140 OH HzNH3 NHO()5N S O 3 / O( l 2) - H N HH NHJ OS~ HO0 H _OH H NH O0=4H Na03SO

HO

WO 99/40108 PCT/JP99/00538 357 Example No. Formula O IH OHO0 N 141 HOClis,. H H 2

H

2 H2H OH O H 0 CH3 O N H H O.. N - O/OH OH O NaO3Sa/ HO 141 :ZH .OH O HzC/f, H H O(CH2)SOMe H2H OH HO NH O CHz NaO3SO-e

HO

WO 99/40108 PCT/JP99/00538 358 Example No. Formula OH OH 0 N NH2

H

2 N 0 HN OH HO NH 0 CH 3 O N H i . H N *;/O H

O

H O NaO3SO_ HO 142 ,OH

H

2 N O OOH H HO NH O CH 3 OH H slO OH O 0N N 'OH47 0N NaO 3 SO %H 0

HO

WO 99/40108 PCT/JP99/00538 359 Example No. Formula OH OH O N HH2 143 O HN OH

H

2 N\-N l==o(H ) 6 ~ HO NH O NH CH3 0 N HH HO N bH O NaO3SO HO OH H HC/ H H O(CH 2)6e H2N OIN O0 HN OH HO NH O CH3 HON O H H JOH Na03SOe0

HO

WO 99/40108 PCT/JP99/00538 360 Example No. Formula OH OHO N/

H

3 0/#,. H

H

2 N N 0 H N OH HO NH O

CH

3 O N 144 H HO N *O bH O NaO3SOHe HO 144 WPH .OH O

H

3 C/I, H H N O(CH 2

)

7 OMe

H

2 N O0 HN OH HO NH 0 CH 3 0 H HO N NaO 3 S H O

HO

WO 99/40108 PCT/JP99/00538 361 Example No. Formula OH OHO

H

3 CIs,.. H

H

2 N N 0 HN OH 0N 145 HO NH O CH3 0 N ~H H~q N-"'/OH OOH Na3SONaO 3 SOH HHO 145 ZH .OH O H3C/1, H HO(CH2)80Me H2 N:O O O N OH HO NH O CH3 HO O HHslO NaO3SO_

HO

WO 99/40108 PCT/JP99/00538 362 Example No. Formula ~OH OH HOH 146 OH0 0 N/ H3C///. H H2 2 O0 HN OHOH HO NH HCH3 3 0 N H HO N ***iiOH bH O NaOO 3SO HO 146 OH O0 H3C0/A HHN H2 O H OH Na~zSO

HOH

WO 99/40108 PCT/JP99/00538 363 Example No. Formula OH OH 0 H3C/Its. H HH

H

2 N NO 0 HN OH 147 HO NH O CH3 H HO N iO bH O NaO3SOS e HO 147 N OH 0 HO H3C/^1 H N O HN N: O Ot O H <H HO NH 0O CH3 OH O NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 364 Example No. Formula OH OHH N H3Ch,. H H2

H

2 N N 0 HN OH HO NH 0 H3 O N H"O H 0 N ' O H bH O NaO3SO~ HO 148

H

3 C/2 , H N 0

H

2 N =N 0= HN -Q HO NH O CH3 HO H(.q N- /O H OH 0 0 H H9. Nao 3 SO0

HO

WO 99/40108 PCT/JP99/00538 365 Example No. Formula OH OH 0 NN /

H

3 /It,. H ~H2

H

2 N N 149 OH N OH O N HH N "OOH OH O NaO3SS0 HO 149 O H H OH O Na 0SO HO N WO 99/40108 PCT/JP99/00538 366 Example No. Formula OH OH 0OH HOH NN NH2 H2N NO O- O H N O H HO NH O CH3 O N H HN N,**WO HbO NaO3SO HO 150 OOH 3 toC/1. H H- No S H2 O '' O OO OH HO O HHO NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 367 Example No. Formula OH OHO O N

H

3 CiH,. H H2

H

2 N NO SHN OH HO NH 0 O N H HO N 'O ""OH bH O NaO 3 SO HO 151 #H OH O O H3C/Is H H N N-Et HN NN NN H2N -N O HO NH O

CH

3 0 O ='N- H HON 1/OH %H NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 368 Example No. Formula OH OH H3c/I,." H'jN OHN 1H22 0 HN OH H, O NH O CH3 O N H =HO,' NNO bH O NaO 3 SO HO 152 OH O 71~ - N NO H3C//s H H>NOf N N

H

2 N O HO NH HO N H NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 369 Example No. Formula OH OH

H

3 C,/,. H

H

2 N O H 0 HN OH NaO3SO 0 HO NH O=0 H HHO N

'O

1 I/OH 'OH 0 NaO 3 SO / HO 153 OH H a 0 0' H3C/I, / H H N N O

H

2 N O -QOI HO NH O = CH 3 0H N .ff '/OH NaO3SO-H

HO

WO 99/40108 PCT/JP99/00538 37 0 Example No. Formula OH OHO0

H

3 01,. H H

H

2 N N 0 0 HN OH 0 N QHH HOHN H NH O H O H9-\ N 0 \N OHH NaO 3 SO HO WO 99/40108 PCT/JP99/00538 371 Example No. Formula N H3Chi1. H Z_ NH2 H2N N O OH H0N OH HO NH O

CH

3 O N H HO N *11WOH bOH O NaO3SO HO 155 OHH OH O O

---

0 , = N-N.' / ' HzC/Is H H O(CH 2

)

4

CH

3

H

2 N N O HO NH O CH3 0 H HO N /OH NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 372 Example No. Formula OH OH

H

3 Cks,,. H /N

H

2 N N 0 H N OH HO NH O CH3 O N H 156 OH O H30 H HS NO(CH 2

)

5 CH 3 HO NH O CH H HHO H 'H 0 NaONSaS

HO

WO 99/40108 PCT/JP99/00538 373 Example No. Formula OH OH 0 OH - N HHhstOH 'H2

H

2 N NO 0 HN OH HO NH O CK 3 O N 157 H H O:::O H N H HO NH O CH 3 /H9 .. N HO O H/OH /, \ OH 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 374 Example No. Formula OH OOH N/

H

3 Ci,,. H %N2

H

2 N N O I- HN OH HO NH O

CH

3 O N H 158 OH OH O H 3C/f , H O N ..k. ./ HO NH O CH 3 OCH)CH O:= N- H HO. N 9O NaO 3 SOH O

HO

WO 99/40108 PCT/JP99/00538 375 Example No. Formula OH OH 0 H3C/Its. H

H

2 N N

-

O HN OH HO NH O

CH

3 O N HO 159 OH OH O

H

3 C/N S

O(CH)

4 CH3 HN N O N-N N-N OO HN oH HO NH 0 CH 3 0 N HO O H NaO 3 SO OH O

HO

WO 99/40108 PCT/JP99/00538 376 Example No. Formula O •OH OHO O C /

H

2 N N H O0 HN tOH HO3S H O HO HO N -""OH 160 H OH 0 0 H3C/Is H SNNHO -- O HN QH HO NH O CH 3 0 H O9 , N NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 377 Example No. Formula OH OHO N

H

3 Cks, . H H2

H

2 N N 0 HN OH HO NH O

CH

3 O N HO N* 0 HO3SbH O 161 H H3C/,, H S N _ N s OO HN OH 0 HO NH o CH3 HO\ O H 0 NaO 3 S_

HO

WO 99/40108 PCT/JP99/00538 378 Example No. Formula OH OH 0 . H = N---- HOH

H

3 C#is. H H2

H

2 N N O0 HN OH HO NH O

CH

3 O N H OH 0 HO3SOOH _O HO 162 OH O O

H

3 C/1, O

H

2 N S,-N NC) H2 Q NH /rj: O0 HN OH 0 N-N HO NH O CH 0 H O H l/OH OH O NaO 3 S _?

HO

WO 99/40108 PCT/JP99/00538 379 Example No. Formula OH OH 0 *zO 0 N-N 3c/I H N O(CH 2

)

7 OMe O2 O H H HO NH O = 4CH 3 0 O H NaO 3 SO HO 163 OH

H

3 C/I, H O O(C 2yOMe O QH HO NH O CH3 ON 9/OH O 4H O~NH HO HO H 0

HO

WO 99/40108 PCT/JP99/00538 380 Example No. Formula OH H20H3/ H O

O(CH

2

)

7 OMe O HN OH HO NH 0 4CH 3 O H N 0 H. ... H NaO 3 SO HO 164 OH OHO0N- H 3 C/, H O )O(CH 2

)

7 0Me

H

2 N -N " O HN H (164-1) HO NH 0 CH 3 0 H N O H Me~ H 0 Meo_ HO OH OH 0 ' 0 N-N H3C/, H w O(CH2)7OMe OO HN OH (164-11) O H H 2N N 4 H O H Me O N H 0 CH 3 0 MeO WO 99/40108 PCT/JP99/00538 381 Example No. Formula HO OH OH 0

H

3 CH H H C/l"e - g - N L(CH2)14CH3

H

2 N N!O O 0 N *OH HO NH O CH 3 0 N H/ HO N ""OH 'OH 0 NaO 3 SO $ HO 165 OH OHO0 C/ N/-- J

H

2 H30N. H H (CH 2

)

14

CH

3 H2 N N-' H= 0 O O HN OH ON HO N O 0CH 3 0 H N N **/OH H 0 NaO 3 SO

HO

WO 99/40108 PCT/JP99/00538 382 Example No. Formula OH OH 0 H C/ 11 -NJc H 3U0, f " H N N'(H2)14CH3

H

2 N N!O 0 HN OH BY NH 0= CH3 0 H N H NaO3 SO / HO 166 OH OH O H2H3CisI. NHO HOS NH 0 O N H N *Nt/OH OH N NaO 3 SO / 0

HO

WO 99/40108 PCT/JP99/00538 383 Example No. Formula OH N HzChis.- H

H

2 N NO O HN OH HO NH O CH3 O N OH N **#p.,/OH H O HO3SO OH OH00 N H2 _ O H- OOH -1x-x O(CH ,)OCH 3 HO N H O = CH 3 OH N HO H2 -0S, O(H2) K WO 99/40108 PCT/JP99/00538 384 Example No. Formula OH 0 H O .OH H2H30I., H ."0N 2 HO OH HO NH O ::: CH 3 OHO HO0 N OH H O H233C/hH H O O(CH )4CH 3 OHO NHN"OH HONH OH CH 0 N HH HOHO/ N HOH H 3 SO H O HOHO 168 O HO - _ OH 00 OH0 H2 N0 HHeS N\ H 0 H HOH HO// N -- o-WK WO 99/40108 PCT/JP99/00538 385 Example No. Formula OH 0 0 H2c/, NH N

(CH

2

)

1 4

CH

3

H

2 N H 0 EN °.OH 0 HO NH O CH 3 0 N H N **/OH NaO 3 SO OH HO 169 ,OH OH 0

H

3 CAI, H IHO

H

2 N0 0 HN OH 0 HO NH O

CH

3 O N H N ,. N *,1 /O H

HO

3 SO / \ H 0

HO

WO 99/40108 PCT/JP99/00538 386 Example 1 To a suspension of Starting Compound (1) (0.6 g) and sodium cyanoborohydride (0.076 g) in dichloromethane (6 ml) was gradually added trifluoroacetic acid (3 ml) at 4 0 C. The mixture 5 was stirred for an hour at 4 0 C. The reaction mixture was evaporated under reduced pressure. The residue was added to water and adjusted to pH 8.5 with IN NaOH aq. The solution was subjected to column chromatography on ODS (YMC-gel ODS-AM S 50) and eluted with 30% acetonitrile aqueous solution. The 10 fractions containing the object compound were combined and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Object Compound (1) (0.417 g) IR (KBr) : 3350, 1668.1, 1629.6, 1241.9 cm -I NMR (DMSO-d 6 , 6) : 0.87 (3H, t, J=6.7Hz), 0.96 (3H, d, 15 J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.2-1.55 (8H, m), 1.55-2.1 (5H, m), 2.1-2.5 (4H, m), 3.01 (1H, m), 3.19 (1H, m), 3.46 (1H, m), 3.6-3.87 (3H, m), 3.87-4.55 (13H, m), 4.6-5.5 (8H, m), 6.52 (1H, d, J=8.1Hz), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 20 6.85 (1H, s), 7.0-7.15 (3H, m), 7.19 (1H, s), 7.27-7.55 (3H, m), 7.55-7.78 (3H, m), 7.8-8.0 (2H, m), 8.76 (1H, s), 8.85 (1H, s) MASS (m/z) : 1248 (M+Na

+

) Elemental Analysis Calcd. for C 53

H

7 2

N

9 NaO 21 S*7H 2 0 : 25 C 47.07, H 6.41, N 9.32 Found : C 46.82, H 6.54, N 9.25 The following compounds (Examples 2 and 3) were obtained in a manner similar to that of Example 1. Example 2 30 IR (KBr) : 3349.7, 1666.2, 1631.5, 1267.0 cm-1 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.9Hz), 1.7-2.0 (2H, m), 2.0-2.6 (4H, m), 2.6-2.8 (1H, m), 3.1-3.3 (1H, m), 3.3-3.5 (1H, m), 3.5-4.5 (16H, m), 4.6-4.9 (2H, m), 5.1-5.5 (5H, m), 6.72 (1H, d, 35 J=8.2Hz), 6.81 (1H, dd, J=8.2 and 1.9Hz), WO 99/40108 PCT/JP99/00538 387 6.9-7.5 (4H, m), 7.05 (1H, d, J=1.9Hz), 7.4-7.9 (3H, m), 8.84 (1H, s) MASS (m/z) : 965 (M+Na + ) Elemental Analysis Calcd. for C 35

H

5 1

N

8

O

1 9 SNa*5.5H 2 O : 5 C 40.35, H 6.00, N 10.75 Found : C 40.33, H 5.92, N 10.63 Example 3 IR (KBr) : 3350, 1648.8, 1276.6 cm-1 MASS (m/z) : 1266 (M-Na + ) 10 Example 4 To a suspension of Starting Compound (4) (46.1 g) and NaBH 3 CN (7.7 g) in dichloromethane (600 ml) was added dropwise trifluoroacetic acid (240 ml) for 15 minutes below 5 0 C. The reaction mixture was stirred for 3 hours at the same temperature. 15 The lower layer (trifluoroacetic acid layer) of the reaction mixture was poured into a large volume of an ice cooled aqueous NaHCO 3 solution (pH=8.5). The upper layer (dichloromethane layer) was also poured into a large volume of an ice cooled aqueous NaHCO 3 solution. The aqueous layer was combined together and 20 was purified by column chromatography on ODS to afford Object Compound (4). NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.04-1.12 (3H, m), 1.48-2.00 (3H, m), 2.07-2.50 (4H, m), 2.90-3.34 (2H, m), 3.60-4.48 (18H, m), 4.60-5.40 (9H, 25 m), 6.72 (1H, d, J=8.2Hz), 6.81 (1H, dd, J=8.2 and 1.6Hz), 6.84 (1H, m), 6.98 (1H, m), 7.04 (1H, d, J=1.6Hz), 7.28-7.50 (6H, m), 7.58 (2H, m), 7.73 (2H, d, J=7.4Hz), 7.84 (1H, m), 7.88 (2H, d, J=7.6Hz), 8.84 (1H, s) 30 MASS (m/z) : 1141 (M + ) Example 5 To a solution of Starting Compound (5) (38.7 g) in dimethylformamide (250 ml) was added piperidine (17 ml) at room temperature. The solution was stirred for 2.5 hours at the same 35 temperature. Ethyl acetate (2.5 L) was added to the reaction WO99/40108 PCT/JP99/00538 388 mixture and the mixture was stirred for 30 minutes. The powder was collected by filtration to give Object Compound (5) (34.6 g). Example 6 5 To a solution of Starting Compound (6) (0.3 g) and triethylsilane (0.44 ml) in methylene chloride (7 ml) at 10'C, was added dropwise trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 4 hours. The reaction mixture was added in iN-sodium hydroxide (31 ml) at 100C. The aqueous 10 layer was subjected to column chromatography on ODS (YMC-gel ODS-AM S-50 (Trademark: prepared by Yamamura Chemical Lab.)) eluting with water. The fractions containing the object compound were combined, and evaporated under reduced pressure. The residue was lyophilized to give Object Compound (6) (0.13 15 g). IR (KBr) : 3361.3, 1668.1, 1631.5, 1268.9 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.06 (3H, d, J=5.5Hz), 1.60-2.50 (9H, m), 2.90-2.97 (1H, m), 3.16-3.50 (2H, m), 3.69-4.50 (13H, m), 4.74-5.31 (10H, 20 m), 6.72-7.65 (14H, m), 7.93-7.97 (1H, m), 8.71 (1H, s) Example 7 To a solution of Starting Compound (7) (110 mg) in water (5 ml) was added 10% palladium on carbon (11 mg), and hydrogen 25 gas at atmosphere pressure for 7 hours. The reaction mixture was filtered through celite and lyophilized to give Object Compound (7) (70 mg). IR (KBr) : 3394, 3327, 1676, 1633, 1439 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.8Hz), 1.08 (3H, d, 30 J=6.0Hz), 1.88-5.83 (35H, m), 6.68-8.71 (10H, m) MASS (m/z) : 903.17 (M-Na + ) Example 8 To a solution of Starting Compound (8) (350 mg) in N,N dimethylformamide (6 ml) was added 4-[4-(4-cyclohexylphenyl) 35 piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (230 mg), WO 99/40108 PCT/JP99/00538 389 and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The powder was dissolved in water, and subjected to 5 column chromatography on ion exchange resin (DOWEX-50WX4 (Trademark: prepared by Dow Chemical)) eluting with water. The fractions containing the object compound were combined, and subjected to column chromatography on ODS (YMC-gel*ODS-AM*S 50 (Trademark: prepared by Yamamura Chemical Lab.)) eluting with 10 30% acetonitrile in water. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Object Compound (8) (160 mg). IR (KBr) : 1666.2, 1633.4, 1608.3, 1511.9, 1230.4 cm 1 15 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.09 (3H, d, J=5.4Hz), 1.2-1.5 (6H, m), 1.6-2.1 (7H, m), 2.1-2.6 (5H, m), 3.02 (1H, m), 3.1-3.5 (10H, m), 3.6-4.5 (14H, m), 4.6-5.3 (9H, m), 6.73 (1H, d, J=8.2Hz), 6.77 (1H, d, J=8.2Hz), 6.80 (1H, s), 6.91 (2H, d, J=8.7Hz), 20 6.9-7.1 (5H, m), 7.26 (1H, s), 7.3-7.5 (2H, m), 7.66 (1H, brs), 7.78 (2H, d, J=8.6Hz), 8.04 (1H, d, J=7.3Hz), 8.31 (1H, d, J=7.3Hz), 8.84 (1H, s) MASS (m/z) : 1311 (M+Na + ) Elemental Analysis Calcd. for C 58

H

77

N

1 00 2 0 S*6H 2 O : 25 C 49.85, H 6.42, N 10.02 Found : C 50.06, H 6.36, N 10.07 The following compounds (Examples 9 to 11) were obtained in a manner similar to that of Example 8. Example 9 30 IR (KBr) : 3350, 1648.8, 1276.6 cm-1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.8Hz), 1.11 (3H, d, J=5.2Hz), 1.5-1.7 (6H, m), 1.7-2.6 (7H, m), 2.94 (1H, m), 3.1-3.5 (6H, m), 3.6-4.6 (14H, m), 4.7-5.3 (9H, m), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.84 35 (1H, s), 7.04 (1H, s), 7.06 (2H, d, J=8.7Hz), 7.18 (1H, WO 99/40108 PCT/JP99/00538 390 s), 7.3-7.5 (2H, m), 7.66 (1H, br s), 7.83 (2H, d, J=8.7Hz), 8.0-8.2 (5H, m), 8.75 (1H, d, J=7.1Hz), 8.84 (1H, s) MASS (m/z) : 1266 (M-Na + ) 5 Example 10 IR (KBr) : 3361.3, 1646.9, 1517.7, 1257.4 cm-1 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.3Hz), 0.96 (3H, d, J=6.5Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (4H, m), 1.6-2.6 (9H, m), 2.95 (1H, m), 3.1-3.5 (2H, m), 3.6-4.6 10 (16H, m), 4.7-5.4 (9H, m), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.90 (1H, s), 7.06 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.23 (1H, s), 7.3-7.5 (2H, m), 7.68 (1H, br s), 7.90 (2H, d, J=8.9Hz), 7.8-8.2 (5H, m), 8.60 (1H, d, J=6.7Hz), 8.85 (2H, s) 15 MASS (m/z) : 1308 (M-Na + ) Elemental Analysis Calcd. for C 57

H

7 0

N

11

O

2 1

S

2 Na*10H 2 0 : C 45.26, H 6.00, N_10.19 Found : C 45.05, H 5.83, N 10.19 Example 11 20 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.12 (3H, d, J=6.0Hz), 1.2-1.6 (SH, m), 1.6-2.6 (9H, m), 2.9-3.1 (1H, m), 3.1-3.5 (7H, m), 3.6-4.6 (16H, m), 4.6-5.4 (9H, m), 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.13 (2H, d, J=8.8Hz), 7.16 25 (1H, m), 7.3-7.6 (2H, m), 7.67 (1H, br), 7.97 (2H, d, J=8.8Hz), 7.9-8.2 (5H, m), 8.7-9.0 (2H, m) MASS (m/z) : 1327.07 (M-Na + ) Elemental Analysis Calcd. for C 5 8

H

75 No 10 NaO 22

S

2 .5H 2 0 C 48.33, H 5.94, N 9.72 30 Found : C 48.27, H 6.05, N 9.69 Example 12 To a solution of Starting Compound (12) (60.0 g) and diethylisopropylamine (16.6ml) in diethylformamide (340ml) was added 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4- WO 99/40108 PCT/JP99/00538 391 thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester (37.4 g) at room temperature. The solution was stirred for 17 hours at the same temperature. Ethyl acetate (3.4 L) was added to the reaction mixture and the mixture was stirred for 30 minutes. The 5 powder was collected by filtration and washed with ethyl acetate (3.5 L) to give crude N-acylated Starting Compound (12) (93.0 g) . This material was used without further purification. To a suspension of crude N-acylated Starting Compound (12) (93.0 g) and NaBH 3 CN (9.0 g) in dichloromethane (900 ml), was added 10 trifluoroacetic acid (450 ml) at 00C over 30 minutes. The solution was stirred for 2 hours at the same temperature. The reaction mixture was slowly poured into an ice cooled aqueous NaOH solution (8<pH<11, Temperature<7 0 C). The separated organic layer was extracted with water twice. The combined 15 aqueous solution was subjected to column chromatography on SP20 (7 L), washing with water, and eluting with 60% aqueous CH 3 CN. The eluent was concentrated to remove CH 3 CN and chromatographed by reverse-phase (ODS) flash chromatography eluting with 17%

CH

3 CN/water, followed by lyophilization of the appropriate 20 fractions to provide 28.3 g of Object Compound (12). NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.9Hz), 1.30-1.60 (6H, m), 1.65-2.60 (9H, m), 2.80-3.50 (5H, m), 3.22 (3H, s), 3.60-4.60 (14H, m), 4.07 (2H, t, J=6.7Hz), 4.60-5.30 (9H, m), 6.73 (1H, 25 d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.13 (2H, d, J=8.9Hz), 7.16 (1H, s), 7.42-7.46 (2H, m), 7.66 (1H, br), 7.97 (2H, d, J=8.8Hz), 8.07-8.13 (5H, m), 8.77 (1H, d, J=6.8Hz), 8.84 (1H, s) 30 MASS (m/z) : 1313.25 (M-Na + ) Elemental Analysis Calcd. for C 5 7

H

73

N

1 00 22

S

2 Na'7H 2 0 : C 46.78, H 5.99, N 9.57 Found : C 46.56, H 5.94, N 9.45 Example 13 35 A solution of Starting Compound (13) (400 mg) in N,N- WO 99/40108 PCT/JP99/00538 392 dimethylformamide (4 ml) was treated with 4-[5-[4-(6 methoxy-n-hexyloxy)phenyl]-1, 3,4-thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester (343 mg) then stirred 15 hours at room temperature. Ethyl acetate was added to the reaction mixture 5 and the resulting precipitate were collected by filtration, washed thoroughly with ethyl acetate and dried. The powder was dissolved in saturated sodium hydrogen carbonate solution, filtered then purified by ODS column chromatography (YMC-gel ODS-AM S-50) eluting with 19-21% aqueous acetonitrile. 10 Product-containing fractions were pooled, evaporated to remove acetonitrile, andlyophilizedto giveObject Compound (13) (306.4 mg) as an amorphous white powder. IR (KBr) : 1675.8, 1650.8, 1631.5, 1540.8, 1513.8, 1452.1, 1257.4 cm -1 15 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.6Hz), 1.09 (3H, d, J=5.4Hz), 1.30-1.60 (6H, m), 1.65-2.60 (10H, m), 2.80-4.60 (17H, m), 3.22 (3H, s), 3.32 (2H, t, J=6.3Hz), 4.07 (2H, t, J=6.5Hz), 4.68-5.80 (8H, m), 6.68 (1iH, d, J=8Hz), 6.76 (1H, d, J=8Hz), 6.86 (1H, s), 6.98 (1H, 20 s), 7.13 (2H, d, J=8.8Hz), 7.16 (1H, s), 7.30-7.50 (3H, m), 7.97 (2H, d, J=8.8Hz), 8.03-8.13 (4H, m), 8.76-8.79 (2H, m) MASS (m/z) : 1343.13 (M+Na + ) Elemental Analysis Calcd. for C 57

H

73

N

1 00 2 1

S

2 Na*8H 2 O : 25 C 46.72, H 6.12, N 9.56 Found : C 46.66, H 5.97, N 9.53 The following compound was obtained in a manner similar to that of Example 13. Example 14 30 IR (KBr) : 1675.8, 1650.8, 1631.5, 1540.8, 1513.8, 1450.2 cm 1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.9Hz), 1.12-1.80 (8H, m), 1.80-2.60 (10H, m), 2.90-3.05 (1H, m), 3.21 (3H, s), 3.27 (2H, t, J=6.3Hz), 35 3.30-3.50 (2H, m), 3.68-4.60 (14H, m), 4.07 (2H, t, WO 99/40108 PCT/JP99/00538 393 J=6Hz), 4.70-5.45 (8H, m), 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.87 (1H, s), 6.97 (1H, s), 7.13 (2H, d, J=8.9Hz), 7.15 (1H, s), 7.42-7.71 (3H, m), 7.97 (2H, d, J=8.7Hz), 8.03-8.12 (4H, m), 8.73-8.81 (3H, m) 5 MASS (m/z) : 1311.32 (M-Na + ) Elemental Analysis Calcd. for C 5 8

H

75

N

10 0 2 1

S

2 Na*7H 2 O : C 47.67, H 6.14, N 9.58 Found : C 47.49, H 6.09, N 9.47 Example 15 10 A solution of Starting Compound (15) (508 mg) in N,N-dimethylformamide (10 ml) was treated with 4-[5-[4-(6 methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester (428 mg) and the mixture was stirred 18 hours at room temperature. Ethyl acetate was added to the 15 reaction mixture and the resulting precipitate was collected by filtration, washed thoroughly with ethyl acetate and dried. The powder was dissolved in saturated sodium hydrogen carbonate solution (100 ml), treated with water (100 ml), then purified by ODS column chromatography (YMC-gel ODS-AM S-50) eluting with 20 16-17% aqueous acetonitrile. Fractions containing the object compound were combined, evaporated to remove acetonitrile, and lyophilized to give Object Compound (15) (400 mg) as an amorphous white powder. IR (KBr) : 1668.1, 1650.8, 1631.5, 1538.9, 1513.8, 25 1450.2, 1259.3 cm-1 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.9Hz), 1.30-1.60 (6H, m), 1.65-2.60 (9H, m), 2.80-3.50 (5H, m), 3.22 (3H, s), 3.60-4.60 (14H, m), 4.07 (2H, t, J=6.7Hz), 4.60-5.30 (9H, m), 6.73 (1iH, 30 d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.13 (2H, d, J=8.9Hz), 7.16 (1H, s), 7.42-7.46 (2H, m), 7.66 (1H, br), 7.97 (2H, d, J=8.8Hz), 8.07-8.13 (5H, m), 8.77 (1H, d, J=6.8Hz), 8.84 (1H, s) 35 MASS (m/z) : 1313.25 (M-Na + ) WO 99/40108 PCT/JP99/00538 394 Elemental Analysis Calcd. for C 57

H

73

N

10 0 22

S

2 Na.7H 2 O : C 46.78, H 5.99, N 9.57 Found : C 46.56, H 5.94, N 9.45 Example 16 5 To a solution of Starting Compound (16) (200 mg) and 4-[5-(4-piperidin-1-yl-phenyl)-1,3,4-thiadiazol-2-yl]benzoic acidbenzotriazol-1-yl ester inN,N-dimethylformamide (3ml) was added dimethylaminopyridine (0.034 g), and the mixture was stirred for 6.5 hours at ambient temperature. The reaction 10 mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The solid was dissolved in water, and subjected to column chromatography on ion exchange resin (DOWEX-50WX4 (Trademark: prepared by Dow Chemical)) eluting with water. The fractions 15 containing the object compound were combined, and subjected to column chromatography on ODS (YMC-gel ODS-AM S-50 (Trademark: prepared by Yamamura Chemical Lab.)) eluting with 50% methyl alcohol aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure 20 to remove methanol. The residue was lyophilized to give Object Compound (16) (190 mg). IR (KBr) : 3367, 1651, 1539, 1443 cm

-

1 NMR (DMSO-d 6 , 6) : 0.95-5.30 (49H, m), 6.63-8.72 (19H, m) MASS (m/z) : 1250.22 (M-Na + ) 25 Elemental Analysis Calcd. for C 55

H

68

N

11 NaOl 9

S

2 -12H 2 0 : C 44.05, H 6.25, N 10.27 Found : C 43.94, H 5.76, N 10.14 Example 17 To a solution of 1-hydroxybenzotriazole (64 mg) and 30 4-[2-(4-butyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl] benzoic acid (125 mg) in N,N-dimethylformamide (4 ml) was added 1-ethyl-3-(3 '-dimethylaminopropyl)carbodiimide hydrochloride (73 mg) and the mixture was stirred for 4 hours at ambient temperature. Then to the reaction mixture was added Starting 35 Compound (17) (200 mg) and the mixture was stirred for 4 hours WO 99/40108 PCT/JP99/00538 395 at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration and dried over reduced pressure. The powder was added to saturated sodium bicarbonate aqueous solution and subjected to 5 column chromatography on ODS (YMC-gel ODS-AM S-50) and eluted with 30% acetonitrile in water. The fractions containing the object compound were combined and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Object Compound (17) (123 mg). 10 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.3Hz), 0.96 (3H, d, J=7.2Hz), 1.11 (3H, d, J=5.5Hz), 1.3-1.6 (2H, m), 1.6-2.6 (9H, m), 2.95 (1H, m), 3.1-3.5 (2H, m), 3.6-4.6 (16H, m), 4.7-5.5 (9H, m), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.14 (2H, 15 d, J=8.9Hz), 7.24 (1H, s), 7.3-7.5 (2H, m), 7.68 (1H, br s), 7.90 (2H, d, J=8.9Hz), 7.8-8.1 (5H, m), 8.56 (1H, d, J=6.7Hz), 8.85 (2H, s) MASS (m/z) : 1341 (M+Na

+

) Example 18 20 To a suspension of Starting Compound (18) (1.70 g) and triethylsilane (1.58 g) in dichloromethane (15 ml) was added trifluoroacetic acid (15 ml) dropwise, and the mixture was stirred for 30 minutes under nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure. The residue was 25 dissolved in pH 6.86 phosphate-buffer, and adjusted to pH 9.5 with 1N sodium hydroxide aqueous solution. The solution was subjected to column-chromatography on ODS (YMC-gel ODS-AM S 50) and elutedwith 30% acetonitrile aqueous solution (v/v) . The fractions containing the object compound were combined and 30 evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Object Compound (18) (136 mg) IR (KBr) : 3350, 2933, 1668, 1635, 1540, 1471, 1249, 1045 cm -1 NMR (DMSO-d 6 , 5) : 0.88 (3H, t, J=6.7Hz), 0.96 (3H, d, 35 J=6.7Hz), 1.08 (3H, d, J=5.8Hz), 1.2-1.6 (8H, m), WO 99/40108 PCT/JP99/00538 396 1.6-2.4 (10H, m), 2.8-4.1 (16H, m), 4.1-5.3 (11H, m), 6.6-7.2 (9H, m), 7.3-7.7 (3H, m), 7.9-8.3 (4H, m), 8.7-8.9 (1H, d, J=6.0Hz), 9.04 (1H, s) MASS (m/z) : 1244.5 (M+Na + ) 5 Elemental Analysis Calcd. for C 54

H

72

N

9 0 20 NaS-6H 2 0 : C 48.75, H 6.36, N 9.48 Found : C 48.53, H 6.24, N 9.40 The following compounds [Examples 19 and 20] were obtained in a manner similar to that of Example 18. 10 Example 19 NMR (DMSO-d 6 , 5) : 0.95 (3H, t, J=7.3Hz), 0.96 (3H, d, J=7.1Hz), 1.10 (3H, d, J=5.8Hz), 1.3-1.6 (2H, m), 1.6-2.6 (10H, m), 2.95 (1H, m), 3.1-3.5 (2H, m), 3.6-4.6 (16H, m), 4.7-5.4 (8H, m), 6.71 (1H, d, 15 J=8.1Hz), 6.78 (1H, d, J=8.1Hz), 6.87 (1H, s), 6.97 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.24 (1H, s), 7.44 (1H, d, J=7.9Hz), 7.5-7.8 (2H, m), 7.89 (2H, d, J=8.9Hz), 7.9-8.0 (6H, m), 8.12 (1H, d, J=7.7Hz), 8.60 (1H, d, J=7.2Hz), 8.72 (1H, s), 8.85 (1H, s) 20 MASS (m/z) : 1278 (M-Na

+

) Example 20 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.3Hz), 0.96 (3H, d, J=7.1Hz), 1.09 (3H, d, J=5.8Hz), 1.3-1.6 (4H, m), 1.6-2.6 (10H, m), 2.95 (1H, m), 3.1-3.5 (2H, m), 25 3.6-4.6 (16H, m), 4.7-5.4 (8H, m), 6.71 (1H, d, J=8.1Hz), 6.78 (1H, d, J=8.1Hz), 6.87 (1H, s), 6.97 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.24 (1H, s), 7.44 (1H, d, J=7.9Hz), 7.5-7.8 (2H, m), 7.89 (2H, d, J=8.9Hz), 7.9-8.0 (6H, m), 8.12 (1H, d, J=7.7Hz), 8.60 (1H, d, 30 J=7.2Hz), 8.72 (1H, s), 8.85 (1H, s) MASS (m/z) : 1338 (M+Na + ) The following compounds [Examples21 to 29] were obtained according to similar manner to that of Example1. Example 21 35 IR (KBr) 3353, 1666.2, 1631.5, 1510, 1236 cm-1 WO 99/40108 PCT/JP99/00538 397 NMR (DMSO-d 6 , 5) : 0.86 (3H, t, J=6.8Hz), 0.95 (3H, d, J=6.7Hz), 1.09 (3H, d, J=5.8Hz), 1.2-1.5 (10H, m), 1.55-2.6 (9H, m), 2.95 (1H, m), 3.0-3.5 (10H, m), 3.6-4.5 (15H, m), 4.6-5.4 (10H, m), 6.6-7.1 (10H, m), 5 7.27 (1H, s), 7.35-7.5 (2H, m), 7.65 (1H, br s), 7.78 (2H, d, J=8.8Hz), 8.03 (1H, d, J=8.7Hz), 8.30 (1H, d, J=8.7Hz), 8.83 (1H, s) MASS (m/z) : 1357 (M+Na) + Elemental Analysis Calcd. for C 60

H

83

N

1 00 2 1 SNa*5H 2 0 : 10 C 50.55, H 6.58, N 9.83 Found : C 50.56, H 6.59, N 9.76 Example 22 IR (KBr) : 3350, 1658.5, 1633, 1278 cm - I NMR (DMSO-d 6 , 6) : 0.86 (3H, t, J=6.7Hz), 0.96 (3H, d, 15 J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.2-1.4 (8H, m), 1.45-2.45 (9H, m), 2.62 (2H, t, J=7.4Hz), 2.98 (1H, m), 3.2 (1H, m), 3.25-3.5 (1H, m), 3.6-5.4 (23H, m), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, dd, J=l.5 and 8.2Hz), 6.88 (1H, s), 7.05 (1H, d, J=1.5Hz), 7.31 (2H, d, 20 J=8.2Hz), 7.1-7.5 (4H, m), 7.64 (2H, d, J=8.2Hz), 7.74 (2H, d, J=8.4Hz), 7.6-7.8 (1H, m), 7.95 (2H, d, J=8.4Hz), 8.0-8.2 (1H, m), 8.61 (1H, d, J=6.7Hz), 8.84 (1H, s) MASS (m/z) : 1243 (M+Na) + 25 Elemental Analysis Calcd. for C 55

H

73

N

8 NaO 2 0 S-6H 2 O : C 49.69, H 6.44, N 8.43 Found : C 49.99, H 6.53, N 8.40 Example 23 IR (Nujol) : 1668.1, 1629.6, 1540.8, 1515.8 cm 1 30 NMR (DMSO-d 6 , 6) : 0.87 (3H, t, J=6.7Hz), 0.95 (3H, d, J=6.7Hz), 1.07 (3H, d, J=5.9Hz), 1.25-1.48 (4H, m), 1.49-2.05 (5H, m), 2.05-2.70 (8H, m), 2.70-3.05 (3H, m), 3.08-3.45 (2H, m), 3.55-3.86 (2H, m), 3.88-4.50 (11H, m), 4.65-5.36 (10H, m), 6.67-6.90 (3H, m), 7.04 35 (1H, d, J=1.0Hz), 7.10-7.80 (12H, m), 8.00 (1H, d, WO 99/40108 PCT/JP99/00538 398 J=8.4Hz), 8.13 (1H, d, J=7.7Hz), 8.84 (1H, s) MASS (m/z) : 1227.5 (M+Na) + Elemental Analysis Calcd. for C 55

H

73

N

8 NaO 20 S-5H 2 O : C 50.38, H 6.38, N 8.54 5 Found : C 50.07, H 6.60, N 8.58 Example 24 IR (KBr) : 3350, 2929, 1664, 1635, 1515, 1440, 1278, 1245, 1085, 1047 cm

-

1 NMR (DMSO-d 6 , 5) : 0.86 (3H, m), 0.96 (3H, d, J=7.7Hz), 10 1.11 (3H, d, J=5.7Hz), 1.30 (6H, m), 1.5-2.4 (9H, m), 2.6-2.8 (2H, t, J=7.2Hz), 2.9-3.1 (1H, m), 3.1-3.3 (1H, m), 3.4-3.6 (1H, m), 3.7-4.6 (14H, m), 4.6-5.3 (9H, m), 6.7-7.0 (3H, m), 7.04 (1H, s), 7.21 (1H, s), 7.30 (2H, d, J=8.2Hz), 7.4-7.5 (1H, m), 7.6-7.8 (5H, m), 15 7.95 (2H, d, J=8.4Hz), 8.10 (1H, d, J=8.4Hz), 8.60 (1H, d, J=8.4Hz), 8.84 (1H, s) MASS (m/z) : 1230 (M+Na) + Elemental Analysis Calcd. for C 54

H

71

N

8 NaO 20 S*4.5H 2 0 : C 50.34, H 6.26, N 8.70 20 Found : C 50.43, H 6.19, N 8.59 Example 25 IR (KBr) : 3350, 1666.2, 1631.5, 1510.0, 1236.1 cm " NMR (DMSO-d 6 , 5) : 0.88 (3H, t, J=6.6Hz), 0.95 (3H, d, J=6.7Hz), 1.08 (3H, d, J=5.7Hz), 1.2-1.5 (6H, m), 25 1.6-2.1 (5H, m), 2.1-2.5 (4H, m), 2.8-3.0 (1H, m), 3.1-3.3 (5H, m), 3.3-3.4 (4H, m), 3.6-5.4 (23H, m), 6.73 (1H, d, J=8.1Hz), 6.8-6.9 (4H, m), 6.94 (2H, d, J=9.3Hz), 7.01 (2H, d, J=8.7Hz), 7.04 (1H, s), 7.2-7.5 (3H, m), 7.6-7.7 (1H, m), 7.78 (2H, d, J=8.7Hz), 8.05 30 (1H, d, J=8Hz), 8.30 (1H, d, J=6.7Hz), 8.85 (1H, s) MASS (m/z) : 1329 (M+Na) + Elemental Analysis Calcd. for C 5 8

H

7 9

N

1 00 21 SNa.6H 2 0 : C 49.22, H 6.48, N 9.90 Found : C 49.46, H 6.44, N 9.96 35 Example 26 WO 99/40108 PCT/JP99/00538 399 IR (KBr) : 3347.8, 1670.1, 1652.7, 1635.3 cm -1 NMR (DMSO-d 6 , 5) : 0.85 (3H, t, J=6.6Hz), 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.9Hz), 1.18-1.40 (8H, m), 1.50-2.10 (5H, m), 2.10-2.60 (4H, m), 2.76 (2H, t, 5 J=7.6Hz), 2.85-3.50 (3H, m), 3.60-4.60 (14H, m), 4.60-5.33 (9H, m), 6.67-7.00 (3H, m), 7.05 (1H, d, J=0.4Hz), 7.20-7.50 (4H, m), 7.60-7.80 (2H, m), 7.85-8.00 (3H, m), 8.10 (1H, d, J=8.5Hz), 8.45 (1H, s), 8.68 (IH, d, J=8.4Hz), 8.48 (1H, s) 10 MASS (m/z) : 1217.4 (M+Na-1) Elemental Analysis Calcd. for C 53

H

71

N

8 0 21 SNa*4H 2 0 : C 49.61, H 6.20, N 8.73 Found : C 49.62, H 6.38, N 8.68 Example 27 15 IR (KBr) : 3361.3, 1668.1, 1635.3 cm -1 NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.8Hz), 0.95 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.9Hz), 1.20-1.48 (6H, m), 1.55-2.13 (5H, m), 2.13-2.60 (4H, m), 2.76 (2H, t, J=7.6Hz), 2.89-3.08 (1H, m), 3.10-3.50 (3H, m), 20 3.60-3.85 (2H, m), 3.85-4.65 (12H, m), 4.65-5.50 (8H, m), 6.62-7.05 (3H, m), 7.06 (1H, d, J=0.4Hz), 7.15-7.55 (4H, m), 7.55-7.80 (2H, m), 7.80-8.03 (3H, m), 8.03-8.20 (1H, m), 8.45 (1H, s), 8.60-9.05 (2H, m) MASS (m/z) : 1203.4 (M+Na-1) 25 Elemental Analysis Calcd. for C 52

H

69

N

8 NaO 20 S*6H 2 0 : C 48.44, H 6.33, N 8.69 Found : C 48.55, H 6.39, N 8.70 Example 28 IR (KBr) : 3359.4, 1664.3, 1631.5, 1510.0, 1230.4, 30 1045.2 cm NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.5Hz), 1.08 (3H, d, J=5.6Hz), 1.2-1.6 (10H, m), 1.6-2.1 (5H, m), 2.1-2.5 (4H, m), 2.95 (1H, m), 3.0-3.2 (5H, m), 3.20 (3H, s), 3.29 (3H, t, J=6.4Hz), 3.2-3.5 (5H, m), 3.6-4.5 (16H, 35 m), 4.6-5.4 (9H, m), 6.73 (1H, d, J=8.2Hz), 6.8-7.1 WO 99/40108 PCT/JP99/00538 400 (10H, m), 7.2-7.5 (2H, m), 7.70 (1H, br s), 7.78 (2H, d, J=8.6Hz), 8.10 (1H, br s), 8.32 (1H, d, J=7.2Hz), 8.90 (1H, br s) MASS (m/z) : 1387 (M+Na) + 5 Elemental Analysis Calcd. for C 61

H

84

N

1 00 2 2 SNa-8H 2 0 : C 48.53, H 6.74, N 9.28 Found : C 48.38, H 7.18, N 9.18 Example 29 IR (KBr) : 3355.5, 1666.2, 1631.5, 1608.3, 1236.1, 10 1045.2 cm-1 NMR (DMSO-d 6 , 5) : 0.93 (3H, d, J=6.6Hz), 1.07 (3H, d, J=5.7Hz), 1.2-1.6 (8H, m), 1.6-2.1 (5H, m), 2.1-2.6 (4H, m), 2.96 (1H, m), 3.1-3.3 (5H, m), 3.19 (3H, s), 3.28 (3H, t, J=6.5Hz), 3.3-3.5 (5H, m), 3.7-4.5 (16H, 15 m), 4.65-5.3 (9H, m), 6.71 (1H, d, J=8.1Hz), 6.8-7.1 (9H, m), 7.26 (1H, s), 7.3-7.5 (2H, m), 7.66 (1H, br s), 7.76 (2H, d, J=8.6Hz), 8.07 (1H, d, J=7.7Hz), 8.31 (1H, d, J=6.8Hz), 8.83 (1H, s) MASS (m/z) : 1373 (M+Na) + 20 The following compounds [Examples 30 to 54] were obtained in a manner similar to that of Example 8. Example 30 IR (KBr) : 3369, 2935, 1664, 1631, 1444, 1257, 1047 cm

-

1 NMR (DMSO-d 6 , 5) : 0.89 (3H, d, J=6.9Hz), 0.95 (3H, d, 25 J=6.8Hz), 1.11 (3H, d, J=5.8Hz), 1.2-1.5 (6H, m), 1.6-2.4 (9H, m), 2.9-3.4 (2H, m), 3.6-4.5 (16H, m), 4.7-5.4 (9H, m), 6.73 (1H, d, J=8.2Hz), 6.8-7.0 (2H, m), 7.0-7.2 (4H, m), 7.3-7.7 (3H, m), 7.97 (2H, d, J=8.7Hz), 8.1-8.3 (5H, m), 8.81 (1H, d, J=7.0Hz), 8.85 30 (1H, s) MASS (m/z) : 1329.8 (M+Na) + Elemental Analysis Calcd. for C 56

H

7 1

N

1 00 2 1

S

2 Na : C 46.93, H 5.98, N 9.77 Found : C 46.72, H 6.11, N 9.72 35 Examle 31 WO 99/40108 PCT/JP99/00538 401 IR (KBr) : 3353, 2935, 2873, 1658, 1635, 1440, 1257, 1047 cm

-

1 NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.9Hz), 0.96 (3H, d, J=6.8Hz), 1.12 (3H, d, J=5.8Hz), 1.2-1.5 (6H, m), 5 1.6-2.4 (9H, m), 2.9-3.2 (2H, m), 3.3-3.4 (1H, m), 3.8-4.6 (16H, m), 4.6-5.4 (9H, m), 6.7-7.0 (3H, m), 7.0-7.2 (4H, m), 7.3-7.7 (3H, m), 7.9-8.3 (7H, m), 8.7-8.9 (2H, m) MASS (m/z) : 1313.0 (M+Na) + 10 Elemental Analysis Calcd. for C 5 6

H

71

N

1 0 0 22 S : C 48.07, H 5.98, N 10.01 Found : C 48.23, H 6.17, N 10.00 Example 32 IR (KBr) : 3350, 2927, 1668, 1627, 1288, 1047 cm -1 15 NMR (DMSO-d 6 , 5) : 0.86 (3H, t, J=6.8Hz), 0.95 (3H, d, J=6.8Hz), 1.13 (3H, d, J=6.7Hz), 1.2-1.5 (10H, m), 1.6-2.4 (8H, m), 2.9-3.2 (2H, m), 3.4-4.6 (16H, m), 4.6-5.3 (9H, m), 6.5-7.5 (8H, m), 7.6-8.2 (4H, m), 8.31 (1H, s), 8.43 (1H, dd, J=8.7 and 2.5Hz), 8.6-8.8 (1H, 20 d, J=6.3Hz), 8.85 (1H, s), 8.99 (1H, d, J=2.5Hz) MASS (m/z) : 1315.3 (M+Na) + Elemental Analysis Calcd. for C 5 6

H

73

N

1 00 22 NaS*7H 2 0 : C 47.39, H 6.18, N 9.87 Found : C 47.11, H 6.29, N 9.72 25 Example 33 IR (KBr) : 3350, 2925, 1670, 1625, 1259, 1047 cm - 1 NMR (DMSO-d 6 , 5) : 0.7-1.0 (6H, m), 1.1-1.2 (3H, d, J=5.7Hz), 1.2-2.5 (15H, m), 3.0-3.3 (2H, m), 3.4-3.6 (1H, m), 3.6-3.8 (2H, m), 3.9-4.6 (16H, m), 4.7-5.4 30 (9H, m), 6.6-7.3 (6H, m), 7.3-8.0 (5H, m), 8.0-8.3 (5H, m), 8.6-9.0 (2H, m) MASS (m/z) : 1286.8 (M+Na) + Elemental Analysis Calcd. for C 55

H

7 0

N

9 0 22 NaS*5.5H 2 0 : C 48.46, H 5.99, N 9.25 35 Found : C 48.47, H 6.01, N 9.26 WO 99/40108 PCT/JP99/00538 402 Example 34 MASS (m/z) : 1387 (M+Na) + Example 35 IR (KBr) : 3363, 1662.3, 1631.5, 1240 cm-1 5 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.8Hz), 0.8-1.5 (15H, m), 1.5-2.6 (16H, m), 2.8-3.5 (11H, m), 3.6-4.6 (14H, m), 4.6-5.3 (9H, m), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.84 (1H, s), 7.00 (2H, d, J=8.8Hz), 7.04 (1H, s), 7.13 (1H, s), 7.3-7.5 (2H, m), 7.63 (1H, br 10 s), 7.79 (2H, d, J=8.8Hz), 8.05 (1H, d, J=7.7Hz), 8.29 (1H, d, J=6.8Hz), 8.83 (1H, s) MASS (m/z) : 1215 (M-SO 3 +Na) Elemental Analysis Calcd. for C 58

H

84

N

1 0 0 20 S-7H 2 0 : C 49.78, H 7.06, N 10.01 15 Found : C 49.93, H 6.92, N 9.98 Example 36 IR (KBr) : 1648, 1631 cm

-

1 NMR (DMSO-d 6 , 6) : 0.95 (3H, d, J=6.8Hz), 1.12 (3H, d, J=5.7Hz), 1.65-2.50 (7H, m), 2.84-3.13 (3H, m), 20 3.74-5.41 (23H, m), 3.83 (3H, s), 6.74 (1H, d, J=8.2Hz), 6.77 (1H, d, J=10.6Hz), 6.83 (1H, m), 7.08 (3H, m), 7.17 (1H, m), 7.43 (2H, m), 7.65 (1H, m), 7.77 (2H, d, J=8.7Hz), 7.92 (2H, d, J=8.5Hz), 8.08 (1H, m), 8.11 (2H, d, J=8.4Hz), 8.22 (2H, d, J=7.6Hz), 8.25 (2H, d, 25 J=7.6Hz), 8.85 (2H, m) MASS (m/z) : 1273 Elemental Analysis Calcd. for C 57

H

65

N

1 00 22 SNa-11H 2 O : C 45.78, H 5.86, N 9.37 Found : C 45.75, H 5.95, N 9.27 30 Example 37 IR (KBr) : 2968, 2937, 2879, 1651, 1632 cm-1 NMR (DMSO-d 6 , 6) : 0.95 (3H, d, J=5.5Hz), 1.01 (3H, t, J=7.1Hz), 1.12 (3H, t, J=5.8Hz), 1.75 (2H, q, J=7.1Hz), 1.60-2.48 (7H, m), 2.75-3.10 (3H, m), 3.60-5.35 (23H, 35 m), 4.01 (2H, t, J=7.1Hz), 6.73 (1H, d, J=8.2Hz), 6.78 WO 99/40108 PCT/JP99/00538 403 (1H, d, J=9.7Hz), 6.87 (1H, m), 7.07 (3H, m), 7.16 (1H, m), 7.43 (2H, m), 7.64 (1H, m), 7.74 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.5Hz), 8.00 (1H, m), 8.10 (2H, d, J=8.5Hz), 8.21 (2H, d, J=7.4Hz), 8.25 (2H, d, J=8.3Hz), 5 8.83 (2H, m) MASS (m/z) : 1301 Elemental Analysis Calcd. for C 59

H

69

N

1 00 22 SNa*10H 2 0 : C 47.07, H 5.96, N 9.30 Found : C 46.88, H 5.70, N 9.14 10 Example 38 IR (KBr) : 2935, 2873, 1668, 1651, 1632 cm -1 NMR (DMSO-d 6 , 5) : 0.92-0.99 (6H, m), 1.12 (3H, d, J=6.1Hz), 1.48 (2H, qt, J=5.5 and 5.5Hz), 1.74 (2H, tt, J=5.5 and 5. 5Hz), 1.60-2.40 (7H, m), 2.80-3.20 (3H, 15 m), 4.05 (2H, t, J=5.5Hz), 3.74-5.25 (23H, m), 6.74 (1H, d, J=8.2Hz), 6.78 (1H, d, J=9.SHz), 6.87 (1H, m), 7.07 (3H, m), 7.17 (1H, m), 7.43 (2H, m), 7.65 (1H, m), 7.70 (1H, m), 7.74 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.5Hz), 8.00 (1H, m), 8.10 (2H, d, J=8.6Hz), 8.21 20 (2H, d, J=7.6Hz), 8.25 (2H, d, J=8.1Hz), 8.88 (2H, m) MASS (m/z) : 1315 Elemental Analysis Calcd. for C 60

H

71

N

1 00 22 SNa-9H 2 0 : C 48.00, H 5.97, N 9.33 Found : C 48.05, H 5.95, N 9.34 25 Example 39 IR (KBr) : 2943, 2870, 1668, 1651, 1632 cm-1 NMR (DMSO-d 6 , 5) : 0.95 (6H, m), 1.13 (3H, d, J=5.7Hz), 1.39 (4H, m), 1.60-2.50 (9H, m), 2.80-3.20 (3H, m), 3.74-5.25 (23H, m), 4.04 (2H, t, J=6.3Hz), 6.74 (1H, 30 d, J=8.2Hz), 6.78 (1H, d, J=11.2Hz), 6.88 (1H, m), 7.07 (3H, m), 7.17 (1H, m), 7.45 (2H, m), 7.67 (1H, m), 7.74 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.3Hz), 8.00 (1H, m), 8.10 (2H, d, J=8.4Hz), 8.21 (2H, d, J=7.9Hz), 8.25 (2H, d, J=7.9Hz), 8.25 (2H, d, J=7.9Hz), 8.80 (1H, m), 8.85 35 (1H, s) WO 99/40108 PCT/JP99/00538 404 MASS (m/z) : 1330, 1329 Elemental Analysis Calcd. for C 61

H

73

N

1 00 22 SNa-10H 2 0 : C 47.78, H 6.11, N 9.18 Found : C 47.90, H 6.05, N 9.18 5 Example 40 IR (KBr) : 2933, 2871, 1666, 1650, 1632 cm -1 NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.9Hz), 0.96 (3H, d, J=6.8Hz), 1.12 (3H, d, J=5.7Hz), 1.32-1.43 (6H, m), 1.60-2.50 (9H, m), 3.02 (3H, m), 4.04 (2H, t, J=6.4Hz), 10 3.74-5.25 (23H, m), 6.74 (1H, d, J=8.2Hz), 6.78 (1H, d, J=11.lHz), 6.88 (1H, m), 7.07 (3H, m), 7.17 (1H, im), 7.43 (2H, m), 7.67 (1H, m), 7.75 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.5Hz), 8.00 (1H, m), 8.11 (2H, d, J=8.5Hz), 8.20 (2H, d, J=7.9Hz), 8.25 (2H, d, J=8.1Hz), 15 8.84 (2H, m) MASS (m/z) : 1343, 1327 Elemental Analysis Calcd. for C 62

H

7 5

N

1 00 22 SNa*7H20 : C 49.86, H 6.01, N 9.38 Found : C 49.87, H 6.01, N 9.30 20 Example 41 IR (KBr) : 2931, 2858, 1651, 1632 cm - 1 NMR (DMSO-d 6 , 5) : 0.88 (3H, t, J=6.6Hz), 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.2Hz), 1.30 (8H, m), 1.60-2.40 (9H, m), 2.80-3.20 (3H, m), 4.03 (2H, t, 25 J=6.3Hz), 3.74-5.25 (23H, m), 6.72 (1H, d, J=8.2Hz), 6.78 (1H, d, J=9.7Hz), 6.87 (1H, m), 7.06 (3H, m), 7.16 (1H, m), 7.44 (2H, m), 7.70 (1H, m), 7.74 (2H, d, J=8.8Hz), 7.90 (2H, d, J=8.5Hz), 8.00 (1H, m), 8.10 (2H, d, J=8.6Hz), 8.20 (2H, d, J=7.8Hz), 8.25 (2H, d, 30 J=8.2Hz), 8.84 (2H, m) MASS (m/z) : 1361, 1357, 1341 Elemental Analysis Calcd. for C 63

H

77

N

1 00 22 SNa-6H 2 0 : C 50.80, H 6.02, N 9.40 Found : C 50.79, H 6.28, N 9.48 35 Example 42 WO 99/40108 PCT/JP99/00538 405 IR (KBr) : 2939, 1668, 1651, 1632 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=5.3Hz), 1.13 (3H, d, J=6.0Hz), 1.35-2.50 (15H, m), 2.60-3.20 (9H, m), 3.65-5.40 (25H, m), 6.73 (1H, d, J=8.5Hz), 6.78 (1H, 5 d, J=11.2Hz), 6.88 (1H, m), 7.09 (3H, m), 7.17 (1H, m), 7.44 (2H, m), 7.70 (1H, m), 7.76 (2H, d, J=7.1Hz), 7.91 (2H, d, J=6.6Hz), 8.08 (1H, m), 8.11 (2H, d, J=7.4Hz), 8.22 (2H, d, J=6.1Hz), 8.25 (2H, d, J=6.3Hz), 8.84 (2H, nm) 10 MASS (m/z) : 1388, 1384, 1368 Elemental Analysis Calcd. for C 64

H

78

N

11

O

22 SNa-7H 2 0 : C 50.09, H 6.04, N 10.04 Found : C 50.18, H 6.03, N 9.65 Example 43 15 IR (KBr) : 1650.8, 1629.6 cm - 1 NMR (DMSO-d 6 , 5) : 0.80-0.86 (3H, m), 0.96 (3H, d, J=6.6Hz), 1.12 (3H, d, J=5.6Hz), 1.23 (14H, br s), 1.74-2.50 (9H, nm), 2.98 (1H, d, J=13.4Hz), 3.10-3.46 (2H, m), 3.70-4.60 (16H, m), 4.64-5.32 (9H, m), 6.73 20 (1H, d, J=8.2Hz), 6.83 (1H; d, J=8.4Hz), 6.89 (1H, br s), 7.05 (1H, d, J=1.7Hz), 7.16 (1H, br s), 7.42-7.47 (2H, m), 7.66 (1H, br s), 8.06-8.17 (6H, m), 8.65 (1H, s), 8.80 (1H, d, J=7.5Hz), 8.84 (1H, s) MASS (m/z) : 1297.03 (M-Na) + 25 Elemental Analysis Calcd. for C 57

H

77

N

1 20 21 SNa-7H 2 0 : C 47.30, H 6.34, N 11.61 Found : C 47.33, H 6.16, N 11.54 Example 44 IR (KBr) : 3361.3, 1650.8, 1631.5 cm

-

1 30 NMR (DMSO-d 6 , 5) : 0.80-0.90 (3H, m), 0.96 (3H, d, J=6.7Hz), 1.15 (3H, d, J=6Hz), 1.23 (14H, br s), 1.70-2.65 (9H, m), 2.90-3.10 (1H, m), 3.20-3.42 (2H, m), 3.65-4.60 (16H, m), 4.66-5.40 (9H, m), 6.73 (1H, d, J=8.3Hz), 6.83 (1H, d, J=8.8Hz), 6.89 (1H, s), 7.05 35 (1H, s), 7.18 (1H, s), 7.42-7.46 (2H, m), 7.66 (1H, WO 99/40108 PCT/JP99/00538 406 br s), 8.05 (4H, s), 8.08 (1H, s), 8.57 (1H, s), 8.57-8.84 (3H, m) MASS (m/z) : 1313.01 (M-Na) + Elemental Analysis Calcd. for C 57

H

77

N

1 20 2 0

S

2 Na-7H 2 0 : 5 C 46.78, H 6.27, N 11.48 Found : C 46.89, H 6.34, N 11.41 Example 45 IR (KBr) : 1650.8, 1631.5 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, 10 J=6Hz), 1.70-2.60 (9H, m), 2.80-3.60 (3H, m), 3.60-4.60 (19H, m), 4.65-5.40 (8H, m), 6.73 (1H, d, J=8.2Hz), 6.81-6.99 (6H, m), 7.05 (1H, s), 7.11 (2H, d, J=8.8Hz),7.34-7.26 (2H,m), 7.34-7.73 (3H,m), 7.76 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.4Hz), 8.11 (2H, d, 15 J=8.4Hz), 8.19-8.30 (4H, m), 8.70-9.00 (3H, m) MASS (m/z) : 1393.13 (M-Na) + Elemental Analysis Calcd. for C 65

H

73

N

1 00 23 SNa*9H 2 0 : C 49.43, H 5.81, N 8.87 Found : C 49.24, H 5.61, N 8.77 20 Example 46 IR (KBr) : 3361.3, 1668.1, 1650.8, 1631.5 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.6Hz), 1.12 (3H, d, J=5.6Hz), 1.70-2.60 (7H, m), 2.80-5.27 (26H, m), 4.65 (2H, d, J=5.2Hz), 5.27-5.48 (2H, m), 5.99-6.18 (1H, 25 m), 6.72 (1H, d, J=8.1Hz), 6.82 (1H, d, J=8.1Hz), 6.89 (1H, s), 7.07 (1H, s), 7.10 (2H, d, J=8.8Hz), 7.12 (1H, s), 7.46 (2H, br s), 7.68 (1H, br s), 7.75 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.4Hz), 8.11 (2H, d, J=8.5Hz), 8.19-8.31 (4H, m), 8.80-8.83 (2H, m) 30 MASS (m/z) : 1298.97 (M-Na) + Elemental Analysis Calcd. for C 59

H

67

N

1 00 2 SNa-9H 2 0 : C 47.71, H 5.77, N 9.43 Found : C 47.90, H 5.61, N 9.41 Example 47 35 IR (KBr) : 1650.8, 1631.5, 1540.8, 1513.8 cm - 1 WO 99/40108 PCT/JP99/00538 407 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.7Hz), 1.70-2.60 (11H, m), 2.80-3.60 (3H, m), 3.60-4.60 (18H, m), 4.65-5.40 (9H, m), 6.73 (1H, d, J=8.1Hz), 6.82 (1H, d, J=9.5Hz), 6.87-6.97 (5H, m), 5 7.06 (1H, s), 7.09 (2H, d, J=8.8Hz), 7.25-7.33 (2H, m), 7.33-7.73 (3H, m), 7.75 (2H, d, J=8.6Hz), 7.91 (2H, d, J=8.5Hz), 8.11 (2H, d, J=8.5Hz), 8.19-8.27 (4H, m), 8.70-8.90 (3H, m) MASS (m/z) : 1407.15 (M-Na) + 10 Elemental Analysis Calcd. for C 6 6

H

7 5

N

1 00 23 SNa-7H 2 0 : C 50.90, H 5.76, N 8.99 Found : C 50.80, H 5.90, N 8.90 Example 48 IR (KBr) : 1675.8, 1650.8, 1540.8, 1513.8 cm

-

1 15 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.9Hz), 1.13 (3H, d, J=5.9Hz), 1.20-1.60 (12H, m), 1.64-2.68 (7H, m), 2.80-3.60 (3H, m), 3.21 (3H, s), 3.60-5.40 (27H, m), 6.73 (1H, d, J=8.4Hz), 6.83 (1H, d, J=9.3Hz), 6.89 (1H, s), 7.05 (1H, s), 7.07 (2H, d, J=8.7Hz), 7.17 (1H, s), 20 7.30-7.70 (3H, m), 7.74 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.4Hz), 8.11 (2H, d, J=8.5Hz), 8.19-8.27 (4H, m ), 8.74-8.90 (3H, m) MASS (m/z) : 1401.12 (M-Na) + Example 49 25 IR (KBr) : 1675.8, 1650.8, 1540.8 cm - 1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.4Hz), 1.03-1.10 (9H, m), 1.50-2.50 (11H, m), 2.70-5.50 (34H, m), 6.71 (1H, d, J=7.3Hz), 6.79-6.90 (2H, m), 7.00-7.10 (4H, m), 7.30-7.80 (3H, m), 7.75 (2H, d, J=8.6Hz), 7.91 (2H, 30 d, J=8.4Hz), 8.11 (2H, d, J=7.4Hz), 8.19-8.27 (4H, m), 8.60-8.90 (3H, m) MASS (m/z) : 1414.08 (M-Na) + Elemental Analysis Calcd. for C 65

H

80

N

11 0O 2 3 SNa

.

11.6H 2 0 : C 47.39, H 6.31, N 9.35 35 Found : C 47.40, H 6.07, N 9.22 WO 99/40108 PCT/JP99/00538 408 Example 50 IR (KBr) : 3353.6, 1650.8, 1631.5, 1538.9, 1515.8, 1442.5, 1114.7 cm -1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, 5 J=5.7Hz), 1.7-2.6 (11H, m), 2.9-3.1 (1H, m), 3.1-3.5 (2H, m), 3.7-4.6 (18H, m), 4.7-5.3 (9H, m), 6.74 (1H, d, J=8.0Hz), 6.83 (1H, d, J=8.0Hz), 6.87-7.02 (4H, m ), 7.05 (1H, s), 7.15 (2H, d, J=8.7Hz), 7.17 (1H, m), 7.2-7.4 (2H, m), 7.4-7.6 (2H, m), 7.67 (1H, br), 7.98 10 (2H, d, J=8.7Hz), 7.9-8.2 (5H, m), 8.77 (1H, d, J=8.5Hz), 8.84 (1H, s) MASS (m/z) : 1346.72 (M-Na) + Elemental Analysis Calcd. for C 60

H

7 1 No 1 0 NaO 22 S*11H 2 0 : C 45.92, H 5.97, N 8.92 15 Found : C 46.13, H 5.75, N 8.92 Example 51 IR (KBr) : 3363.2, 1650.8, 1538.9, 1515.8, 1442-5, 1247.7 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, 20 J=5.9Hz), 1.5-2.5 (13H, m), 2.9-3.1 (1H, m), 3.1-3.5 (2H, m), 3.6-5.4 (27H, m), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.87-7.00 (4H, m), 7.05 (1H, s), 7.14 (2H, d, J=8.7Hz), 7.16 (1H, s), 7.27 (2H, m), 7.42 (2H, m), 7.66 (1H, br), 7.97 (2H, d, J=8.7Hz), 7.9-8.2 (5H, 25 m), 8.7-8.9 (2H, m) MASS (m/z) : 1360.75 (M-Na) + Elemental Analysis Calcd. for C 61

H

7 3 No 10 NaO 22

S

2 .9H 2 0 : C 47.34, H 5.93, N 9.05 Found : C 47.27, H 5.76, N 8.94 30 Example 52 IR (KBr) : 3365.2, 1650.8, 1631.5, 1538.9, 1515.8, 1442.5, 1245.8 cm-1 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.6Hz), 1.7-2.7 (9H, m), 2.9-3.1 (1H, m), 3.1-3.5 35 (2H, m), 3.6-4.6 (18H, m), 4.6-5.5 (9H, m), 6.73 (1H, WO 99/40108 PCT/JP99/00538 409 d, J=8.3Hz), 6.83 (1H, d, J=8.3Hz), 6.84-7.00 (4H, m ), 7.05 (1H, s), 7.17 (2H, d, J=8.7Hz), 7.19 (1H, m), 7.2-7.6 (4H, m), 7.67 (1H, br), 7.98 (2H, d, J=8.7Hz), 7.8-8.2 (5H, m), 8.6-9.0 (2H, m) 5 MASS (m/z) : 1332.97 (M-Na)+ Elemental Analysis Calcd. for C 5 9

H

69 No 10 NaO 22 S*8H 2 0 : C 47.20, H 5.71, N 9.33 Found : C 47.10, H 5.59, N 9.24 Example 53 10 IR (KBr) : 3353.6, 1650.8, 1631.5, 1538.9, 1513.8, 1450.2, 1442.5, 1257.4 cm NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.6Hz), 1.12 (3H, d, J=5.7Hz), 1.3-2.6 (13H, m), 2.9-3.1 (1H, m), 3.1-3.6 (7H, m), 3.6-4.6 (16H, m), 4.6-5.5 (9H, m), 6.73 (1H, 15 d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.13 (2H, d, J=8.8Hz), 7.15 (1H, m), 7.3 7.8 (3H, m), 7.97 (2H, d, J=8.8Hz), 7.8-8.2 (5H, m), 8.6-9.0 (2H, br) MASS (m/z) : 1298.85 (M-Na)+ 20 Elemental Analysis Calcd. for C 56

H

71 No 10 NaO 22 S-10H 2 O : C 44.74, H 6.10, N 9.32 Found : C 44.78, H 5.96, N 9.27 Example 54 IR (KBr) : 3365, 1647, 1541, 1516, 1437, 1248, 1047 cm - I 25 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.6Hz), 1.49-1.74 (6H, m), 1.74-2.55 (7H, m), 2.90-3.50 (3H, nm), 3.60-3.85 (6H, m), 3.85-4.59 (13H, m), 4.70-5.40 (8H, m), 6.74 (1H, d, J=8.2Hz), 6.81 (1H, s), 6.87 (1H, d, J=8.2Hz), 6.99 (1H, d, J=9.1Hz), 7.06 30 (1H, s), 7.19 (1H, s), 7.35-7.50 (2H, m), 7.68 (1H, m), 8.05 (1H, m), 8.06 (4H, s), 8.08 (1H, dd, J=9.1 and 2.5Hz), 8.71 (1H, d, J=2.5Hz), 8.77 (1H, d, J=7.4Hz), 8.82 (1H, br s) MASS (m/z) : 1266.93 (M-Na) + 35 Elemental Analysis Calcd. for C 54

H

67

N

12 NaO 2 0

S

2 -10H 2 0 : WO 99/40108 PCT/JP99/00538 410 C 44.08, H 5.96, N 11.42 Found : C 44.28, H 5.81, N 11.48 The following compounds [Examples 55 and 56] were obtained in a manner similar to that of Example 17. 5 Example 55 IR (KBr) : 3359, 1651, 1539, 1522 cm 1 NMR (DMSO-d 6 , 5) : 0.8-1.0 (6H, m), 1.11 (3H, d, J=5.5Hz), 1.3-1.6 (4H, m), 1.6-2.15 (5H, m), 2.2-2.5 (4H, m), 2.97 (1H, m), 3.20 (1H, m), 3.74 (2H, m), 10 3.8-4.6 (14H, m), 4.6-5.4 (10H, m), 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.22 (1H, m), 7.45 (3H, m), 7.52 (2H, d, J=4.9Hz), 7.66 (1H, m), 7.96 (5H, m), 8.08 (1H, d, J=8.2Hz), 8.59 (1H, d, J=6.4Hz), 8.85 (1H, s), 8.89 15 (1H, s) MASS (m/z) : 1307.69 (M-Na) + Elemental Analysis Calcd. for C 57

H

7 0

N

11

O

2 1

S

2 Na-10H 2 O : C 45.26, H 6.00, N 10.19 Found : C 45.11, H 5.84, N 10.28 20 Example 56 IR (KBr) : 3359, 1651, 1539, 1524, 1458, 1254 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.6Hz), 1.12 (3H, d, J=5.5Hz), 1.2-1.6 (6H, m), 1.6-2.1 (7H, m), 2.1-2.4 (4H, m), 2.96 (1H, m), 3.19 (1H, m), 3.42 (1H, m), 3.74 25 (2H, m), 3.8-4.6 (12H, m), 4.73 (1H, m), 4.8-5.0 (3H, m), 5.06 (1H, d, J=5.8Hz), 5.1-5.3 (5H, m), 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.15 (2H, d, J=8.8Hz), 7.23 (1H, s), 7.3 7.5 (2H, m), 7.66 (1H, s), 7.88 (2H, d, J=8.8Hz), 7.95 30 (4H, s), 8.07 (1H, d, J=7.8Hz), 8.58 (1H, d, J=7.8Hz), 8.85 (2H, s) MASS (m/z) : 1319.74 (M-Na) + Elemental Analysis Calcd. for C 58

H

7 0

N

11

O

2 1

S

2 Na-10H2O : C 45.70, H 5.95, N 10.11 35 Found : C 45.58, H 5.80, N 10.13 WO 99/40108 PCT/JP99/00538 411 The following compounds [Examples 57 to 60] were obtained in a manner similar to that of Example 18. Example 57 IR (KBr) : 3350, 2929, 1664, 1629, 1446, 1284, 5 1047.2 cm-1 NMR (DMSO-d 6 , 6) : 0.86 (3H, t, J=6.7Hz), 0.96 (3H, d, J=6.7Hz), 1.07 (3H, d, J=5.9Hz), 1.2-1.5 (10H, m), 1.6-2.5 (9H, m), 2.9-3.5 (4H, m), 3.7-4.5 (16H, m), 4.7-4.8 (1H, m), 4.87 (1H, d, J=5.9Hz), 5.0-5.4 (5H, 10 m), 6.7-6.9 (4H, m), 6.96 (1H, s), 7.17 (1H, s), 7.40 (1H, d, J=8.4Hz), 7.5-7.8 (2H, m), 8.0-8.2 (2H, m), 8.61 (1H, d, J=7.7Hz), 8.68 (1H, d, J=8.9Hz) MASS (m/z) : 1182.4 (M+Na) + Elemental Analysis Calcd. for C 4 9

H

70

N

9 NaO 2 0 S.4H 2 0 : 15 C 47.76, H 6.38, N 10.23 Found : C 47.81, H 6.73, N 10.12 Example 58 IR (KBr) : 3349, 2929, 1664, 1633, 1535, 1515, 1440, 1272, 1045 cm-1 20 NMR (DMSO-d 6 , 5) : 0.86 (3H, t, J=6.8Hz), 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.8Hz), 1.2-1.4 (8H, m), 1.5-2.5 (10H, m), 2.58 (2H, t, J=7.6Hz), 2.9-3.1 (1H, m), 3.2-3.6 (3H, m), 3.7-4.2 (5H, m), 4.1-4.6 (8H, m), 4.7-5.2 (7H, m), 5.3-5.4 (1H, m), 6.7-7.8 (14H, m), 25 7.95 (2H, d, J=8.3Hz), 8.10 (1H, d, J=8.4Hz), 8.63 (1H, d, J=7.7Hz), 8.71 (1H, s) MASS (m/z) : 1227.5 (M+Na) + Elemental Analysis Calcd. for C 55

H

73

N

8 NaOl 9 S*5H 2 0 : C 51.00, H 6.46, N 8.65 30 Found : C 50.90, H 6.54, N 8.81 Example 59 IR (Nujol) : 3353.0, 1668,1, 1629.6, 1540.8, 1515.8 cm-1 NMR (DMSO-d 6 , 5) : 0.87 (3H, t, J=6.7Hz), 0.96 (3H, d, J=6.7Hz), 1.06 (3H, d, J=6.0Hz), 1.18-1.48 (4H, m), 35 1.48-2.06 (5H, m), 2.06-2.70 (8H, m), 2.70-3.08 (3H, WO 99/40108 PCT/JP99/00538 412 m), 3.09-3.50 (2H, m), 3.60-4.65 (14H, m), 4.65-5.50 (9H, m), 6.65-6.90 (3H, m), 6.90-7.90 (13H, m), 8.02 (1H, d, J=8.4Hz), 8.15 (1H, d, J=7.7Hz), 8.71 (1H, s) MASS (m/z) : 1227.5 (M+Na) + 5 Elemental Analysis Calcd. for C 55

H

73

N

8 NaOl 9 S-5H 2 0 : C 50.99, H 6.46, N 8.65 Found : C 50.84, H 6.62, N 8.81 Example 60 IR (KBr) : 3353.6, 1635.3, 1257.4 cm - I 10 NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.8Hz), 0.97 (3H, d, J=6.7Hz), 1.09 (3H, d, J=5.7Hz), 1.2-1.5 (6H, m), 1.65-2.6 (10H, m), 2.97 (1H, m), 3.1-3.5 (2H, m), 3.6-4.6 (16H, m), 4.7-5.4 (8H, m), 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.87 (1H, s), 6.97 15 (1H, s), 7.13 (2H, d, J=8.9Hz), 7.16 (1H, s), 7.4 7.8 (3H, m), 7.97 (2H, d, J=8.9Hz), 7.9-8.2 (5H, m), 8.72 (1H, s), 8.78 (1H, d, J=7.1Hz) MASS (m/z) : 1267 (M-Na) + The following compounds [Examples 61 to 22] were obtained 20 in a manner similar to that of Example 13. Example 61 IR (KBr) : 1650.8, 1631.5 cm-1 NMR (DMSO-d 6 , 5) : 0.80-0.87 (3H, s), 0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.9Hz), 1.23 (14H, br s), 25 1.73-2.65 (10H, m), 2.92-3.50 (3H, m), 3.60-4.60 (16H, m), 4.70-5.50 (8H, m), 6.71 (1H, d, J=8.2Hz), 6.77-6.81 (1H, m), 6.86 (1H, s), 6.97 (1H, s), 7.07-7.86 (4H, m), 8.11 (1H, s), 8.06-8.17 (4H, m), 8.66 (1H, s), 8.66-8.88 (3H, m) 30 MASS (m/z) : 1326.62 (M+Na) + Elemental Analysis Calcd. for C 57

H

77

N

1 20 20 SNa-7H 2 0 : C 47.83, H 6.41, N 11.74 Found : C 47.77, H 6.45, N 11.62 Example 62 35 IR (KBr) : 1668.1, 1650.8, 1631.5 cm

-

1 WO 99/40108 PCT/JP99/00538 413 NMR (DMSO-d 6 , 6) : 0.81-0.90 (3H, m), 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=6Hz),1.23 (14H, br s), 1.75-2.70 (10H, m), 2.95-3.02 (1H, m), 3.17-3.30 (2H, m), 3.60-4.60 (16H, m), 4.70-5.46 (8H, m), 6.71 (1H, 5 d, J=8.2Hz), 6.79 (1H, d, J=8.5Hz), 6.87 (1H, br s), 6.98 (1H, s), 7.18 (1H, br s), 7.40-7.80 (3H, m), 8.05-8.10 (4H, m), 8.08 (1H, s), 8.57 (1H, s), 8.71-8.80 (3H, m) MASS (m/z) : 1297.14 (M-Na) + 10 Elemental Analysis Calcd. for C 57

H

77

N

12 0 19

S

2 Na*7H 2 0 : C 47.30, H 6.34, N 11.61 Found : C 47.07, H 6.23, N 11.42 Example 63 IR (KBr) : 1675.8, 1650.8 cm

-

1 15 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.6Hz), 1.11 (3H, d, J=6.4Hz), 1.70-2.60 (10H, m), 2.90-3.60 (3H, m), 3.60-4.60 (18H, m), 4.68-5.60 (SH, m), 6.70 (1H, d, J=8.3Hz), 6.78 (1H, d, J=9.7Hz), 6.87 (1H, s), 6.93-6.99 (4H, m), 7.11 (2H, d, J=8.8Hz), 7.26-7.34 20 (2H, m), 7.09-7.78 (4H, m), 7.76 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.5Hz), 8.12 (2H, d, J=8.6Hz), 8.19-8.27 (4H, m), 8.60-9.00 (3H, m) MASS (m/z) : 1377.26 (M-Na) + Elemental Analysis Calcd. for C 65

H

7 3

N

1 00 22 SNa-6H 2 0 : 25 C 51.72, H 5.68, N 9.28 Found : C 51.54, H 5.73, N 9.25 Example 64 IR (KBr) : 1675.8, 1650.8, 1631.5 cm - 1 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, 30 J=5.6Hz), 1.70-2.60 (8H, m), 2.80-3.60 (3H, m), 3.60-5.26 (22H, m), 4.65 (2H, d, J=5.2Hz), 5.26-5.48 (2H, m), 5.99-6.18 (1H, m), 6.70 (1H, d, J=8Hz), 6.78 (1H, d, J=9.9Hz), 6.87 (1H, s), 6.97 (1H, s), 7.00-7.20 (1H, m), 7.10 (2H, d, J=8.9Hz), 7.30-7.80 (3H, m), 7.75 35 (2H, d, J=8.9Hz), 7.92 (2H, d, J=8.5Hz), 8.12 (2H, d, WO 99/40108 PCT/JP99/00538 414 J=8.6Hz), 8.19-8.27 (5H, m), 8.50-9.00 (2H, m) MASS (m/z) : 1282.84 (M-Na) + Elemental Analysis Calcd. for C 59

H

67

N

10 0 2 1 SNa*7H 2 0 : C 49.44, H 5.70, N 9.77 5 Found : C 49.33, H 5.64, N 9.74 Example 65 IR (KBr) : 1650.8, 1631.5, 1540.8, 1513.8, 1245.8 cm - I NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.9Hz), 1.80-2.60 (11H, m), 2.80-3.60 (3H, m), 10 3.65-4.60 (19H, m), 4.63-5.50 (8H, m), 6.70 (1H, d, J=8Hz), 6.77 (1H, d, J=7.9Hz), 6.87-6.97 (5H, m), 7.02-7.22 (1H, m), 7.09 (2H, d, J=8Hz), 7.25-7.33 (2H, m), 7.40-7.80 (3H, m), 7.75 (2H, d, J=8.9Hz), 7.91 (2H, d, J=8.5Hz), 8.11 (2H, d, J=8.4Hz), 8.23-8.27 (4H, m ), 15 8.50-9.00 (3H, m) MASS (m/z) : 1391.07 (M-Na) + Elemental Analysis Calcd. for C 66

H

7 5

N

1 00 2 2 SNa*7H 2 0 : C 51.42, H 5.82, N 9.09 Found : C 51.37, H 5.78, N 9.05 20 Example 66 IR (KBr) : 3353.6, 2939.0, 1650.8, 1631.5, 1538.9, 1513.8, 1442.5 cm - 1 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=5.7Hz), 1.7-2.6 (12H, m), 2.9-3.1 (1H, m), 3.1-3.7 25 (2H, m), 3.7-4.7 (18H, m), 4.7-5.5 (8H, m), 6.71 (1H, d, J=8.0Hz), 6.78 (1H, d, J=8.0Hz), 6.83-7.05 (5H, m), 7.15 (2H, d, J=8.7Hz), 7.17 (1H, m), 7.2-7.35 (2H, m), 7.35-7.9 (3H, nm), 7.98 (2H, d, J=8.7Hz), 7.9-8.2 (5H, m), 8.75 (1H, br), 8.80 (1H, d, J=7.0Hz) 30 MASS (m/z) : 1331.28 (M-Na) + Elemental Analysis Calcd. for C 60

H

7 1

N

10 NaO 2 1

S

2 *9H 2 0 : C 47.49, H 5.91, N 9.23 Found : C 47.41, H 5.71, N 9.17 Example 67 35 IR (KBr) : 3353.6, 1666.2, 1650.8, 1631.5, 1538.9, WO 99/40108 PCT/JP99/00538 415 1513.8, 1442.5, 1247.7 cm-1 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.4-2.7 (14H, m), 2.9-3.1 (1H, m), 3.1-3.5 (2H, m), 3.6-4.6 (18H, m), 4.7-5.5 (8H, m), 6.71 (1H, 5 d, J=8.1Hz), 6.79 (1H, d, J=8.1Hz), 6.84-7.00 (5H, m ), 7.14 (2H, d, J=8.7Hz), 7.16 (1H, m), 7.27 (2H, m), 7.44 (1H, d, J=8.6Hz), 7.59 (1H, br), 7.71 (1H, br), 7.98 (2H, d, J=8.7Hz), 7.9-8.2 (5H, m), 8.75 (1H, br), 8.79 (1H, d, J=7.2Hz) 10 MASS (m/z) : 1345.3 (M-Na) + Elemental Analysis Calcd. for C 61

H

73 No 10 NaO 2 1

S

2 -8H 2 0 : C 48.41, H 5.93, N 9.25 Found : C 48.30, H 5.91, N 9.17 Example 68 15 IR (KBr) : 3353.6, 2937.1, 1650.8, 1540.8, 1513.8, 1452.1, 1243.9 cm - 1 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.7-2.7 (10H, m), 2.9-3.1 (1H, m), 3.1-3.6 (2H, m), 3.6-4.7 (18H, m), 4.7-5.5 (8H, m), 6.71 (1H, 20 d, J=8.1Hz), 6.79 (1H, d, J=8.1Hz), 6.84-7.10 (5H, m ), 7.17 (2H, d, J=8.7Hz), 7.19 (1H, m), 7.2-7.4 (2H, m ), 7.44 (1H, d, J=9.2Hz), 7.5-7.9 (2H, m), 7.98 (2H, d, J=8.7Hz), 7.9-8.2 (5H, m), 8.6-9.0 (2H, m) MASS (m/z) : 1316.8 (M-Na) + 25 Elemental Analysis Calcd. for C 59

H

69 No 1 0 NaO 2 1

S

2 *9H 2 0 : C 47.13, H 5.83, N 9.32 Found : C 47.40, H 5.67, N 9.30 Example 69 IR (KBr) : 3361.3, 2937.1, 1650.8, 1631.5, 1538.9, 30 1513.8, 1450.2, 1440.6, 1257.4 cm - 1 NMR (DMSO-d 6 , 6) : 0.99 (3H, m), 1.11 (3H, m), 1.3-2.7 (14H, m), 2.9-3.1 (1H, m), 3.1-3.6 (7H, m), 3.6-4.7 (16H, m), 4.7-5.6 (8H, m), 6.69 (1H, d, J=8.2Hz), 6.77 (1H, d, J=8.2Hz), 6.86 (1H, s), 6.98 (1H, s), 7.13 (2H, 35 d, J=8.7Hz), 7.15 (1H, m), 7.3-7.9 (3H, m), 7.97 (2H, WO 99/40108 PCT/JP99/00538 416 d, J=8.7Hz), 7.9-8.2 (5H, m), 8.6-8.9 (2H, m) MASS (m/z) : 1283.2 (M-Na) + Elemental Analysis Calcd. for C 56

H

7 1 No 10 NaO 21

S

2 10H 2 0 : C 45.22, H 6.17, N 9.42 5 Found : C 45.30, H 5.90, N 9.38 Example 70 IR (KBr) : 3400, 1651, 1541, 1261 cm

-

1 NMR (DMSO-d 6 , 5): 0.95-5.40 (58H, m), 6.67-8.77 (19H, m) MASS (m/z) : 1325.29 (M-Na) + 10 Elemental Analysis Calcd. for C 5 9

H

77 No 10 NaO 2 1

S

2 *37/4H 2 0 : C 46.74, H 6.35, N 9.24 Found : C 46.74, H 6.10, N 9.15 Example 71 IR (KBr) : 3363, 1648, 1619, 1506, 1257 cm

-

1 15 NMR (DMSO-d 6 , 5) : 0.97 (3H, t, J=3.3Hz), 1.02 (3H, d, J=7.3Hz), 1.11 (3H, d, J=5.5Hz), 1.68-5.40 (38H, m), 6.69-8.86 (22H, m) MASS (m/z) : 1254 (M-Na) + Elemental Analysis Calcd. for C 59

H

6 9 No 10 NaO 21 S-41/5H 2 0 : 20 C 48.64, H 5.91, N 9.61 Found : C 48.63, H 5.85, N 9.55 Example 72 IR (KBr) : 3300, 1651, 1506, 1437 cm-1 NMR (DMSO-d 6 , 5): 0.87-5.30 (50H, m), 6.66-8.73 (20H, m) 25 MASS (m/z) : 1236.29 (M-Na) + Elemental Analysis Calcd. for C 56

H

7 0

N

9 NaO 21 S-23/3H 2 0 : C 48.10, H 6.15, N 9.01 Found : C 48.14, H 6.03, N 8.97 The following compounds [Examples 73 and 74] were obtained 30 in a manner similar to that of Example 17. Example 73 IR (KBr) : 3359, 1676, 1651, 1632, 1514 cm -1 NMR (DMSO-d 6 , 5) : 0.87-1.0 (6H, m), 1.09 (3H, d, J=5.4Hz), 1.2-1.6 (4H, m), 1.6-2.1 (SH, m), 2.1-2.6 35 (SH, m), 3.00 (1H, m), 3.2 (1H, m), 3.5 (1H, m), 3.6-4.6 WO 99/40108 PCT/JP99/00538 417 (16H, m), 4.6-5.6 (8H, m), 6.70 (1H, d, J=8.2Hz), 6.77 (1H, d, J=8.2Hz), 6.87 (1H, s), 6.97 (1H, s), 7.20 (1H, m), 7.3-7.8 (6H, m), 7.8-8.4 (6H, s), 8.4-8.8 (2H, m), 8.89 (1H, s) 5 MASS (m/z) : 1292.51 (M-Na) + Elemental Analysis Calcd. for C 57

H

7 0

N

11 0 2 0

S

2 Na-12H 2 0 : C 44.67, H 6.18, N 10.05 Found : C 44.89, H 6.05, N 10.02 Example 74 10 IR (KBr) : 3359, 1668, 1650, 1631 cm-1 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.4Hz), 1.08 (3H, d, J=5.4Hz), 1.2-1.6 (6H, m), 1.6-2.0 (7H, m), 2.1-2.4 (4H, m), 3.01 (1H, m), 3.20 (1H, m), 3.67 (1H, m), 3.7-4.6 (16H, m), 4.6-5.6 (8H, m), 6.68 (1H, d, 15 J=8.2Hz), 6.76 (1H, d, J=8.2Hz), 6.85 (1H, s), 7.15 (2H, d, J=8.9Hz), 7.16 (1H, s), 7.2-7.8 (4H, m), 7.88 (2H, d, J=8.9Hz), 7.96 (4H, s), 8.56 (1H, s), 8.84 (2H, s) MASS (m/z) : 1304.08 (M-Na) + 20 Elemental Analysis Calcd. for C 5 8

H

70

N

11 0 2 0

S

2 Na-12H 2 O : C 45.10, H 6.13, N 9.98 Found : C 45.33, H 5.89, N 9.94 The following compounds [Examples 75 to 85] were obtained according to a similar manner to that of Example 13. 25 Example 75 IR (KBr) : 1668, 1649, 1632, 1541, 1516 cm -1 NMR (DMSO-d 6 , 5) : 0.86 (3H, m) 0.97 (3H, d, J=6.7Hz), 1.0-1.2 (3H, m), 1.2-1.4 (8H, m), 1.45-1.65 (2H, m), 1.7-2.6 (8H,m), 2.8-3.5 (3H,m), 3.46 (2H, t, J=6.4Hz), 30 3.6-4.6 (14H, m), 4.51 (2H, s), 4.7-5.4 (8H, m), 6.65-6.85 (2H, m), 6.88 (1H, s), 6.97 (1H, s), 7.18 (1H, s), 7.4-7.8 (3H, m), 7.50 (2H, d, J=8.6Hz), 8.02 (2H, d, J=8.6Hz), 8.0-8.2 (5H, m), 8.41 (1H, s), 8.72 (1H, s), 8.7-8.9 (1H, m), 9.35 (1H, s) 35 MASS (m/z) : 1407 (M'+23) WO 99/40108 PCT/JP99/00538 418 Elemental Analysis Calcd. for C 61

H

77

N

12 NaO 20

S

2 *7H 2 0 : C 48.47, H 6.07, N 11.12 Found : C 48.51, H 6.01, N 11.17 Example 76 5 IR (KBr) : 1632, 1518, 1441, 1250 cm-1 NMR (DMSO-d 6 , 5) : 0.89 (3H, t, J=6.6Hz), 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.3Hz), 1.1-1.5 (6H, m), 1.6-2.5 (10H, m), 2.9-3.1 (1H, m), 3.1-3.5 (2H, m), 3.6-4.6 (14H, m), 4.03 (2H, t, J=6.4Hz), 4.7-5.1 (4H, 10 m), 5.15-5.25 (3H, m), 5.3-5.45 (1H, m), 6.7-6.85 (2H, m), 6.87 (1H, s), 6.97 (1H, s), 7.10 (2H, d, J=8.9Hz), 7.18 (1H, s), 7.4-7.8 (3H, m), 7.85 (2H, d, J=8.9Hz), 8.0-8.2 (5H, m), 8.06 (1H, s), 8.72 (1H, s), 8.75 8.9 (1H, m), 9.23 (1H, s) 15 MASS (m/z) : 1333 (M+-23) Elemental Analysis Calcd. for C 59

H

7 3

N

1 2 NaO 20

S

2 -8H 2 0 : C 47.20, H 5.97, N 11.19 Found : C 47.27, H 6.04, N 11.26 Example 77 20 IR (KBr) : 1633, 1608, 1531, 1444, 1419 cm-1 NMR (DMSO-d 6 , 6) : 0.88-1.25 (6H, m) 1.49-2.50 (11H, m), 2.84-5.48 (33H, m), 6.62-6.98 (3H, m), 7.00-7.16 (2H, m), 7.10 (2H, d, J=8.5Hz), 7.25-7.80 (7H, m), 7.85 (2H, d, J=8.SHz), 7.91-8.14 (6H, m), 8.65-8.89 (2H, m) 25 MASS (m/z) : 1371.69(M-Na') Elemental Analysis Calcd. for C 62

H

74

N

11 NaO 21

S

2 -8H 2 0 : C 48.34, H 5.89, N 10.00 Found : C 48.39, H 5.65, N 9.95 Example 78 30 IR (KBr) : 1649, 1605, 1541, 1516, 1448 cm-1 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.9Hz), 1.40-2.45 (12H, m), 2.78-3.50 (7H, m), 3.64-5.34 (23H, m), 6.47 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.00-7.50 (10H, m), 7.67 35 (1H, brs), 7.98-8.20 (6H, m), 8.74(1H, d, J=2.5Hz), WO 99/40108 PCT/JP99/00538 419 8.65-8.92 (2H, m) MASS (m/z) : 1343.11 (M-Na') Elemental Analysis Calcd. for C 60

H

71

N

12 NaO 2 0

S

2 -7H 2 0 : C 48.25, H 5.74, N 11.25 5 Found : C 48.32, H 5.62, N 11.24 Example 79 IR (KBr) : 1637, 1539, 1512, 1443 cm -1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=7.1Hz), 1.36 (3H, t, J=6.9Hz), 1.73-2.52 (8H, m ), 10 2.79-3.34 (3H, m), 4.10 (2H, q, J=7.0Hz), 3.66-4.60 (14H, m), 4.70-5.54 (8H, m), 6.71 (1H, d, J=8.1Hz), 6.79 (1H, dd, J=8.4 and 1.7Hz), 6.87 (1H, s), 6.98 (1H, d, J=1.7Hz), 7.06(2H, d, J=8.9Hz), 7.19 (1H, s), 7.45(1H, d, J=8.8Hz), 7.60 (1H, m), 7.73 (2H, 15 d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 7.96-8.24 (8H, m), 8.73 (1H, brs), 8.80(1H, d, J=7.3Hz) MASS (m/z) : 1287.49 (M-Na ) Elemental Analysis Calcd. for C 58

H

67 No 10 NaO 2 0

S

2 -7H 2 0 : C 48.46, H 5.68, N 9.74 20 Found : C 48.19, H 5.69, N 9.56 Example 80 IR (KBr) : 1649, 1635, 1510, 1443 cm

-

1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.8Hz), 1.12 (3H, d, J=5.8Hz), 1.55-2.51 (11H, m), 2.76-3.64 (3H, m), 25 3.25 (3H, s), 3.64-4.60 (18H, m), 4.60-5.54 (9H, m ), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.6Hz), 6.89 (1H, s), 7.02-7.15 (3H, nm), 7.36-7.79 (3H, m), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.4Hz), 8.00-8.26 (8H, m), 8.70-8.92 (2H, m) 30 MASS (m/z) : 1361.12 (M-Na +) Elemental Analysis Calcd. for C 61

H

73 No 10 NaO 22

S

2 -7H 2 0 : C 48.47, H 5.80, N 9.27 Found : C 48.63, H 5.71, N 9.19 Example 81 35 IR (KBr) : 1633, 1533, 1512, 1443 cm-1 WO 99/40108 PCT/JP99/00538 420 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.10-1.20 (3H, m), 1.56-2.50 (12H, m), 2.88-3.28 (3H, m), 3.25 (3H, s), 3.63-4.56 (18H, m), 4.70-5.50 (8H, m), 6.69 (1H, d, J=8.1Hz), 6.77 (1H, d, J=8.1Hz), 6.87 (1H, s), 5 6.98 (1H, s), 7.07 (2H, d, J=8.8Hz), 7.28-7.72 (3H, m), 7.73 (2H, d, J=8.7Hz), 7.87 (2H, d, J=8.4Hz), 7.94-8.20 (8H, m), 8.64-8.92 (2H, m) MASS (m/z) : 1345.44 (M-Na') Elemental Analysis Calcd. for C 61

H

7 3 No 10 NaO 2 1

S

2 *6H 2 0 : 10 C 49.59, H 5.80, N 9.48 Found : C 49.52, H 5.68, N 9.39 Example 82 IR (KBr) : 1635, 1608, 1531, 1444, 1419 cm-1 NMR (DMSO-d 6 , 5) : 0. 97 (3H, d, J=6.8Hz), 1.10 (3H, d, 15 J=5.7Hz), 1.03-1.20 (5H, m), 1.50-2.55 (14H,m), 2.55-2.77 (4H,n m), 2.89-3.55(7H, m), 3.67-4.63 (14H, m), 4.68-5.50(8H, m), 6.71 (1H, d, J=8.2Hz), 6.78 (1H, d, J=8.2Hz), 6.87 (1H,s), 6.97 (1H,s), 7.08 (2H, d, J=8.7Hz), 7.18 (1H, s), 7.44 (1H, d, J=7.5Hz), 20 7.58 (1H, m), 7.71(1H, m), 7.85 (2H, d, J=8.8Hz), 7.94-8.20 (5H, m), 8.72 (1H,s), 8.78 (1H, d, J=7.0Hz), MASS (m/z) : 1332.99 (M-Na') Elemental Analysis Calcd. for C 60

H

77

N

12 NaOl 9

S

2 *7H 2 O : 25 C 48.58, H 6.18, N 11.33 Found : C 48.58, H 6.02, N 11.22 Example 83 IR (KBr) : 1633, 1535, 1512, 1443 cm-1 NMR (DMSO-d 6 , 5) : 0.95 (3H, t, J=7.4Hz), 0.97 (3H, d, 30 J=7.1Hz), 1.11 (3H, d, J=5.6Hz), 1.35-1.56 (2H, m ), 1.66-2.55(10H, m), 2.90-3.38 (3H, m), 3.68-4.62 (16H, m), 4.75-5.52 (8H, m), 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.88 (1H, s), 6.99 (1H, s), 7.07 (2H, d, J=8.8Hz), 7. 10-7.68 (3H, m), 7.73 (2H, 35 d, J=8.7Hz), 7.86 (2H, d, J=8.4Hz), 8.05-8.25 (8H, WO 99/40108 PCT/JP99/00538 421 m), 8.50-8.92 (2H, m) MASS (m/z) : 1315.58 (M-Na') Elemental Analysis Calcd. for C 60

H

7 1 No 10 NaO 2 0

S

2 10H 2 0 : C 47.43, H 6.04, N 9.22 5 Found : C 47.60, H 5.66, N 9.24 Example 84 IR (KBr) : 1647, 1539, 1512, 1448 cm -I NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.16-1.20 (3H, m), 1.15 (3H, t, J=7.0Hz), 1.73-2.58 (8H, m), 10 2.84-3.35 (3H, m), 3.49 (2H, q, J=7.0Hz), 3.66-4.62 (18H, m), 4.74-5.50 (8H, m), 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.3 and 1.7Hz), 6.88 (1H, brs), 6.98 (1H, d, J=1.7Hz), 7.09 (2H, d, J=8.8 Hz), 7. 19 (1H, brs), 7.36-7.69 (2H,m), 7.74 (2H, d, J=8.8Hz), 15 7.87(2H, d, J=8.5Hz), 8.02-8.24 (8H, m), 8.63-8.90 (2H, m) MASS (m/z) : 1331.2 (M-Na +) Elemental Analysis Calcd. for C 60

H

71 No 10 NaO 21

S

2 -8H 2 O : C 48.06, H 5.85, N 9.34 20 Found : C 47.93, H 5.82, N 9.23 Example 85 IR (KBr) : 1633, 1537, 1513, 1443 cm -I NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.8Hz), 1. 11 (3H, d, J=5.8Hz) 1.74-2.52 (8H, m), 2.90-3.40(3H, m), 3.35 25 (3H, s), 3.62-4.57 (18H, m), 4.70-5.49 (8H, m), 6.70 (1H, d, J=8.1Hz), 6.78 (1 H, d, J=8.1Hz), 6.87 (1H, s), 6.97 (1H, s), 7.09 (2H, d, J=8.8Hz), 7.10-7.51 (3H, m), 7.74 (2H, d, J=8.7Hz), 7.87 (2H, d, J=8.7Hz), 7.94-8.28 (8H, m), 8.56-8.92 (2H, m) 30 MASS (m/z) : 1317.28 (M-Na +) Elemental Analysis Calcd. for C 5 9

H

69 No 10 NaO 2 1

S

2 -9H 2 O : C 47.13, H 5.83, N 9.32 Found : C 47.24, H 5.55, N 9.35 Example 86 35 To a solution of Starting Compound (86) (0.15 g) and WO 99/40108 PCT/JP99/00538 422 4-[4-[4-(5-methoxypentyloxy)biphenyl-4-yl]piperazin-1 yl]benzoic acid benzotriazol-1-yl-ester (0.12 g) in N,N dimethylformamide (3 ml) was added diaminopyridine (0.024g), and the mixture was stirred for 15 hours at ambient temperature. 5 The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The solid was dissolved in diluted NaHCO 3 aq., and subjected to column chromatography on ODS (YMC-gel ODS-AM S-50 (Trademark :prepared by Yamamura Chemical Lab.)) 10 eluting with 60% methanol aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove methanol. The residue was lyophilized to give Object Compound (86) (0.16 g). IR (KBr) : 1666.2, 1629.6, 1228.4, 1043.3 cm

-

1 15 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.4Hz), 1.08 (3H, d, J=5.4Hz), 1.44-5.17 (55H, m), 6.69-8.72(22H, m) MASS (m/z) : 1405.4 (M+Na) Elemental Analysis Calcd. for C 64

H

83

N

10 NaO 2 1 S*7.5H 2 0 : C 50.62, H 6.50, N 9.32 20 Found : C 50.52, H 6.42, N 9.16 The following compounds [Examples 87 to 105] were obtained in a manner similar to that of Example 86. Example 87 IR (KBr) : 1668.1, 1629.6, 1230.4 cm-1 25 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.6Hz), 1.07 (3H, d, J=5.7Hz), 1.24-5.50 (59H,m), 6.68-8.80 (18H,m) MASS (m/z) : 1327.5 (M-Na) Elemental Analysis Calcd. for C 60

H

83

N

10 NaO 2 0

S

-

6.5H 2 0 : C 49.07, H 6.59, N 9.54 30 Found : C 49.05, H 6.64, N 9.44 Example 88 IR (KBr) : 1666.2, 1631.5, 1240.0 cm

-

1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.07 (3H, d, J=5.9Hz), 1.40-5.40 (52H, m), 6.69-8.71 (19H, m) 35 MASS (m/z) : 1249.3 (M-Na) WO 99/40108 PCT/JP99/00538 423 Elemental Analysis Calcd. for C 5 8

H

77 No 1 0 NaOl 9 S*8H 2 0 : C 49.15, H 6.61, N 9.88 Found : C 48.96, H 6.49, N 9.79 Example 89 5 IR (KBr) : 1668.1, 1631.5, 1238.1 cm

-

1 NMR (DMSO-d 6 , 5) : 0.82-5.38 (69H, m), 6.69-8.40 (14H, m) MASS (m/z) : 1265.6, 1243.5 (M-Na) Elemental Analysis Calcd. for C 57

H

8 3 No 10 NaOl 9 S-7H 2 O : 10 C 49.13, H 7.02, N 10.05 Found : C 49.19, H 7.02, N 10.00 Example 90 IR (KBr) : 1664.3, 1629.6, 1232.3 cm - 1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.07 (3H, d, 15 J=5.6Hz), 1.16-5.20 (53H,m), 6.70-8.30(18H,m) MASS (m/z) : 1265.4 (M-Na) Elemental Analysis Calcd. for C 5 8

H

77 No 10 NaO 2 0

S

.

8.5H 2 0 : C 48.29, H 6.57, N 9.71 Found : C 48.04, H 6.21, N 9.60 20 Example 91 IR (KBr) : 1666.2, 1631.5, 1232.3, 1045.2cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.07 (3H, d, J=5.8Hz), 1.30-5.40 (53H, m), 6.69-8.71 (18H,m) MASS (m/z) : 1296.3 (M+Na) 25 Elemental Analysis Calcd. for C 5 8

H

77 No 10 NaOl 9 S*8H 2 0 : C 49.15, H 6.61, N 9.88 Found : C 49.14, H 6.53, N 9.90 Example 92 IR (KBr) : 3330.5, 1666.2, 1631.5, 1255.4cm - 1 30 NMR (DMSO-d 6 , 5) : 0.94-5.26 (68H, m), 6.66-8.26 (11H, m) MASS (m/z) : 1319.35 (M-Na) Elemental Analysis Calcd. for C 57

H

7 9 No 10 NaO 2 2

S

2 *4.5H 2 0 : C 48.06, H 6.23, N 9.83 35 Found : C 48.10, H 6.26, N 9.72 WO 99/40108 PCT/JP99/00538 424 Example 93 IR (KBr) : 1660.4, 1631.5, 1442.5, 1249.6 cm - 1 NMR (DMSO-d 6 , 5) : 0.88-1.45 (11H, m), 1.60-3.40 (18H, m), 3.75-5.30 (22H, m), 6.72-9.00 (20H, m) 5 MASS (m/z) : 1334.69 (M-Na) Elemental Analysis Calcd. for C 59

H

7 1

N

10 NaO 2 2

S

2 *6H 2 0 : C 48.29, H 5.70, N 9.54 Found : C 48.40, H 5.62, N 9.44 Example 94 10 IR (KBr) : 1666.2, 1631.5, 1515.8, 1257.4, 1178.3cm

-

1 NMR (DMSO-d 6 , 6) : 0.94-5.25 (51H,m), 6.67-8.84 (16H,m) MASS (m/z) : 1341.55 (M-Na) Elemental Analysis Calcd. for C 59

H

77 No 10 NaO 22

S

2 *6H 2 0 : 15 C 48.09, H 6.09, N 9.51 Found : C 47.98, H 6.01, N 9.49 Example 95 IR (KBr) : 1666.2, 1629.6, 1257.4, 1178.3 cm-1 NMR (DMSO-d 6 , 6) : 0.94-5.16 (55H,m), 6.41-8.84 (18H, m) 20 MASS (m/z) : 1289.3 (M-Na) Elemental Analysis Calcd. for C 55

H

73 No 10 NaO 2 2

S

2 *7H 2 0 : C 45.89, H 6.09, N 9.73 Found : C 45.67, H 5.91, N 9.74 Example 96 25 IR (KBr) : 1666.2, 1633.4, 1249.6 cm -1 NMR (DMSO-d 6 , 5) : 0.96-5.20 (47H, m) ,6.72-9.29 (24H,m) MASS (m/z) : 1351.41 (M-Na) Elemental Analysis Calcd. for C 63

H

7 1 No 1 0 NaO 22 S-8.5H 2 0 : C 49.51, H 5.80, N 9.16 30 Found : C 49.64, H 5.49, N 9.13 Example 97 IR (KBr) : 1666.2, 1631.5, 1515.8, 1257.4, 1178.3 cm-1 NMR (DMSO-d 6 , 5) : 0.94-5.24 (55H, m) ,6.72-8.84 (20H, 35 m) WO 99/40108 PCT/JP99/00538 425 MASS (m/z) : 1363.41 (M-Na) Elemental Analysis Calcd. for C 61

H

7 5 No 1 0 NaO 2 2

S

2 -7H 2 0 : C 48.41, H 5.93, N 9.25 Found : C 48.45, H 5.80, N 9.14 5 Example 98 IR (KBr) : 3355.5, 2935.1, 2873.4, 1633.4, 1521.6, 1438.6, 1255.4 cm-1 NMR (DMSO-d 6 , 5) : 0.85-1.05 (m, 6H), 1.10 (d, 3H, J=5.8Hz), 1.25-1.60 (m, 4H), 1.60-2.60 (m, 9H), 10 2.80-3.10(m, 1H), 3.10-3.60 (in, 2H), 3.60-4.60 (in, 16H), 4.60-5.60 (in, 9H), 6.71 (d, 1H, J=8.2Hz), 6.81 (d, 1H, J=8.2Hz), 6.89 (s, 1H), 7.05 (s, 1H), 7.08 (d, 2H, J=8.9Hz), 7.15-7.30 (m, 1H), 7.30-7.55 (m, 2H), 7.55-7.70 (in, 1H), 7.80 (d, 2H, J=8.3Hz), 7.91 15 (d, 2H, J=8.9Hz), 7.96 (d, 2H, J=8.3Hz), 8.00-8.20 (m, 1H), 8.38 (s, 1H), 8.65 (d, 1H, J=6.8Hz), 8.75-9.00 (m, 1H) MASS (m/z) : 1268.40 (M-Na) Elemental Analysis Calcd. for C 5 6

H

70

N

9 NaO 21

S

2 *8H 2 0 : 20 C 46.82, H 6.03, N 8.78 Found : C 47.11, H 5.84, N 8.82 Example 99 IR (KBr) : 3396.0, 2933.2, 2871.5, 1648.8, 1631.5, 1538.9, 1515.8, 1456.0, 1438.6, 1253.5cm-1 25 NMR (DMSO-d 6 , 5) : 0.75-0.90(m, 3H), 0.96(d, 3H, J=6.7Hz), 1.11 (d, 3H, J=5.8Hz), 1.10-1,60 (m, 6H), 1.60-2.60(m, 9H), 2.80-3.10(m, 1H), 3.10-3.60(m, 2H), 3.60-4.65 (m, 16H), 4.65-5.60 (m, 9H), 6.73 (d, 1H, J=8.2Hz), 6.82(d, 1H, J=8.2Hz), 6.89 (s, 1H), 30 7.05 (s, 1H), 7.07 (d, 2H, J=8.9Hz), 7.15-7.30 (m, 1H), 7.30-7.55 (mn, 2H), 7.55-7.75 (m, 1H), 7.80 (d, 2H, J=8.3Hz), 7.91(d, 2H, J=8.9Hz), 7.96 (d, 2H, J=8.3Hz), 8.00-8.20 (m, 1H), 8.38 (s, 1H), 8.65 (d, 1H, J=6.8Hz), 8.75-9.00 (m, 1H) 35 MASS (m/z) : 1282.09 (M-Na) WO 99/40108 PCT/JP99/00538 426 Elemental Analysis Calcd. for C 57

H

72

N

9 NaO 2 1

S

2 *7H 2 0 : C 47.79, H 6.05, N 8.80 Found : C 47.89, H 5.96, N 8.77 Example 100 5 IR (KBr) : 3430.7, 2931.3, 2858.0, 1668.1, 1648.0, 1631.5, 1515.8, 1456.0, 1438.6, 1255.4 cm-1 NMR (DMSO-d 6 , 5) : 0.75-0.90 (m, 3H), 0.96 (d, 3H, J=6.7Hz), 1.11(d, 3H, J=5.6Hz), 1.10-1.55 (m, 8H), 1.60-2.60 (in, 9H), 2.80-3.10 (m, 1H), 3.10-3.60 (in, 10 2H), 3.60-4.65 (m, 16H), 4.65-5.40 (in, 9H), 6.74 (d, 1H, J=8.2Hz), 6.83 (d, 1H, J=8.2Hz), 6.89 (s, 1H), 7.05 (s, 1H), 7.08 (d, 2H, J=8.8Hz), 7.20(s, 1H), 7.30-7.55 (mn, 2H), 7.60-7.75 (m, 1H), 7.80 (d, 2H, J=8.2Hz), 7.92 (d, 2H, J=8.8Hz), 7.96 (d, 2H, 15 J=8.2Hz), 8.07 (d, 1H, J=7.0Hz), 8.38 (s, 1H), 8.66 (d, 1H, J=6.8Hz), 8.85 (s, 1H) MASS (m/z) : 1296.16 (M-Na) Elemental Analysis Calcd. for C 5 8

H

7 4

N

9 NaO 2 1

S

2 *6H 2 0 : C 48.77, H 6.07, N 8.82 20 Found : C 48.61, H 6.06, N 8.78 Example 101 IR (KBr) : 3425.0, 2969.8, 2937.1, 2881.1, 1633.4, 1517.7, 1438.6, 1247.7cm - 1 NMR (DMSO-d 6 , 5) : 0.80-1.10 (m, 6H), 1.10 (d, 3H, 25 J=5.7Hz), 1.60-2.60 (m, 10H), 2.85-3.10 (m, 1H), 3.10-3.60 (m, 2H), 3.60-4.60 (m, 16H), 4.65-5.50 (m, 8H), 6.71 (d, 1H, J=8.1Hz), 6.79 (d, 1H, J=8.1Hz), 6.88 (s, 1H), 6.98 (s, 1H), 7.06 (d, 2H, J=8.8Hz), 7.20 (in, 1H), 7.30-8.20 (in, 12H), 7.70 (d, 2H, 30 J=8.8Hz), 8.48 (s, 1H), 8.60-8.85 (mn, 2H) MASS (m/z) : 1300.35 (M-Na) Elemental Analysis Calcd. for C 60

H

7 0

N

9 NaO 20

S

2 -7H 2 0 : C 49.68, H 5.84, N 8.69 Found : C 49.59, H 5.49, N 8.68 WO 99/40108 PCT/JP99/00538 427 Example 102 IR (KBr) : 3349.7, 2937.1, 2871.5, 1633.4, 1519.6, 1438.6, 1255.4 cm-1 NMR (DMSO-d 6 , 6) : 0.70-1.05 (m, 6H), 1.08 (d, 3H, 5 J=5.9Hz), 1.20-1.55 (m, 4H), 1.60-2.60 (m, 10H), 2.80-3.10 (m, 1H), 3.10-3.60 (m, 2H), 3.60-4.60 (m, 16H), 4.60-5.50 (m, 8H), 6.70 (d, 1H, J=8.1Hz), 6.77 (d, 1H, J=8.1Hz), 6.86 (s, 1H), 6.96 (s, 1H), 7.07 (d, 2H, J=8.9Hz), 7.20 (m, 1H), 7.30-7.50 (m, 1H), 10 7.50-7.80 (mn, 2H), 7.79 (d, 2H, J=8.4Hz), 7.90 (d, 2H, J=8.9Hz), 7.96 (d, 2H, J=8.4Hz), 8.00-8.20 (m, 1H), 8.37 (s, 1H), 8.50-8.80 (m, 2H) MASS (m/z) : 1252.57 (M-Na) Elemental Analysis Calcd. for C 5 6

H

7 0

N

9 NaO 2 0

S

2 -7H 2 O : 15 C 47.96, H 6.04, N 8.99 Found : C 47.78, H 5.87, N 8.87 Example 103 IR (KBr) : 3432.7, 2935.1, 2869.6, 1633.4, 1535.1, 1438.6, 1251.6 cm-1 20 NMR (DMSO-d 6 , 5) : 0.75-0.95 (m, 3H), 0.97 (d, 3H, J=6.8Hz), 1.10 (d, 3H, J=5.9Hz), 1.20-1.55 (m, 6H), 1.60-2.60 (m, 10H), 2.80-3.10 (m, 1H), 3.10-3.60 (m, 2H), 3.60-4.60(m, 16H), 4.65-5.50 (m, 8H), 6.71 (d, 1H, J=8.2Hz), 6.78 (d, 1H, J=8.2Hz), 6.87 (s, 1H), 25 6.97 (s, 1H), 7.04 (d, 2H, J=8.7Hz), 7.20 (m, 1H), 7.30-7.90 (m, 3H), 7.67 (d, 2H, J=8.7Hz), 8.01 (s, 4H), 8.05-8.20 (m, 1H), 8.26 (s, 1H), 8.60-8.90 (m, 2H) MASS (m/z) : 1266.27 (M-Na) 30 Elemental Analysis Calcd. for C 57

H

72

N

9 NaO 20

S

2 *6H 2 0 : C 48.96, H 6.05, N 9.01 Found : C 49.07, H 5.97, N 8.94 Example 104 IR (KBr) : 3353.6, 2931.3, 2861.8, 1631.5, 1519.6, 35 1438.6, 1253.5 cm-1 WO 99/40108 PCT/JP99/00538 428 NMR (DMSO-d 6 , 5) : 0.70-0.95 (mn, 3H), 0.97 (d, 3H, J=6.8Hz), 1.10 (d, 3H, J=6.0Hz), 1.20-1.60 (in, 6H), 1.60-2.60 (m, 10H), 2.80-3.10 (m, 1H), 3.10-3.60 (m, 2H), 3.60-4.65 (m, 16H), 4.70-5.50 (m, 8H), 6.71 (d, 5 1H, J=8.1Hz), 6.79 (d, 1H, J=8.1Hz), 6.88 (s, 1H), 6.98 (s, 1H), 7.08 (d, 2H, J=8.9Hz), 7.21 (m, 1H), 7.44 (d, 1H, J=7.4Hz), 7.50-7.80 (in, 2H), 7.80 (d, 2H, J=8.4Hz), 7.91 (d, 2H, J=8.9Hz), 7.97 (d, 2H, J=8.4Hz), 8.12 (d, 1H, J=8.1Hz), 8.37 (s, 1H), 10 8.60-8.80 (in, 1H), 8.72 (s, 1H) MASS (m/z) : 1266.27 (M-Na) Elemental Analysis Calcd. for C 57

H

72

N

9 NaO 2 0

S

2 -6H 2 0 : C 48.96, H 6.05, N 9.01 Found : C 48.75, H 5.98, N 8.91 15 Example 105 IR (KBr) : 1666.2, 1629.6, 1240.0, 1047.2 cm-1 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.6Hz), 1.07 (3H, d, J=5.8Hz), 1.60-5.40(47H,m), 6.68-8.80(18H,m) MASS (m/z) : 1231.3 (M+1) 20 Elemental Analysis Calcd. for C 55

H

7 1 No 10 NaOl 9 S*8H 2 O : C 48.03, H 6.38, N 10.18 Found : C 47.84, H 6.46, N 10.12 Example 106 A solution of Starting Compound (106) (200 mg) in 25 N,N-dimethylformamide (4 ml) was treated with 4-[5-[4-[4 [2-(2-methoxyethoxy)ethoxy]phenyl]phenyl]-1,3,4 thiadiazol-2-yl]benzoic acid benzotrizol-1-yl ester (144 mg) anddiisopropylethylamine (58 il), and the mixture was stirred for 19 hours at room temperature. Ethyl acetate was added to 30 the reaction mixture and the resulting precipitate was collected by filtration, washed thoroughly with ethyl acetate and diisopropyl ether and dried. The powder was dissolved in saturated aqueous sodium hydrogen carbonate solution, filtered and purified by ODS column chromatography (YMC-gel 35 ODS-AM S-50) eluting with 17-18% aqueous acetonitrile.

WO 99/40108 PCT/JP99/00538 429 Product-containing fractions were pooled, evaporated to remove acetonitrile, and lyophilized to give Object Compound (106) (225 mg) as an amorphous pale yellow powder. IR (KBr) : 1659, 1633, 1533, 1510, 1444 cm-1 5 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d J=5.6Hz), 1.76-2.47 (8H, m), 2.83-3.32 (3H, m), 3.26 (3H, s), 3.40-4.60 (22H, m), 4.70-5.54 (8H, m), 6.69 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=8.2Hz), 6.87 (1H, brs), 6.98 (1H, s), 7.09 (2H, d, J=8.8Hz), 7.34 10 7.55 (3H, m), 7.74 (2H, d, J=8.7Hz), 7.87 (2H, d, J=8.5Hz), 8.00-8.20 (8H, m), 8.66-8.92 (2H, m) MASS (m/z) : 1361.4 (M-Na +) Elemental Analysis Calcd. for C 61

H

73 No 10 NaO 22

S

2 *10H 2 0 : C 46.80, H 5.99, N 8.95 15 Found : C 46.93, H 5.80, N 8.89 The following compounds [Examples 107 to 132] were obtained in a manner similar to that of Example 106. Example 107 IR (KBr) : 3367, 2925, 1668, 1631, 1538, 1511, 1450, 1265, 20 1230, 1085, 1047 cm -1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.07 (3H, d J=5.9Hz), 1.2-1.6 (5H, m), 1.6-2.1 (10H, m), 2.1-2.5 (8H, nm), 2.63 (4H, m), 2.79 (2H, m), 2.98 (2H, m), 3.06 (4H, m), 3.20 (1H, m), 3.71 (2H, m), 3.8-4.6 25 (14H, m), 4.6-5.6 (9H, m), 6.70 (1H, d, J=8.2 Hz), 6.78 (1H, s), 6.83 (3H, d, J=8.2Hz), 6.94 (2H, d, J=8.7Hz), 7.04 (3H, nm), 7.2-7.7 (3H, m), 7.74 (2H, d, J=8.7Hz), 8.07 (1H, m), 8.23 (1H, m), 8.56 (1H, nm), 8.84 (1H, s) 30 MASS (m/z) : 1348.35 (M-Na ) Elemental Analysis Calcd. For C 63

H

8 6

N

11 NaO 20

S

2 *11H 2 0 : C 48.18, H 6.93, N 9.81 Found : C 48.19, H 6.68, N 9.71 Example 108 35 IR (KBr) : 1676, 1651, 1622, 1514 cm-1 WO 99/40108 PCT/JP99/00538 430 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.6Hz), 1.05-1.1 (3H, m), 1.7-2.65 (12H, m), 2.8-3.2 (7H, m), 3.60 (2H, s), 2.65-4.1 (5H, m), 4.1-4.6 (9H, m), 4.7-5.45 (8H, m), 6.65-7.85 (3H, m), 7.85-7.05 (4H, m), 7.15-7.3 5 (3H, m), 7.4-7.8 (3H, m), 7.52 (2H, d, J=8.6Hz), 7.94 (2H, d, J=8.6Hz), 8.0-8.2 (5H, m), 8.41 (1H, s), 8.72 (1H, s), 8.75-8.9 (1H, m), 9.34 (1H, s) MASS (m/z) : 1407 (M+-23) Elemental Analysis Calcd. For C 64

H

75

N

1 4 NaOl 9

S

2 *9H 20 : 10 C 48.24, H 5.88, N 12.30 Found : C 48.41, H 5.68, N 12.22 Example 109 IR (KBr) : 1649, 1632, 1541, 1514 cm - 1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.6Hz), 1.10 (3H, 15 d, J=5.7Hz), 1.1-1.35 (5H, m), 1.35-2.5 (17H, m), 2.85-3.55 (6H, m), 3.55-4.1 (8H, m), 4.1-4.6 (9H, m), 4.7-5.45 (8H, m), 6.71 (1H,d, J=8.3Hz), 6.78 (1H,d, J=8.3Hz), 6.85-6.9 (1H, m), 6.9-7.0 (1H, m ), 7.08 (2H, d, J=8.9Hz), 7.1-7.25 (1H, m), 7.35-7.75 20 (3H, m), 7.84 (2H, d, J=8.9Hz), 7.9-8.2 (SH, m), 8.6-8.85 (2H, m) MASS (m/z) : 1348 (M+-23) Example 110 IR (KBr) : 1651, 1632, 1539, 1514 cm -1 25 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.8Hz), 1.2-1.6 (5H, m), 1.6-2.75 (14H, m), 2.85-3.1 (1H, m), 3.1-3.55 (2H, m), 3.65-4.1 (5H, m), 4.1-4.6 (9H, m), 4.6-5.45 (8H, m), 6.71 (1H, d, J=9.0Hz), 6.78 (1H, d, J=9.0Hz), 6.85-6.95 (1H, m ), 30 6.95-7.0 (1H, m), 7.1-7.25 (1H, m), 7.4-7.8 (3H, m), 7.46 (2H, d, J=8.3Hz), 7.96 (2H, d, J=8.3Hz), 8.0-8.2 (1H, m), 8.06 (2H, d, J=8.8Hz), 8.12 (2H, d, J=8.8Hz), 8.72 (1H, s), 8.75-8.85 (1H, m) MASS (m/z) : 1249 (M+-23) 35 Elemental Analysis Calcd. For C 5 6

H

69 No 10 NaOl 9

S

2 -7H 2 0 : WO 99/40108 PCT/JP99/00538 431 C 46.86, H 6.11, N 9.76 Found : C 47.02, H 6.01, N 9.77 Example 111 IR (KBr) : 1649, 1632, 1541, 1522 cm-1 5 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=6.1Hz), 1.1-1.65 (6H, m), 1.65-2.5 (12H, m), 2.85-3.6 (3H, m), 3.6-4.1 (5H, m), 4.1-4.6 (10H, m), 4.75-5.45 (8H, m), 6.71 (1H, d, J=8.9Hz), 6.78 (1H, d, J=8.9Hz), 6.85-6.9 (1H, m), 6.9-7.0 (1H, m), 10 7.14 (2H, d, J=8.9Hz), 7.15-7.25 (1H, m), 7.4-7.8 (3H, m), 7.95 (2H, d, J=8.9Hz), 8.05 (2H, d, J=8.9Hz), 8.1-8.2 (1H, m), 8.11 (2H, d, J=8.9Hz), 8.72 (1H, s), 8.75-8.85 (1H, m) MASS (m/z) : 1265 (M'-23) 15 Elemental Analysis Calcd. For C 5 6

H

69 No 1 0 NaO 2 0

S

2 *9H 20 : C 46.34, H 6.04, N 9.65 Found : C 46.24, H 5.95, N 9.58 Example 112 IR (KBr) : 1664, 1628 cm-1 20 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.5Hz), 1.05-1.2 (3H, m), 1.5-1.75 (6H, m), 1.75-2.5 (8H, m), 2.8-3.5 (7H, m), 3.6-4.1 (5H, m), 4.1-4.6 (9H, m), 4.7-5.5 (8H, m), 6.65-6.85 (2H, m), 6.87 (1H, s), 6.97 (1H, s), 7.07 (2H, d, J=9.2Hz), 7.1-7.25 (1H, m), 7.35-7.8 25 (3H, m), 7.75 (2H, d, J=9.2Hz), 8.0-8.2 (1H, m), 8.06 (4H, s), 8.32 (1H, s), 8.6-8.9 (2H, m), 9.17 (1H, s) MASS (m/z) : 1316 (M+-23) Elemental Analysis Calcd. For C 5 8

H

70

N

13 NaOl 9

S

2 *10H 2 0 : 30 C 45.82, H 5.97, N 11.98 Found : C 45.80, H 5.74, N 11.91 Example 113 IR (KBr) : 1633, 1518, 1250 cm-1 NMR (DMSO-d 6 , 5) : 0.8-1.05 (6H, m), 1.12 (3H, d, J=5.4Hz), 35 1.2-1.55 (6H, m), 1.65-2.5 (9H, m), 2.9-3.5 (3H, m), WO 99/40108 PCT/JP99/00538 432 3.6-4.6 (16H, m), 4.7-5.35 (9H, m), 6.73 (11H, d, J=8.3Hz), 6.83 (1H, d, J=8.3Hz), 6.85-6.95 (1H, m ), 7.0-7.25 (2H, m), 7.10 (2H, d, J=9.1Hz), 7.3-7.55 (2H, m), 7.6-7.75 (1H, m), 7.85 (2H, d, J=9.1Hz), 5 8.0-8.2 (5H, nm), 8.36 (1H, s), 8.7-8.9 (1H, m), 8.84 (1H, s), 9.24 (1H, s) MASS (m/z) : 1349(M+-23) Elemental Analysis Calcd. For C 59

H

7 3

N

1 2 NaO 2 1

S

2 *8H 20 : C 46.70, H 5.91, N 11.08 10 Found : C 46.64, H 5.88, N 10.90 Example 114 IR (KBr) : 1612, 1497, 1446 cm

-

1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=6.1Hz), 1.6-2.5 (12H, m), 2.6-3.1 (4H, m), 3.1-3.5 15 (2H, m), 3.6-4.6 (16H, m), 4.6-5.45 (8H, m), 6.71 (1H, d, J=8.9Hz), 6.78 (1H, d, J=8.9Hz), 6.87 (1H, s), 6.98 (1H, d, J=1.8Hz), 7.18 (3H, d, J=8.9Hz), 7.2-7.35 (5H, m), 7.4-7.8 (3H, m), 7.97 (2H, d, J=8.9Hz), 8.0-8.2 (1H, m), 8.09 (2H, d, J=8.4Hz), 20 8.20 (2H, d, J=8.4Hz), 8.72 (1H, s), 8.75-8.9 (1H, m) MASS (m/z) : 1310 (}M+-23) Elemental Analysis Calcd. For C 61

H

72

N

11 NaO 2 0 S-9H 2 0 : C 48.67, H 6.06, N 10.30 25 Found : C 48.67, H 5.89, N 10.15 Example 115 IR (KBr) : 1672, 1628, 1605, 1531, 1444 cm - 1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.5Hz), 1.10 (3H, d, J=5.9Hz), 1.6-2.5 (12H, m), 2.6-3.1 (4H, m), 3.1-3.5 30 (2H, m), 3.6-4.6 (16H, m), 4.7-5.45 (8H, m), 6.71 (1H, d, J=8.1Hz), 6.78 (1H, d, J=8.1Hz), 6.8-6.9 (1H, m), 6.9-7.0 (1H, m), 7.18 (3H, d, J=9.2Hz), 7.2 7.35 (5H,m), 7.35-7.8 (3H, m), 7.87 (2H, d, J=9.2Hz), 8.0-8.2 (5H, m), 8.72 (1H, s), 8.75-8.85 (1H, m) 35 MASS (m/z) : 1326 (M+-23) WO 99/40108 PCT/JP99/00538 433 Elemental Analysis Calcd. For C 61

H

72

N

11 NaOl 9

S

2 .

9H 20 : C 48.44, H 6.00, N 10.19 Found : C 48.54, H 5.91, N 10.15 Example 116 5 IR (KBr) : 1676, 1649, 1541, 1514, 1255 cm-1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.6Hz), 1.2-2.5 (18H, m), 2.9-3.1 (1H, m), 2.9-3.6 (2H, m), 3.65-4.1 (5H, m), 4.1-4.6 (10H, m), 4.7-5.45 (8H, m), 6.72 (1H, d, J=9.3Hz), 6.78 (1H, 10 d, J=9.3Hz), 6.85-6.95 (1H, m), 6.95-7.0 (1H, m), 7.1-7.25 (1H, m), 7.18 (2H, d, J=8.9Hz), 7.4-7.8 (3H, m), 8.0-8.15 (5H, m), 8.21 (2H, d, J=8.6Hz), 8.72 (1H, s), 8.75-8.95 (1H, m) MASS (m/z) : 1249 (M+-23) 15 Elemental Analysis Calcd. For C 5 6

H

69 No 10 NaO 21 S.9H 2 0 : C 46.86, H 6.11, N 9.76 Found : C 47.13, H 5.98, N 9.79 Example 117 IR (KBr) : 1659, 1628 cm - 1 20 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.8Hz), 1.09 (3H, d, J=6.0Hz), 1.2-1.6 (5H, m), 1.6-2.7 (14H, m), 2.8-3.6 (3H, m), 3.6-4.1 (5H, m), 4.1-4.6 (9H, m), 4.6-5.4 (8H, m), 6.7-7.0 (4H, m), 7.1-7.2 (1H, m), 7.4-7.8 (3H, m), 7.49 (2H, d, J=7.2Hz), 8.05-8.2 (5H, m), 25 8.21 (2H, d, J=8.4Hz), 8.70 (1H, s), 8.8-8.9 (1H, m) MASS (m/z) : 1233 (M -23) Elemental Analysis Calcd. For C 56

H

69 No 10 NaO 2 0 S*8H 2 0 : C 48.00, H 6.11, N 9.99 30 Found : C 47.81, H 6.04, N 9.93 Example 118 IR (KBr) : 1664, 1635, 1605, 1531, 1510, 1444 cm

-

1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.1Hz), 1.11 (3H, d, J=6.0Hz), 1.07-1.37 (5H, m), 1.50-2.44 (14H, m), 35 2.56-3.50 (11H, m), 3.65-4.60 (14H, m), 4.73-5.44 WO 99/40108 PCT/JP99/00538 434 (8H, m), 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.87 (1H, s), 6.97 (1H, s), 7.05 (2H, d, J=8.9Hz), 7.18 (1H, s), 7.35-7.77 (2H, m), 7.44 (1H, d, J=9.4Hz), 7.66 (2H, d, J=8.8Hz), 7.85 (2H, d, 5 J=8.5Hz), 7.95-8.21 (7H, m), 8.72 (1H, s), 8.80 (1H, d, J=7.5Hz) MASS (m/z) : 1409.4 (M-Na ) Elemental Analysis Calcd. For C 66 H8 1

N

1 2 NaOl 9

S

2 *7H 2 0 : C 50.83, H 6.14, N 10.78 10 Found : C 51.17, H 6.03, N 10.42 Example 119 IR (KBr) : 1659, 1633, 1531, 1508, 1443 cm-1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.6Hz), 1.00 (3H, t, J=7.4Hz), 1.10 (3H, d, J=5.6Hz), 1.66-2.56 (10H, mn), 15 2.91-3.36 (3H, m), 3.65-4.60 (14H, m), 4.00 (2H, d, J=6.4Hz), 4.72-5.52 (8H, m), 6.70 (1H, d, J=8.1Hz), 6.77 (1H, d, J=8.1Hz), 6.87 (1H, s), 6.98 (1H, s), 7.07 (2H, d, J=8.9Hz), 7.34-7.82 (3H, m), 7.73 (2H, d, J=8.8Hz), 7.86 (2H, d, J=8.5Hz), 8.04-8.22 (8H, 20 m), 8.74-8.92 (2H, m) MASS (m/z) : 1301.2 (M-Na) + Elemental Analysis Calcd. For C 59

H

69 No 10 NaO 2 0

S

2 10H 2 O : C 47.07, H 5.96, N 9.30 Found : C 46.90, H 5.72, N 9.22 25 Example 120 IR (KBr) : 1659, 1635, 1533, 1510, 1444 cm-1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.1Hz), 1.11 (3H, d, J=5.8Hz), 1.18 (6H, d, J=6.1Hz), 1.74-2.69 (10H, m), 2.80-3.52 (3H, m), 3.59-4.59 (18H,m), 4.72-5.49 (8H, 30 m), 6.71 (1H, d, J=8.1Hz), 6.79 (1H, dd, J=8.1 and 1.6Hz), 6.87 (1H, s), 6.98 (1H, d, J=1.6Hz) 7.07 (2H, d, J=9.0Hz), 7.18 (1H, s), 7.33-7.72 (3H, m), 7.68 (2H, d, J=8.8Hz), 7.85 (2H, d, J=8.SHz), 7.96-8.25 (7H, m), 8.72 (1H, s), 8.80 (1H, d, J=7.5Hz) 35 MASS (m/z) : 1356.3 (M-Na') WO 99/40108 PCT/JP99/00538 435 Elemental Analysis Calcd. For C 62

H

74

N

11 NaO 2 0

S

2 .

9H 20 : C 48.28, H 6.01, N 9.99 Found : C 48.54, H 5.94, N 9.95 Example 121 5 IR (KBr) : 1659, 1635, 1606, 1529, 1518, 1444, 1419 cm-1 NMR (DMSO-d 6 , 5) : 0.90 (6H, s) 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.8Hz), 1.03-2.66 (21H, m), 2.66 3.54 (8H, nm), 3.65-4.58 (14H, m), 4.68-5.43 (8H, m), 6.71 (1H, d, J=8.1Hz), 6.79 (1H, dd, J=8.1 andl.6Hz), 10 6.87 (1H, s), 6.98 (1H, d, J=l.6Hz) 7.11 (2H, d, J=8.6Hz), 7.18 (1H, s), 7.44 (1H, d, J=9.0Hz), 7.48-7.77 (2H, m), 7.88 (2H, d, J=8.7Hz), 7.95-8.20 (5H, m), 8.72 (1H, s), 8.78 (1H, d, J=7.7Hz) MASS (m/z) : 1361.4 (M -1) 15 Elemental Analysis Calcd. For C 62

H

82

N

1 2 0 1

O

9

S

2 -10H 2 0 : C 48.24, H 6.66, N 10.89 Found : C 48.22, H 6.38, N 10.79 Example 122 IR (KBr) : 1659, 1633, 1531, 1510, 1444 cm-1 20 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.8Hz), 1.10-2.68 (18H, m), 2.90-3.55 (3H, m), 3.66-4.62 (15H, m), 4.72-5.52 (8H, m), 6.71 (1H, d, J=8.1Hz), 6.79 (1H, d, J=8.1Hz), 6.87 (1H, s), 6.98 (1H, s), 7.07 (2H, d, J=8.9Hz), 7.19 (1H, s), 7.45 25 (1H, d, J=8.9Hz), 7.47-7.77 (1H, m), 7.71 (2H, d, J=8.8Hz), 7.86 (2H, d, J=8.5Hz), 7.93-8.28 (8H, m), 8.54-8.92 (1H, m), 8.81 (1H, d, J=7.7Hz) MASS (m/z) : 1341.3 (M-Na ) Elemental Analysis Calcd. For C 62

H

7 3 No 1 0 NaO 20

S

2 *8H 2 0 : 30 C 49.33, H 5.94, N 9.28 Found : C 49.40, H 5.87, N 9.23 Example 123 IR (KBr) : 1659, 1633, 1531, 1443 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, 35 J=6.1Hz), 1.36 (3H, t, J=6.9Hz), 1.64-2.50 (7H, m), WO 99/40108 PCT/JP99/00538 436 2.65-3.46 (3H, m), 4.13 (2H, q, J=7.0Hz), 3.67-4.58 (14H, m), 4.70 5.34 (9H, m), 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.90 (1H, s), 6.97-7.13 (3H, m), 7.19 (1H, 5 s), 7.33 (1H, s), 7.44 (2H, m), 7.70 (1H, brs), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 8.00-8.22 (6H, m), 8.80 (1H, d, J=6.9Hz), 8.84 (1H, s) MASS (m/z) : 1303.3 (M-Na') Elemental Analysis Calcd. For C 58

H

67 No 10 NaO 21

S

2 10H 2 0 : 10 C 46.21, H 5.82, N 9.29 Found : C 46.47, H 5.65, N 9.29 Example 124 IR (KBr) : 1633, 1608, 1531, 1444, 1419 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, 15 J=5.5Hz), 1.05-1.36 (5H, m), 1.47-2.50 (13H, m), 2.58-3.46 (11H, m), 3.64-4.60 (14H, m), 4.70-5.34 (9H, m), 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J---8.2Hz), 6.89 (1H, s), 7.08 (2H, d, J=8.7Hz), 7.01-7.25 (2H, m), 7.35-7.74 (3H, m), 7.86 (2H, d, J=8.8Hz), 20 7.98-8.26 (5H, m), 8.53-8.86 (1H, m), 8.85 (1H, s) MASS (m/z) : 1349.05 (M-Na +) Elemental Analysis Calcd. For C 60

H

7 7

N

12 NaO 2 0

S

2 -6H 20 : C 48.64, H 6.05, N 11.34 Found : C 48.38, H 6.09, N 11.15 25 Example 125 IR (KBr) : 1658, 1633, 1606, 1531, 1444, 1419 cm-1 NMR (DMSO-d 6 , 5) : 0.90 (3H, d, J=6.7Hz), 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=5.9Hz), 1.31-2.51 (18H, mn), 2.51-2.70 (4H, m), 2.88-3.46 (7H, m), 3.55-4.59 (14H, 30 m), 4.69-5.56 (8H, m), 6.70 (1H, d, J=8.1Hz), 6.77 (1H, d, J=8.1Hz), 6.86 (1H, s), 6.97 (1H, s) 7.08 (2H, d, J=8.7Hz), 7.09-7.78 (3H, m), 7.86 (2H, d, J=8.7Hz), 7.96-8.18 (6H, m), 8.63-8.92 (1H, s), 8.78 (1H, d, J=6.9Hz) 35 MASS (m/z) : 1347.3 (M-Na

+)

WO 99/40108 PCT/JP99/00538 437 Elemental Analysis Calcd. For C 61

H

7 9

N

12 NaOl 9

S

2 *11H 20 : C 46.68, H 6.49, N 10.71 Found : C 46.67, H 6.19, N 10.64 Example 126 5 IR (KBr) : 1658, 1633, 1606, 1531, 1518, 1444, 1417 cm-1 NMR (DMSO-d 6 , 5) : 0.86 (3H, d, J=6.4Hz), 0.87-1.44 (2H, m), 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.9Hz), 1.60-2.55 (16H, m), 2.55-2.73 (4H, m), 2.96-3.54 (7H, m), 3.65-4.60 (14H, m), 4.70-5.28 (8H, m), 6.71 (1H, 10 d, J=8.3Hz), 6.79 (1H, dd, J=8.3 and 1.7Hz), 6.87 (1H, s), 6.98 (1H, d, J=1.7Hz), 7.07 (2H, d, J=9.0Hz), 7.18 (1H, s), 7.44 (1H, d, J=8.4Hz), 7.50-7.78 (2H, m), 7.85 (2H, d, J=8.9Hz), 7.95-8.24 (5H, m), 8.72 (1H, s), 8.79 (1H, d, J=7.1Hz) 15 MASS (m/z) : 1347.3 (M-Na') Elemental Analysis Calcd. For C 61

H

7 9

N

12 NaOl 9

S

2 -11H 2 O : C 46.68, H 6.49, N 10.71 Found : C 46.77, H 6.20, N 10.65 Example 127 20 IR (KBr) : 1633, 1533, 1516, 1443, cm-1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.6Hz), 1.18 (3H, t, J=7.0Hz), 1.73-2.52 (8H, m), 2.86-3.38 (3H, m), 3.52 (2H, q, J=7.0Hz), 3.63-4.60 (16H, m), 4.53 (2H, s), 4.71-5.53 (6H, m), 6.68 (1H, 25 d, J=8.0Hz), 6.76 (1H, d, J=7.8Hz), 6.87 (1H, s), 6.98 (1H,s), 7.28-7.83 (3H, m), 7.47 (2H, d, J=8.5Hz), 7.77 (2H, d, J=8.2Hz), 7.92 (2H, d, J=8.5Hz), 8.00-8.25 (8H, m), 8.70-8.85 (2H, m) MASS (m/z) : 1301.3 (M-Na ) 30 Elemental Analysis Calcd. For C 5 9

H

69 No 10 NaO 20

S

2 -9H 2 0 : C 47.64, H 5.89, N 9.42 Found : C 47.92, H 5.84, N 9.39 Example 128 IR (KBr) : 1659, 1633, 1533, 1514, 1443, cm-1 35 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, WO 99/40108 PCT/JP99/00538 438 J=5.9Hz), 1.75-2.53 (8H, m), 2.81-3.36 (3H, m), 3.28 (3H, s), 3.47-4.64 (20H, m), 4.56 (2H, s), 4.74 5.60 (6H, m), 6.69 (1H, d, J=8.3Hz), 6.77 (1H, d, J=8.3Hz), 6.87 (1H, s), 6.98 (1H,s), 7.26-7.84 (3H, 5 m), 7.47 (2H, d, J=8.4Hz), 7.78 (2H, d, J=8.3Hz), 7.92 (2H, d, J=8.5Hz), 8.03-8.28 (8H, m), 8.74-8.90 (2H, m) MASS (m/z) : 1331.3 (M-Na +) Elemental Analysis Calcd. For C 60

H

7 1 No 1 0 NaO 2 1

S

2 -9H 2 O : 10 C 47.49, H 5.91, N 9.23 Found : C 47.36, H 5.81, N 9.16 Example 129 IR (KBr) : 1668, 1651, 1632, 1539, 1512 cm-1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.10-1.12 (3H, 15 m) 1.12 (3H, t, J=7.0Hz), 1.70-2.50 (10H, m), 2.80-3.30 (3H, m), 3.41 (2H, q, J=7.0Hz), 3.53 (2H, t, J=6.4Hz), 3.66-4.60 (14H, m), 4.10 (2H, t, J=6.4Hz), 4.70-5.52 (8H, m), 6.71 (1H, d, J=8.1Hz), 6.79 (1H, dd, J=8.1 and 1.6Hz), 6.87 (1H, s), 6.98 20 (1H, d, J=1.6Hz), 7.08 (2H, d, J=8.8Hz), 7.18 (1H, s), 7.32-7.68 (3H, m), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 8.04-8.24 (7H, m), 8.56-8.91 (1H, m), 8.81 (1H, d, J=7.0Hz) MASS (m/z) : 1345.3 (M-Na') 25 Elemental Analysis Calcd. For C 61

H

7 3 No 10 NaO 2 1

S

2 -10H 2 0 : C 47.28, H 6.05, N 9.04 Found : C 47.44, H 5.91, N 9.02 Example 130 IR (KBr) : 1649, 1537, 1512 1443 cm-1 30 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=5.7Hz), 1.74-2.22 (10H, nm), 2.80-3.30 (3H, m), 3.27 (3H, s), 3.50 (2H, t, J=6.3Hz), 3.65-4.60 (14H, m), 4.09 (2H, t, J=6.4Hz), 4.60-5.58 (8H, m), 6.70 (1H, d, J=8.1Hz), 6.77 (1H, d, J=8.1Hz), 6.87 (1H, 35 s), 6.99 (1H, s), 7.07 (2H, d, J=8.9Hz), 7.10-7.72 WO 99/40108 PCT/JP99/00538 439 (3H, m), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 8.00-8.35 (8H, m), 8.64-8.96 (2H, m) MASS (m/z) : 1331.3 (M-Na') Elemental Analysis Calcd. For C 60

H

71 N1 0 NaO 2 1

S

2 -9H 2 0 : 5 C 47.49, H 5.91, N 9.23 Found : C 47.39, H 5.75, N 9.16 Example 131 IR (KBr) : 3349.7, 1633.4, 1537.0, 1515.8, 1442.5, 1419.4 cm-1 10 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.3Hz), 1.7-2.5 (12H, m), 2.94 (3H, s), 2.94-4.6 (21H, m), 4.7-5.4 (8H, m), 6.71 (1H, d, J=8Hz), 6.79 (1H, dd, J=8.4and 1.7Hz), 6.88 (1H, brs), 6.97 (1H, brs), 7.15 (2H, d, J=9Hz), 15 7.17 (1H, brs), 7.45 (4H, s), 7.4-7.8 (3H, m), 7.87 (2H, d, J=8.8Hz), 8.02 (4H, s), 8.02-8.07 (1H, m), 8.72 (1H, s), 8.78 (1H, d, J=7.6Hz) MASS (m/z) : 1390.23 (M-Na) Elemental Analysis Calcd. For C 62

H

73 ClN 11

O

2 0

S

2 Na-7H 2 0 : 20 C 48.32, H 5.69, N 10.00 Found : C 48.15, H 5.51, N 9.93 Example 132 IR (KBr) : 1633.4, 1535.1, 1523.5, 1442.5, 1419.4, 1276.6, 1243.9 cm-1 25 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.8Hz), 1.12 (3H, d, J=6Hz), 1.7-2.5 (10H, m), 2.94 (3H, s), 2.9-5.4 (31H, m), 6.73 (1H, d, J=8.3Hz), 6.81-6.85 (1H, m), 6.89 (1H, brs), 7.05 (1H, brs), 7.15 (2H, d, J=8.7Hz), 7.17 (1H, brs), 7.45 (4H, s), 30 7.3-7.7 (3H, m), 7.87 (2H, d, J=8.7Hz), 8.06 (4H, s), 8.0-8.15 (1H, m), 8.7-9.0 (2H, m) MASS (m/z) : 1405.8 (M-Na') Elemental Analysis Calcd. For C 62

H

73 ClN 11

O

21

S

2 Na.6H 2 0 : C 48.39, H 5.57, N 10.01 35 Found : C 48.39, H 5.52, N 9.90 WO 99/40108 PCT/JP99/00538 440 Example 133 To a solution of 4-[2-[4-(4-piperidin-l-yl butyloxy)phenyl]limidazo[2,1-b] [1,3,4]thiadiazol-6 yl]benzoic acid (147 mg), 1-ethyl-3-(3' 5 dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HCl) (74 mg) and l-hydroxybenzotriazole (66 mg) in N,N dimethylformamide (4 ml)was added diisopropylethylamine (0.5 ml). After stirring for 24 hours at ambient temperature, the Starting Compound (133) (200 mg) was added to the solution and 10 the mixture was stirred for 8 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The powder was dissolved in water, and subjected to column chromatography on ion exchange resin 15 (DOWEX-50WX4(Trademark : prepared by Dow Chemical)) eluting with water. The fractions containing the object compound were combined, and subjected to column chromatography on-ODS (YMC-gel*ODS-AM*S-50 (Trademark : prepared by Yamamura Chemical Lab.)) elutingwith20% acetonitrileaqueous solution. 20 The fractions containing the object compound were combined, and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Object Compound (133) (30 mg). IR (KBr) : 3326, 2933, 1666, 1631, 1523, 1463, 1367, 25 1257 cm-1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (8H, m), 1.6-2.15 (5H, nm), 2.2-2.5 (10H, m), 2.97 (2H, m), 3.20 (1H, m), 3.74 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.74 (1H, d, 30 J=8.2Hz), 6.83 (1H, d, J=8.2Hz),6.88 (1H, s), 7.04 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.66 (1H, m), 7.88 (2H, d, J=8.8Hz), 7.95 (4H, s), 8.07 (1H, d, J=7.8Hz), 8.58 (1H, d, J=7.8Hz), 8.85 (1H, s), 8.95 (1H, s) 35 MASS (m/z) : 1377.25 (M-Na

+)

WO 99/40108 PCT/JP99/00538 441 The following compounds [Examples 134 to 159] were obtained in a manner similar to that of Example 133. Example 134 IR (KBr) : 3353, 2940, 1666, 1631, 1523, 1465, 1257 cm

-

1 5 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (10H, m), 1.6-2.15 (5H, m), 2.2-2.5 (10H, m), 2.97 (2H, m), 3.20 (1H, m) 3.74 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 10 7.05 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, d, J=8.8Hz), 7.96 (4H, s), 8.07 (1H, d, J=7.8Hz), 8.57 (1H, d, J=7.8Hz), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1391.13 (M-Na +) 15 Example 135 IR (KBr) : 3349, 2939, 1666, 1633, 1523, 1440, 1257 cm-1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (12H, m), 1.6-2.15 (5H, m), 2.2-2.5 (10H, m), 2.97 (2H, m), 3.20 (1H, m) 3.74 20 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, d, J=8.8Hz), 7.96 (4H, s), 8.07 (1H, d, J=7.8Hz), 8.60 (1H, d, 25 J=7.8Hz), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1405.31 (M-Na ) Elemental Analysis Calcd. For C 63

H

81

N

12 NaO 21

S

2 *8H 2 0 : C 48.09, H 6.21, N 10.68 Found : C 48.04, H 6.15, N 10.49 30 Example 136 IR (KBr) : 3351, 2939, 1658, 1633, 1527, 1465, 1444, 1257 cm - 1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (4H, m), 1.6-2.15 (5H, m), 2.2-2.5 35 (10H, m), 2.97 (2H, m), 3.20 (1H, m) 3.56 (4H, t, WO 99/40108 PCT/JP99/00538 442 J=4.6Hz), 3.71 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.74 (1H, d, J=8.2Hz), 6.85 (1H, d, J=8.2Hz), 6.93 (1H, s), 7.04 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 5 (2H, d, J=8.8Hz), 7.96 (4H, s), 8.07 (1H, d, J=7.8Hz), 8.57 (1H, d, J=7.8Hz), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1392.65 (M-Na ) Elemental Analysis Calcd. For C 61

H

77

N

12 NaO 22

S

3 -10H 2 0 : C 45.86, H 6.12, N 10.52 10 Found : C 45.75, H 5.83, N 10.46 Example 137 IR (KBr) : 3347, 2935, 1666, 1631, 1523, 1463, 1255, 1078, 1047 cm

-

1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.03 (6H, d, 15 J=6.3Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (6H, m), 1.6-2.15 (5H, m), 2.2-2.5 (6H, m), 2.71 (2H, d, J=10.2Hz), 2.97 (2H, m), 3.20 (1H, m) 3.56 (2H, m) 3.71 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.74 (1H, d, J=8.2Hz), 6.85 (1H, d, J=8.2Hz), 6.93 (1H, 20 s), 7.04 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, d, J=8.8Hz), 7.96 (4H, s), 8.07 (1H, d, J=7.8Hz), 8.57 (1H, d, J=7.8Hz), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1420.94 (M-Na +) 25 Elemental Analysis Calcd. For C 63

H

81

N

12 NaO 22

S

2 -8H 2 0 : C 47.60, H 6.15, N 10.57 Found : C 47.84, H 6.06, N 10.50 Example 138 IR (KBr) : 3347, 2937, 1666, 1631, 1521, 1465, 1257, 1074, 30 1047 cm -1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.03 (6H, d, J=6.3Hz), 1.08 (3H, d, J=5.7Hz), 1.3-1.6 (6H, m), 1.6-2.15 (SH, m), 2.2-2.5 (6H, m), 2.45 (2H, m), 2.71 (2H, d, J=10.2Hz), 2.97 (2H, m), 3.20 (1H, m) 3.56 35 (2H, m) 3.71 (2H, m), 3.8-4.6 (13H, m), 4.6-5.4 (8H, WO 99/40108 PCT/JP99/00538 443 m), 6.68 (1H, d, J=8.2Hz), 6.76 (1H, d, J=8.2Hz), 6.86 (1H, s), 6.97 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, m), 7.96 (4H, s), 8.07 (1H, m), 8.60 (1H, m), 5 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1405.74 (M-Na +) Elemental Analysis Calcd. For C 63

H

81

N

12 NaO 21

S

2 *9H 2 0 : C 47.54, H 6.27, N 10.56 Found : C 47.68, H 6.21, N 10.50 10 Example 139 MASS (m/z) : 1435.29 (M-Na +) Example 140 IR (KBr) : 3328, 2939, 1664, 1633, 1525, 1465, 1442, 1257, 1047 cm - I 15 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.3-1.6 (6H, m), 1.6-2.15 (5H, m), 2.2-2.5 (6H, m), 2.5-2.7 (2H, m), 2.59 (4H, s), 2.97 (2H, m), 3.20 (1H, m) 3.73 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.69 (1H, d, J=8.2Hz), 6.80 (1H, 20 d, J=8.2Hz), 6.88 (1H, s), 7.05 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, d, J=8.8Hz), 7.96 (4H, s), 8.07 (1H,d, J=7.8Hz), 8.57 (1H, d, J=7.8Hz), 8.85 (1H, s), 8.95 (1H, s) 25 MASS (m/z) : 1408.94 (M-Na +) Elemental Analysis Calcd. For C 61

H

77

N

12 NaO 21

S

3 -10H 2 0 : C 45.40, H 6.06, N 10.42 Found : C 45.49, H 5.59, N 10.26 Example 141 30 IR (KBr) : 3340, 2939, 1631, 1523, 1465, 1442, 1257, 1047 cm - I NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.3-1.6 (4H, m), 1.6-2.15 (5H, m), 2.2-2.5 (4H, m), 2.97 (2H, m), 3.20 (1H, m) 3.23 (3H, s), 35 3.34 (2H, t J=6.2Hz), 3.73 (2H, m), 3.8-4.6 (14H, WO 99/40108 PCT/JP99/00538 444 m), 4.6-5.4 (9H, m), 6.69 (1H, d, J=8.2Hz), 6.76 (1H, d, J=8.2Hz), 6.88 (1H, s), 7.04 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, d, J=8.8Hz), 7.95 (4H, s), 8.07 (1H,m), 5 8.57 (1H, m), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1338.33 (M-Na') Elemental Analysis Calcd. For C 58

H

72

N

11 NaO 22

S

2 *10H 2 0 : C 45.16, H 6.01, N 9.99 Found : C 45.39, H 5.80, N 10.02 10 Example 142 IR (KBr) : 3340, 2935, 1648, 1631, 1537, 1515, 1456, 1257, 1047 cm

-

1 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.3-1.6 (4H, m), 1.6-2.15 (5H, m), 2.2-2.5 15 (6H, m), 2.97 (2H, m), 3.20 (1H, m) 3.23 (3H, s), 3.34 (2H, t J=6.2Hz), 3.74 (2H, m), 3.8-4.6 (13H, m), 4.6-5.4 (8H, m), 6.68 (1H, d, J=8.2Hz), 6.-76 (1H, d, J=8.2Hz), 6.86 (1H, s), 6.97 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, 20 m), 7.90 (2H, m), 7.96 (4H, s), 8.07 (1H,m), 8.60 (1H, m), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1322.3 (M-Na +) Elemental Analysis Calcd. For C 58

H

72

N

11 NaO 21

S

2 -9H 2 0 : C 46.18, H 6.01, N 10.21 25 Found : C 45.96, H 5.86, N 10.12 Example 143 IR (KBr) : 3349, 2937, 1666, 1631, 1523, 1465, 1257, 1047 cm - 1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, 30 J=5.7Hz), 1.3-1.6 (6H, m), 1.6-2.15 (SH, m), 2.2-2.5 (4H, m), 2.97 (2H, m), 3.20 (1H, m) 3.23 (3H, s), 3.34 (2H, t J=6.2Hz), 3.73 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.69 (1H, d, J=8.2Hz), 6.76 (1H, d, J=8.2Hz), 6.88 (1H, s), 7.04 (1H, s), 7.14 (2H, 35 d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, WO 99/40108 PCT/JP99/00538 445 m), 7.90 (2H, d, J=8.8Hz), 7.95 (4H, s), 8.07 (1H,m), 8.57 (1H, m), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1352.48 (M-Na +) Elemental Analysis Calcd. For C 5 9

H

74

N

11 NaO 22

S

2 -12H 2 0 : 5 C 44.50, H 6.20, N 9.67 Found : C 44.74, H 5.71, N 9.70 Example 144 IR (KBr) : 3330, 2931, 1666, 1631, 1523, 1465, 1257, 1047 cm-1 10 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.3-1.6 (8H, m), 1.6-2.15 (5H, m), 2.2-2.5 (4H, m), 2.97 (2H, m), 3.20 (1H, m) 3.23 (3H, s), 3.34 (2H, t J=6.2Hz), 3.73 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.69 (1H, d, J=8.2Hz), 6.76 (1H, 15 d, J=8.2Hz), 6.88 (1H, s), 7.04 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, d, J=8.8Hz), 7.95 (4H, s), 8.07 (1H,m), 8.57 (1H, m), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1366.46 (M-Na') 20 Elemental Analysis Calcd. For C 6 0

H

7 6

N

11 NaO 22

S

2 -13H 2 0 : C 44.36, H 6.33, N 9.48 Found : C 44.40, H 5.88, N 9.30 Example 145 25 IR (KBr) : 3324, 2933, 1666, 1631, 1523, 1465, 1257, 1047 cm-1 NMR (DMSO-d 6 , 6) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.3-1.6 (10H, m), 1.6-2.15 (5H, m), 2.2-2.5 (4H, m), 2.97 (2H, m), 3.20 (1H, m) 3.23 (3H, 30 s), 3.34 (2H, t J=6.2Hz), 3.73 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.69 (1H, d, J=8.2Hz), 6.76 (1H, d, J=8.2Hz), 6.88 (1H, s), 7.04 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.90 (2H, d, J=8.8Hz), 7.95 (4H, s), 8.07 (1H,m), 35 8.57 (1H, m), 8.85 (1H, s), 8.95 (1H, s) WO 99/40108 PCT/JP99/00538 446 MASS (m/z) : 1380.30 (M-Na +) Elemental Analysis Calcd. For C 61

H

78

N

1 1 NaO 22

S

2 .10H 2 0 : C 46.24, H 6.23, N 9.72 Found : C 46.29, H 6.02, N 9.71 5 Example 146 IR (KBr) : 3351, 3330, 2935, 1664, 1633, 1606, 1529, 1465, 1446, 1267, 1238 cm

-

1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.4Hz), 1.10 (3H, d, J=5.4Hz), 1.60 (6H, s), 1.7-2.1 (3H,m), 2.1-2.6 (4H, 10 m), 2.98 (2H, m), 3.20 (1H, m) 3.4 (4H, m), 3.73 (2H, m), 3.8-4.6 (12H, m), 4.6-5.6 (9H, m), 6.70 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.06 (2H, d, J=8.9Hz), 7.2-7.7 (4H, m), 7.74 (2H, d, J=8.9Hz), 7.94 (4H, s), 8.07 (1H,m), 8.56 15 (1H, m), 8.79 (1H, s), 8.95 (1H, s) MASS (m/z) : 1304.84 (M-Na') Elemental Analysis Calcd. For C 57

H

69

N

12 NaO 20

S

2 -7H 2 0 : C 47.04, H 5.75, N 11.55 Found : C 47.32, H 5.75, N 11.67 20 Example 147 IR (KBr) : 3351, 3330, 2933, 1668, 1631, 1515, 1454, 1268, 1236 cm -I 1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.4Hz), 1.11 (3H, d, J=5.4Hz), 1.6-2.1 (3H, m), 2.1-2.6 (4H, m), 2.98 (2H, 25 m), 3.20 (1H, m) 3.4 (4H, m), 3.76 (6H, m), 3.8 4.6 (12H, m), 4.6-5.6 (9H, m), 6.70 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, s), 7.06 (2H, d, J=8.9Hz), 7.2-7.7 (4H, m), 7.74 (2H, d, J=8.9Hz), 7.94 (4H, s), 8.07 (1H,m), 8.56 (1H, 30 m), 8.79 (1H, s), 8.95 (1H, s) MASS (m/z) : 1306.85 (M-Na ) Example 148 IR (KBr) : 3355, 2975, 2935, 1666, 1631, 1610, 1523, 1465, 1241 cm-1 35 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, WO 99/40108 PCT/JP99/00538 447 J=5.7Hz), 1.18 (6H, d, J=6.2Hz), 1.6-2.1 (3H, m), 2.1-2.6 (6H, m), 2.98 (2H, m), 3.20 (1H, m) 3.4 (2H, m), 3.73 (4H, m), 3.8-4.6 (12H, m), 4.6-5.6 (9H, m), 6.70 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.89 5 (1H, s), 7.04 (1H, s), 7.11 (2H, d, J=8.9Hz), 7.2-7.7 (4H, m), 7.78 (2H, d, J=8.9Hz), 7.95 (4H, s), 8.07 (1H,m), 8.54 (1H, m), 8.80 (1H, s), 8.95 (1H, s) MASS (m/z) : 1334.95 (M-Na') Elemental Analysis Calcd. For C 5 8

H

71

N

1 2 NaO 2 1

S

2 *10H 2 0 : 10 C 45.25, H 5.96, N 10.92 Found : C 45.25, H 5.76, N 10.94 Example 149 IR (KBr) : 3355, 2971, 2933, 1668, 1648, 1631, 1610, 1535, 1515, 1463, 1241 cm-1 15 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.18 (6H, d, J=6.2Hz), 1.6-2.1 (3H, m), 2.1-2.6 (8H, m), 2.98 (2H, m), 3.20 (1H, m) 3.4 (2H, m), 3.73 (4H, m), 3.8-4.6 (11H, m), 4.6-5.6 (8H, m), 6.70 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.89 20 (1H, s), 6.96 (1H, s), 7.12 (2H, d, J=8.9Hz), 7.2-7.7 (4H, m), 7.78 (2H, d, J=8.9Hz), 7.95 (4H, s), 8.12 (1H,m), 8.56 (1H, m), 8.80 (1H, s), 8.95 (1H, s) MASS (m/z) : 1319.3 (M-Na +) Elemental Analysis Calcd. For C 5 8

H

71

N

12 NaO 2 0

S

2 *9H 2 0 : 25 C 46.27, H 5.96, N 11.16 Found : C 46.03, H 5.85, N 11.02 Example 150 IR (KBr) : 3353, 2927, 1666, 1631, 1608, 1535, 1465, 1432, 1265, 1193, 1047 cm-1 30 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.6-2.1 (3H, m), 2.1-2.6 (4H, m), 2.66 (4H, m), 2.98 (2H, m), 3.20 (1H, m), 3.73 (2H, m), 3.79 (4H, m), 3.8-4.6 (12H, m), 4.6-5.6 (9H, m), 6.72 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.88 (1H, s), 35 7.04 (1H, s), 7.11 (2H, d, J=8.9Hz), 7.2-7.7 (4H, WO 99/40108 PCT/JP99/00538 448 m), 7.77 (2H, d, J=8.9Hz), 7.94 (4H, s), 8.07 (1H,m), 8.54 (1H, m), 8.80 (1H, s), 8.95 (1H, s) MASS (m/z) : 1322.96 (M-Na +) Example 151 5 IR (KBr) : 3353, 1666, 1629, 1523, 1454, 1378, 1268, 1238 cm

-

1 NMR (DMSO-d 6 , 5) : 0.9-1.4 (9H, m), 1.4-2.1 (3H, m), 2.1-2.6 (10H, m), 2.98 (2H, m), 3.20 (1H, m), 3.4 (4H, m), 3.74 (2H, m), 3.8-4.6 (12H, m), 4.6-5.6 (9H, 10 m), 6.72 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.88 (1H, s), 7.05 (1H, s), 7.09 (2H, d, J=8.9Hz), 7.2-7.7 (4H, m), 7.78 (2H, d, J=8.9Hz), 7.94 (4H, s), 8.07 (1H, m), 8.54 (1H, m), 8.80 (1H, s), 8.95 (1H, s) 15 MASS (m/z) : 1334.63 (M-Na + ) Example 152 IR (KBr) : 3353, 2927, 1675, 1650, 1538, 1513, 1456, 1396, 1340, 1238, 1047 cm - 1 NMR (DMSO-d 6 , 5) : 0.95 (3H, d, J=6.7Hz), 1.0-1.4 (8H, 20 m), 1.58 (1H, nm), 1.78 (4H, m), 1.8-2.1 (3H, m), 2.1-2.6 (5H, m), 2.63 (4H, m), 2.98 (2H, m), 3.20 (1H, m), 3.4 (4H, m), 3.74 (2H, m), 3.8-4.6 (12H, m), 4.6-5.6 (9H, m), 6.72 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.88 (1H, s), 7.04 (1H, s), 7.08 (2H, 25 d, J=8.9Hz), 7.2-7.7 (4H, m), 7.77 (2H, d, J=8.9Hz), 7.94 (4H, s), 8.10 (1H,m), 8.58 (1H, m), 8.80 (1H, s), 8.95 (IH, s) MASS (m/z) : 1388.3 (M-Na') Example 153 30 IR (KBr) : 3353, 2931, 1668, 1650, 1631, 1537, 1513, 1456, 1396,1270, 1238, 1197 cm-1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.7Hz), 1.0-1.4 (8H, m), 1.58 (1H, m), 1.75 (4H, m), 1.7-2.1 (3H, m), 2.1-2.6 (7H, m), 2.63 (4H, m), 2.98 (2H, m), 3.20 35 (1H, m), 3.4 (4H, m), 3.74 (2H, m), 3.8-4.6 (11H, WO 99/40108 PCT/JP99/00538 449 m), 4.6-5.6 (8H, m), 6.72 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.88 (1H, s), 7.04 (1H, s), 7.08 (2H, d, J=8.9Hz), 7.2-7.7 (4H, m), 7.77 (2H, d, J=8.9Hz), 7.94 (4H, s), 8.11 (1H,m), 8.58 (1H, m), 8.80 (1H, 5 s), 8.95 (1H, s) MASS (m/z) : 1372.3 (M-Na) Example 154 IR (KBr) : 3353, 2935, 1666, 1633, 1540, 1513, 1461, 1440, 1247 cm-1 10 NMR (DMSO-d 6 , 5) : 0.9-1.1 (6H, m), 1.10 (3H, d,J=5.7Hz), 1.47 (2H, m), 1.6-2.1 (5H, m), 2.1-2.6 (4H, m), 2.98 (2H, m), 3.20 (1H, m), 3.71 (2H, m), 3.8-4.6 (14H, m), 4.6-5.6 (9H, m), 6.67 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.88 (1H, s), 6.99 (2H, d, J=8.8Hz), 15 7.05 (1H, s), 7.2-7.7 (4H, nm), 7.82 (2H, d, J=8.8Hz), 7.97 (4H, s), 8.10 (1H,m), 8.58 (1H, m), 8.66 (1H, s), 8.78 (1H, s) MASS (m/z) : 1294.53 (M-Na +) Elemental Analysis Calcd. For C 5 6

H

68

N

11 NaO 21

S

2 -9H 2 0 : 20 C 45.43, H 5.85, N 10.41 Found : C 45.52, H 5.81, N 10.41 Example 155 IR (KBr) : 3361, 2935, 1650, 1631, 1540, 1515, 1463, 1442, 1247, 1047 cm -1 25 NMR (DMSO-d 6 , 5) : 0.9-1.1 (6H, m), 1.10 (3H, d,J=5.7Hz), 1.2-1.5 (4H, m), 1.6-2.1 (5H, m), 2.1-2.6 (4H, m), 2.98 (2H, m), 3.20 (1H, nm), 3.71 (2H, m), 3.8-4.6 (14H, m), 4.6-5.6 (9H, m), 6.69 (2H, d, J=8.2Hz), 6.80 (1H, d, J=8.2Hz), 6.87 (1H, s), 6.99 (2H, d, 30 J=8.8Hz), 7.05 (1H, s), 7.2-7.7 (4H, m), 7.82 (2H, d, J=8.8Hz), 8.06 (4H, s), 8.10 (1H,m), 8.58 (1H, m), 8.67 (1H, s), 8.76 (1H, s) MASS (m/z) : 1308.25 (M-Na') Elemental Analysis Calcd. For C 57

H

7 0

N

11 NaO 2 1

S

2 -8H20 : 35 C 46.37, H 5.87, N 10.44 WO 99/40108 PCT/JP99/00538 450 Found : C 46.29, H 5.44, N 10.19 Example 156 IR (KBr) :3359, 2933, 1666, 1631, 1540, 1513, 1463, 1440, 1295, 1247, 1047 cm-1 5 NMR (DMSO-d 6 , 5) : 0.9-1.1 (6H, m), 1.10 (3H, d,J=5.7Hz), 1.2-1.5 (6H, m), 1.6-2.1 (5H, m), 2.1-2.6 (4H, m), 2.98 (2H, m), 3.20 (1H, m), 3.71 (2H, m), 3.8-4.6 (14H, m), 4.6-5.6 (9H, m), 6.69 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.87 (1H, s), 6.98 (2H, d, 10 J=8.8Hz), 7.04 (1H, s), 7.2-7.7 (4H, m), 7.82 (2H, d, J=8.8Hz), 8.06 (4H, s), 8.10 (1H,m), 8.58 (1H, m), 8.67 (1H, s), 8.77 (1H, s) MASS (m/z) : 1322.61 (M-Na +) Elemental Analysis Calcd. For C 58

H

72

N

11 NaO 21

S

2 11H 2 0 : 15 C 45.10, H 6.13, N 9.98 Found : C 45.31, H 5.81, N 9.84 Example 157 IR (KBr) : 3351, 2933, 1631, 1523, 1465, 1440, 1255, 1178, 1047 cm-1 20 NMR (DMSO-d 6 , 5) : 0.8-1.0 (6H, m), 1.10 (3H, d,J=5.7Hz), 1.2-1.6 (6H, m), 1.6-2.1 (5H, nm), 2.1-2.5 (4H, m), 2.98 (2H, m), 3.20 (1H, m), 3.73 (2H, m), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.69 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.88 (1H, s), 7.05 (1H, s), 25 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, m), 7.67 (1H, m), 7.89 (2H, d, J=8.8Hz), 7.96 (4H, s), 8.07 (1H, m), 8.54 (1H, m), 8.85 (1H, s), 8.95 (1H, s) MASS (m/z) : 1322.12 (M-Na ) 30 Elemental Analysis Calcd. For C 5 8

H

72

N

11 NaO 21

S

2 -8H 20 : C 46.74, H 5.95, N 10.34 Found : C 46.81, H 5.67, N 10.23 Example 158 IR (KBr) : 3359, 2935, 1652, 1631, 1538, 1523, 1429, 1382, 35 1299, 1253, 1047 cm

-

1 WO 99/40108 PCT/JP99/00538 451 NMR (DMSO-d 6 , 5) : 0.8-1.0 (6H, m), 1.10 (3H, d,J=5.7Hz), 1.3-1.5 (4H, m), 1.6-2.1 (5H, m), 2.1-2.5 (4H, m), 2.98 (2H, m), 3.20 (1H, m), 3.75 (2H, s), 3.8-4.6 (14H, m), 4.6-5.4 (9H, m), 6.69 (1H, d, J=8.2Hz), 5 6.77 (1H, d, J=8.2Hz), 6.85 (1H, s), 7.01 (2H, d, J=8.8Hz), 7.05 (1H, s), 7.23 (1H, m), 7.43 (2H, d, J=8.2Hz), 7.69 (1H, m), 7.77 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.3Hz), 8.05 (1H, d, J=7.9Hz), 8.19 (2H,d, J=8.3Hz), 8.54 (1H, m), 8.61 (1H, d, J=6.7Hz), 8.82 10 (1H, s) MASS (m/z) : 1312.10 (M-Na') Elemental Analysis Calcd. For C 56

H

70

N

11 NaO 22

S

2 .13H 2 0 : C 42.83, H 6.16, N 9.81 Found : C 42.83, H 5.39, N 9.75 15 Example 159 MASS (m/z) : 1429.04 (M-Na') Example 160 To a solution of 1-hydroxybenzotriazole (26 mg) and 4-[5-[4-(4-propoxypiperidin-1-yl)phenyl] -1,3,4-thiadiazol 20 2-yl]benzoic acid hydrochloride (60 mg) in N,N dimethylformamide (2.4 ml) was added 1-ethyl-3-(3' dimethylaminopropyl)carbodiimide (48 pl) and the mixture was stirred for 19 hours at ambient temperature. Then to the reaction mixture was added Starting Compound (160) (120 mg) 25 and N,N'-diisopropylethylamine (34 iil) and the mixture was stirred for 24 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The resulting precipitate was collected by filtration, washed with diisopropyl ether and dried under reducedpressure. The solid 30 was added to saturated aqueous sodium hydrogen carbonate solution, subjected to column chromatography on ODS (YMC-gel ODS-AM S-50) and eluted with 20% acetonitrile in water. The fractions containing the object compound were combined and evaporated under reduced pressure to remove acetonitrile. The 35 residue was lyophilized to give Object Compound (160) (48 mg) WO 99/40108 PCT/JP99/00538 452 as a yellow powder. NMR (DMSO-d 6 , 6) : 0.88 (3H, d, J=7.4Hz), 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d,J=5.6Hz), 1.38-2.47 (16H, m), 2.80-5.50 (30H, m), 6.70 (1H, d, J=8.2Hz), 6.81 (1H, 5 d, J=8.2Hz), 6.87 (1H, s), 7.04 (1H, s), 7.09 (2H, d, J=9.2Hz), 7.26-7.76 (3H, m), 7.84 (2H, d, J=8.8Hz), 7.97-8.14 (6H, m), 8.64-8.95 (2H,m) MASS (m/z) : 1347.44 (M-Na +) The following compounds [Examples 161 and 162] were 10 obtained in a manner similar to that of Example 160. Example 161 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.6Hz), 1.10 (3H, d,J=5.6Hz), 1.68-2.50 (7H, m), 2.80-5.50 (34H, m), 6.71 (1H, d, J=8.2Hz), 6.80 (1H, d, J=8.2Hz), 6.86 15 (1H, s), 6.76-6.94 (1H, m), 6.94-7.09 (3H, m), 7.09-7.34 (4H, m), 7.34-7.78 (3H, m), 7.90 (2H, d, J=8.7Hz), 7.96-8.17 (6H, m), 8.49-8.88 (21-,m) MASS (m/z) : 1343.23 (M-Na ) Example 162 20 IR (KBr) : 1655, 1527 cm -1 NMR (DMSO-d 6 , 5) : 0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.7Hz), 1.8-2.6 (12H, m), 2.8-3.6 (7H, m), 3.7-4.6 (14H, m), 4.7-5.5 (8H, m), 6.6-6.85 (4H, m), 6.85-6.95 (1H, m), 6.97 (1H, s), 7.15-7.25 (1H, mn), 25 7.4-7.8 (3H, m), 7.72 (2H, d, J=8.9Hz), 8.0-8.2 (5H, m), 8.30 (1H, s), 8.71 (1H, s), 8.7-8.9 (1H, m), 9.11 (1H, s) MASS (m/z) : 1302 (M -23) Elemental Analysis Calcd. For C 57

H

68

N

1 3 NaOl 9

S

2 -9H2 0 : 30 C 45.99, H 5.82, N 12.23 Found : C 45.92, H 5.73, N 12.09 Example 163 To a solution of Starting Compound (163) (2.0 g) in trifluoroacetic acid (48 ml) was added 1N hydrochloric acid 35 (8 ml) with stirring at ambient temperature. The mixture was WO99/40108 PCT/JP99/00538 453 stirred at the same temperature overnight. The reaction mixture was evaporated to remove trifluoroacetic acid under reduced pressure. To the residue were added standard solution (pH 6.86) (100 ml) and acetonitrile (50 ml), and the solution 5 was adjusted to pH 3 with 1N sodium hydroxide. The solution was chromatographed on reverse phase silica gel, YMC-gel ODS-AM 120-S50 (Trademark, made by YMC) (600 ml) eluting in turn with 20% aqueous acetonitrile (2 L), 30% aqueous acetonitrile (3 L), and 40% aqueous acetonitrile (4 L). The 10 fractions containing the desired compound were collected and evaporated in vacuo to remove organic solvent. The resulting residue was lyophilized to give a white powder. The white powder was washed with ethyl acetate (30 ml) and dried in vacuo at ambient temperature for 3 hours to give Object Compound (163) 15 (1.02 g). NMR (DMSO-d 6

+D

2 0 , 5) : 0.96 (3H, d, J=6.7Hz), 1.09 (3H, d,J=6.0Hz), 1.25-1.60 (8H, m), 1.60-2.45 (10H, m), 2.80-3.10 (1H, m), 3.21 (3H, s), 3.30 (2H, t, J=6.4Hz), 3.60-4.50 (15H, m), 4.65-4.95 (2H, m), 20 6.41 (1H, d, J=8.3Hz), 6.50-6.70 (2H, m), 7.11 (1H, s), 7.16 (1H, s), 7.25-7.60 (2H, m), 7.85-8.25 (8H,m) ESI-MASS (m/z) : 1255.08 (M++Na ) Elemental Analysis Calcd. For C 58

H

76

N

10

O

18 S-4H 2 O : 25 C 53.37, H 6.49, N 10.73 Found : C 53.61, H 6.44, N 10.84 Example 164 To a solution of the Starting Compound (164) (6.0 g) in a mixture of tetrahydrofuran (120 ml) and N,N-dimethylamide 30 (30 ml) were added trimethylsilyl chloride (22.8 ml) and triethylamine (37.6 ml) with stirring under ice-cooling and the mixture was stood at ambient temperature overnight. To the reaction mixture was added tetrahydrofuran (50 ml). The resulting precipitates were filtered off. The filtrate was 35 stood at 2-5 0 C overnight and evaporated in vacuo. The residue WO99/40108 PCT/JP99/00538 454 was dissolved in a mixture of hexane (50 ml) and ethyl acetate (50 ml) (1:1, v/v) and the solution was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (600 ml) eluting in turn with a mixture of hexane and ethyl 5 acetate (3:2, v/v) and a mixture of hexane and ethyl acetate (1:1, v/v). The fractions containing the desired compound were collected and evaporated in vacuo. The resulting residue (5.68 g) was dissolved in a mixture of acetonitrile (30 ml) and methanol (30 ml). To the solution were added in turn 10 diisopropylethylamine (1.68 ml) and trimethylsilyldiazomethane (4.82 ml) with stirring at ambient temperature and the mixture was allowed to stand at the same temperature overnight. To the reaction mixture were added ethyl acetate (150 ml) and saturated aqueous hydrogen 15 carbonate solution (100 ml). The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran (30 ml) and acetic acid (3.68 ml). To the 20 solution was added 1M solution of tetrabutyl ammonium fluoride in water with stirring under ice-cooling and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was evaporated in vacuo and dissolved in 20% aqueous acetonitrile. The solution was chromatographed on reverse 25 phase silica gel, YMC-gel ODS-AM 120-S50 (Trademark, made by YMC) (700 ml) eluting in turn with 20% aqueous acetonitrile (3.5 L), 30% aqueous acetonitrile (3.5 L) and 40% aqueous acetonitrile (3.5 L). The fractions containing the desired compound were collected and evaporated in vacuo to remove 30 organic solvent. The resulting residue was lyophilized to give a white powder. The white powder was purified by liquid chromatography eluting with 38% acetonitrile in pH 6.86 standard buffer solution to give two compounds. The first compound was chromatographed on reverse phase 35 silica gel, YMC-gel ODS-AM 120-S50 (Trademark, made by YMC) WO 99/40108 PCT/JP99/00538 455 (700 ml) eluting in turn with 20% aqueous acetonitrile (3.5 L) and 50% aqueous acetonitrile (3.5 L). The fractions containing the desired compound were collected and evaporated in vacuo to remove organic solvent. The resulting residue was 5 lyophilized to give Object Compound (164-I) (1.37 g). The other Object Compound (164-II) was chromatographed on reverse phase silica gel, YMC-gelODS-AM 120-S50 (Trademark, made by YMC) (700 ml) eluting in turn with 20% aqueous acetonitrile (3.5L) and50% aqueous acetonitrile (3.5L) . The 10 fractions containing the desired compound were collected and evaporated in vacuo to remove organic solvent. The resulting residue was lyophilized to give Object Compound (164-II) (275 mg). Object Compound (164-I) 15 NMR (DMSO-d 6

+D

2 0 , 5) : 0.96 (3H, d, J=6.7Hz), 1.09 (3H, d,J=6.1Hz), 1.25-2.50 (19H, m), 2.85-3.00 (1H, m), 3.74 (3H, s), 3.31 (2H, t, J=6.4Hz), 3.75-4.55 (17H, m), 4.70-5.00 (2H, m), 6.40-6.70 (3H, m), 7.14 (2H, d, J=8.9Hz), 7.98 (2H, d, J=8.9Hz), 8.05 (2H, d, 20 J=8.7Hz), 8.12 (2H, d, J=8.7Hz) ESI-MASS (m/z) : 1269.4 (M++Na ) (positive) 1246.4 (M+-1) (negative) Elemental Analysis Calcd. For C 59

H

78

N

1 0 01 8

S

3H20 : C 54.45, H 6.51, N 10.76 25 Found : C 54.11, H 6.74, N 11.18 Object Compound (164-II) NMR (DMSO-d 6

+D

2 0 , 5) : 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=6.1Hz), 1.20-2.45 (19H, m), 3.72 (3H, s), 3.73 (3H, s), 3.80-5.00 (15H, m), 6.55-6.90 (3H, m), 7.13 30 (2H, d, J=8.9Hz), 7.97 (2H, d, J=8.9Hz), 8.00-8.20 (4H, m) ESI-MASS (m/z) : 1283.4 (M+Na') (positive) The following compound was obtained according to a similar manner by using tert-butyldimethylsilane instead of 35 tert-butylsilane of Exazmple 6.

WO 99/40108 PCT/JP99/00538 456 Example 165 The following compound was obtained in a manner similar to that of Example 2-3 of WO97/32975. Example 166 5 IR (KBr) : 3394, 3327, 1676, 1633, 1439 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.8Hz), 1.08 (3H, d, J=6.0Hz), 1.88-5.83 (35H, m), 6.68-8.71 (10H, m) MASS (m/z) : 903.17 (M-Na ) Example 167 10 To a solution of Starting Compound (167) (0.1 g) and 4-[5-[4-(7-methoxyheptyloxy)phenyl] -1,3,4-thiadiazol-2 yl]benzoic acid benzotriazol-1-yl ester (66.1 mg) in dimethylformamide (1 ml) was added diisopropylethylamine (0.029 ml) and the mixture was stirred for 5 hours at ambient 15 temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration and dried under reduced pressure to give Object Compound (1697) (159 mg). IR (KBr) : 3344, 1648.8, 1637.3, 1513.8, 1257.4, 20 1043.3 cm-1 NMR (DMSO-d 6 , 6) : 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=5.6Hz), 1.2-1.6 (23H, m), 1.6-2.6 (12H, m), 2.9-4.6 (25H, m), 4.7-5.5 (9H, m), 6.71 (1H, d, J=8.2Hz), 6.78 (1H, d, J=8.2Hz), 6.88 (1H, s), 6.97 25 (1H, s), 7.13 (2H, d, J=8.8Hz), 7.16 (1H, s), 7.44 (1H, d, J=8.0Hz), 7.59 (1H, br s), 7.70 (1H, brs), 7.97 (2H, d, J=8.8Hz), 7.9-8.2 (6H, m), 8.72 (1H, s), 8.79 (1H, d, J=7.3Hz) MASS (m/z) : 1311 (M-diisopropylamine-1) 30 Elemental Analysis Calcd. For C 66

H

95

N

11 0 21 S2-5H 2 0 : C 51.72, H 6.90, N 10.05 Found : C 51.89, H 6.57, N 9.98 The following compound was obtained in a manner similar to that of Example 167.

WO 99/40108 PCT/JP99/00538 457 Example 168 IR (KBr) : 3344, 1664.3, 1633.4, 1506.1, 1436.7, 1257.4 cm-1 NMR (DMSO-d 6 , 5) : 0.91 (3H, t, J=7.0Hz), 0.97 (3H, d, 5 J=6.6Hz), 1.10 (3H, d, J=5.6Hz), 1.0-1.5 (19H, m), 1.6-2.7 (10H, m), 3.0-3.3 (3H, m), 3.7-4.6 (15H, m), 4.8-5.3 (11H, m), 5.54 (1H, d, J=5.6Hz), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, dd, J=8.2 and 1.5Hz), 6.85 (1H, s), 7.04 (1H, d, J=1.5Hz), 7.12 (2H, d, J=8.8Hz), 10 7.2-7.5 (3H, m), 7.23 (1H, s), 7.56 (1H, s), 7.58 (1H, m), 7.85 (2H, d, J=8.8Hz), 7.9-8.1 (5H, m), 8.26 (1H, d, J=8.7Hz),8.85 (1H, s), 8.87 (1H, d, J=7.3Hz) MASS (m/z) : 1268 (M-diisopropylamine-1) The following compound was obtained in a manner similar 15 to that of Example 2-3 of WO97/32975. Example 169 IR (KBr) : 1664, 1627, 1234, 1086, 1043 cm-1 NMR (DMSO-d 6 , 5) : 0.96 (3H, d, J=6.7Hz), 1.14 (3H, d, J=5.9Hz), 1.3-2.55 (8H, m), 2.6-3.6 (3H, m), 20 3.65-4.5 (15H, m), 4.7-5.4 (7H, m), 6.65-7.05 (4H, m), 7.07 (1H, s), 7.4-8.25 (7H, m), 8.71 (1H, s) MASS (m/z) : 903 (M-1)

Claims (10)

1. A polypeptide compound of following the general formula [I] 5 OH 0 HO H 3 C N NH- R N 0 HO 0 HN OH 10 0 NH O CH 3 H

2 N O N R2 NH OH 15 - OH R4 wherein 20 R 1 is hydrogen; arylamino(lower)alkanoyl which may have one or more suitable substituent(s); aroyl substituted with heterocyclic group which may have one or more suitable substituent(s); 25 aroyl substituted with aryl having higher alkyl; aroyl substituted with aryl having lower alkyl; aryl(C 2 -C 6 )alkanoyl substituted with aryl having lower alkyl; 30 lower alkanoyl substituted with unsaturated condensed heterocyclic group which may have one or more suitable substituent(s); lower alkanoyl substituted with pyridyl which may have one or more suitable substituent(s); 35 amino protective group; WO99/40108 PCT/JP99/00538 459 heptylnaphthoyl; hexylnaphthoyl; aroyl substituted with heterocyclic carbamoyl which may have one or more suitable substituent(s); 5 lower alkanoyl substituted with cyclo(lower)alkyl which may have one or more suitable substituent(s); lower alkanoyl substituted with thienyl having heterocyclic group which may have one or more 10 suitable substituent(s); or lower alkenoyl substituted with heterocyclic group which may have one or more suitable substituent(s), R 2 is hydrogen or hydroxy, 15 R 3 is hydroxy, hydroxysulfonyloxy or lower alkoxy, and R 4 is hydroxy or lower alkoxy, or a salt thereof. 20 2. A compound of claim 1, wherein R 1 is aroyl substituted with heterocyclic group which may have one or more suitable substituent(s).

3. A compound of claim 2, wherein 25 R 1 is benzoyl substituted with unsaturated 3 to 8 membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) having phenyl which has a suitable substituent selected from the group consisting of saturated 3 to 8 30 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have cyclo(lower)alkyl having di(lower)alkyl, lower alkoxy(lower)alkoxy, lower alkoxy(higher)alkoxy and phenyl substituted with saturated 3 to 8-membered heteromonocyclic 35 group containing 1 or 2 oxygen atom(s) and 1 to 3 WO 99/40108 PCT/JP99/00538 460 nitrogen atom(s) having di(lower)alkyl; or benzoyl substituted with unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s)and 1 to 3 nitrogen atom(s) having 5 phenyl which has lower alkoxy.

4. A compound of claim 3, wherein R 1 is benzoyl substituted with thiadiazolyl which has phenyl having piperidyl, 10 benzoyl substituted with thiadiazolyl which has phenyl having lower alkoxy(lower)alkoxy, benzoyl substituted with thiadiazolyl which has phenyl having lower alkoxy(higher)alkoxy, benzoyl substituted with thiadiazolyl having 15 phenyl which has piperazinyl substituted with cyclohexyl, benzoyl substituted with thiadiazolyl-having phenyl substituted with phenyl which has morpholino having di(lower)alkyl, or 20 benzoyl substituted with imidazothiadiazolyl having phenyl which has lower alkoxy.

5. A compound of claim 4, wherein R 1 is benzoyl substituted with thiadiazolyl which 25 has phenyl having piperidyl, or benzoyl substituted with thiadiazolyl which has phenyl having lower alkoxy(higher)alkoxy, R 3 is hydroxysulfonyloxy, and R 4 is hydroxy. 30

6. A process for preparing a polypeptide compound [I] of claim 1 or a salt thereof, which comprises, i) reacting a compound [Ib] of the formula : 35 WO 99/40108 PCT/JP99/00538 461 OH 0 HO H 3 C NH NH 2 N2 N 0 HO O HN OH 0 NH CH 3 :([Ib] H 2 N O N R 2 NH OH 10 - OH O R 3 R4 R 15 wherein R 2 , R 3 and R 4 are as defined in Claim 1 or its reactive derivative at the amino group or a salt thereof, with a compound [III] of the formula : Ra - OH [III] 20 wherein Ra is arylamino(lower)alkanoyl which may have one or more suitable substituent(s); aroyl substituted with heterocyclic group which may have one or more suitable substituent(s); 25 aroyl substituted with aryl having higher alkyl; aroyl substituted with aryl having lower alkyl; aryl(C 2 -C 6 )alkanoyl substituted with aryl 30 having lower alkyl; lower alkanoyl substituted with unsaturated condensed heterocyclic group which may have one or more suitable substituent(s); WO 99/40108 PCT/JP99/00538 462 lower alkanoyl substituted with pyridyl which may have one or more suitable substituent(s); amino protective group; heptylnaphthoyl; 5 hexylnaphthoyl; aroyl substituted with heterocyclic carbamoyl which may have one or more suitable substituent(s); lower alkanoyl substituted with cyclo(lower)alkyl which may have one or more suitable 10 substituent(s); lower alkanoyl substituted with thienyl having heterocyclic group which may have one or more suitable substituent(s); or lower alkenoyl substituted with heterocyclic 15 group which may have one or more suitable substituent(s), or its reactive derivative at the carboxy group or a salt thereof, to give a compound [Ia] of the formula: OH 20 HO 0 NH H 3 C N- R NH a N O0 HO O HN OH 25 0 NH O CH 3 [1a] H 2 N O N R2 NH OH -- OH 0 30 R3 wherein R 2 , R 3 and R 4 are as defined in Claim 1, and WO 99/40108 PCT/JP99/00538 463 R1 is as defined above a or a salt thereof, or ii) reducing a compound [II] of the formula: HO OH 5 HO 0 H 3 C NH NH- R a N 0 HO 0 HN OH 10 0 NH O -CH3 [II] H 2 N O N HO NH OH - OH O 15 R 3 wherein 4 Ra, R 3 and R 4 are as defined above, or a salt thereof, to give a compound [Ia] of the formula: 20 OH HO 0 NH H 3 C--- NH- R a N O0 25 HO 0 HN OH 0 5O NH O CH 3 H 2 N O N 2 NH OH 30 - OH 0 R3 R4 WO 99/40108 PCT/JP99/00538 464 wherein R 2 , R 3 and R 4 are as defined in Claim 1, and R1 is as defined above, or a salt thereof, or 5 iii) reducing a compound [IV] of the formula : HO OH HO 0 10N 10 HO o HN OH NH 0O=CH 3 [IV] H 2 N O N HO NH OH 15 - OH 0 R3 wherein R 20 R 3 and R 4 are as defined in Claim 1, or a salt thereof, to give a compound [Ib] of the formula: OH 0 HO NH H 3 C NH 2 N2 25 N 0 HO O HN OH 0 NH O CH 3 [Ib] H 2 N O N 30 NH OH - OH 0 R3 WO99/40108 PCT/JP99/00538 465 wherein R 2 , R 3 and R 4 are as defined in Claim 1, or a salt thereof. 5

7. A pharmaceutical composition which comprises, as an active ingredient, a compound of Claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carrier or excipients. 10

8. Use of a compound of Claim 1 or a pharmaceutically acceptable salt thereof as a medicament.

9. A compound of Claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament. 15

10. A method for the prophylactic and/or therapeutic treatment of infectious diseases caused by pathogenic microorganisms, which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof 20 to a human being or an animal.