AU756792B2 - New compound - Google Patents
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- AU756792B2 AU756792B2 AU22998/99A AU2299899A AU756792B2 AU 756792 B2 AU756792 B2 AU 756792B2 AU 22998/99 A AU22998/99 A AU 22998/99A AU 2299899 A AU2299899 A AU 2299899A AU 756792 B2 AU756792 B2 AU 756792B2
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Description
DESCRIPTION
NEW COMPOUND TECHNICAL FIELD The p.resent 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 disclosed the polypeptide compound and a pharmaceutically acceptable salt thereof, which have antimicrobial activities (especially antifungal activity).
DISCLOSURE OF INVENTION The present invention relates to new polypeptide compound and a salt thereof.
More particularly, it relates to new polypeptide 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 B-l,3-glucan synthase, and further which are expected to be useful for the prophylactic and/or therapeutic treatment of Pneumocystis carinii infection 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 incl-uding -Pneumoe.ysts- eari-si infection- Pneumocystis carinii pneumonia) in a human being or an animal.
The polypeptide compounds of the present invention are new and can be represented by the following general formula WO 99/40108 PCT/JP99/00538 2
OH
HO
H
3 C NH NH- R' 0 HO O HN OH O NH O CH 3
H
2 N 0 N
R
2 NH YOH OH 0 R3 Wherein
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); 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; 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); amino protective group; heptylnaphthoyl; hexylnaphthoyl; aroyl substituted with heterocyclic carbamoyl which WO 99/40108 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 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), R2 is hydrogen or hydroxy,
R
3 is hydroxy, hydroxysulfonyloxy or lower alkoxy, and
R
4 is hydroxy or lower alkoxy, or a salt thereof.
The new polypeptide compound and a salt thereof can be prepared by the process as illustrated in the following reaction schemes.
WO 99/40108 WO 9940108PCT/JP99/00538 1 -OH I1111] or its reactive derivative at the carboxy group or a salt thereof or its reactive derivative at the amino group or a salt thereof Ia or a salt thereof WO 99/40108 WO 9940108PCT/JP99/00538 Reduction or a salt thereof WO 99/40108 PCT/JP99/00538 Process 3 Reduction WO 99/40108 PCT/JP99/00538 7 The starting compound [II] and or a salt thereof can be prepared by the process as illustrated in the following reaction schemes.
Process A
RI-OH
II or its reactive derivative at the carboxy group or a salt thereof
[IV]
R
4 or its reactive derivative at the amino group or a salt thereof WO 99/40108 WO 9940108PCT/JP99/00538 Hydrolysis 0 11 HO-S-0- Y IVa I or its reactive derivative at the suifonic acid group or a salt thereof [IWbbI or a salt thereof WO 99/40108 WO 9940108PCT/JP99/00538 Alkylation [NIb]j or its reactive derivative at the bydroxy group or a salt thereof
[NIC]I
or a salt thereof WO 99/40108 PCT/JP99/00538 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); 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 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 have one or more suitable substituent(s); amino protective group; heptylnaphthoyl; 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 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 group which may have one or more suitable substituent(s), R3 is lower alkoxy, and R4 is hydroxy or lower alkoxy.
Suitable salt of the new polypeptide compound is a pharmaceutically acceptable and conventional non-toxic salt, and may include a salt with a base or an acid addition salt WO 99/40108 PCT/JP99/00538 11 such as a salt with an inorganic base, for example, an alkali metal salt sodium salt, potassium salt, etc.), an alkaline earth metal salt calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt triethylamine salt, diisopropylethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'dibenzylethylenediamine salt, etc.); an inorganic acid addition salt hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic sulfonic acid addition salt formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid arginine, aspartic acid, glutamic acid, etc.).
Suitable examples and illustration of the various 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 6 carbon atom(s), unless otherwise provided.
The term "higher" is used to intend a group having 7 to 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 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 the like.
WO 99/40108 PCT/JP99/00538 12 Suitable example of "suitable substituent(s)" in the
R
1 and Ra 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 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 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, 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 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 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 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 WO 99/40108 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, 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 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 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 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.
Suitable example of "higher alkoxy" may include straight or branched one such as heptyloxy, octyloxy, 3,7-dimethyloctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, and the like, in which the preferred one may be (C7-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, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, WO 99/40108 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.
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, 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 phenyl which may have lower alkyl phenyl, mesityl, xylyl, tolyl, etc.), naphthyl, anthryl, indanyl, and the like, in which the preferred one may be phenyl and naphthyl, 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 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 6membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl 4H-1,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, WO 99/40108 PCT/JP99/00538 indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl 1,2,4-oxadiazolyl, 1,3,4oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 oxygen 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.; unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example thiazolidinyl, thiomorpholinyl, thiomorpholino, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensed heterocyclic group containing 1 or 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 6membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.; WO 99/40108 PCT/JP99/00538 16 saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing an oxygen atom, for example, tetrahydrofuran, tetrahydropyran, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6membered) 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.; 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.
Suitable example of "lower alkenyloxy" may include vinyloxy, 1-(or 2-)propenyloxy, l-(or 2- or 3-)butenyloxy, 1-(or 2- or 3- or 4-)pentenyloxy, l-(or 2- or 3- or 4- or and the like, in which the preferred one may be (C 2
-C
6 )alkenyloxy, and the most preferred one may be 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 "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) benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc.), [5-(lower)alkyl-2-oxo-l,3-dioxol-4-yl](lower)alkyl (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 heterocyclicaliphatic acyl derived from carboxylic acid, carbonic acid, WO 99/40108 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 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.); lower or higher alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl methoxysulfonyl, ethoxysulfonyl, etc.); or the like; Aromatic acyl such as aroyl benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl phenyl(C 1
-C
6 )alkanoyl phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(C 1
-C
6 )alkanoyl naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl phenyl(C 3
-C
6 )alkenoyl phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl (C 3
-C
6 alkenoyl naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; ar (lower) alkoxycarbonyl phenyl (C 1
-C
6 alkoxycarbonyl benzyloxycarbonyl, etc.), fluorenyl (C 1
-C
6 alkoxycarbonyl fluorenylmethyloxycarbonyl, etc.), etc.]; aryloxycarbonyl phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl phenoxyacetyl, phenoxypropionyl, etc.); WO 99/40108 PCT/JP99/00538 18 arylcarbamoyl phenylcarbamoyl, etc.); arylthiocarbamoyl phenylthiocarbamoyl, etc.); arylglyoxyloyl phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl which may have 1 to 4 lower alkyl phenylsulfonyl, p-tolylsulfonyl, etc.); or the like; Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic(lower)alkenoyl heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); 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 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.
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.
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 the term of "arylamino(lower)alkanoyl which may have one or WO 99/40108 PCT/JP99/00538 19 more suitable substituent(s)" can be referred to aforementioned "suitable substituent(s)", in which the preferred one may be higher alkoxy, and the most preferred one may be heptyloxy.
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.
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 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 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 condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen 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 may have one or more suitable substituent 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 alkoxy(higher) alkoxy, aryl which has one or more heterocyclic WO 99/40108 PCT/JP99/00538 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 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, 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 has one or more heterocyclic(lower)alkoxy, in which heterocyclic group may have one or more lower alkyl, 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 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 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 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, 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 WO 99/40108 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 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 which may have one or more lower alkyl, cyclo (lower) alkyl which may have one or more aryl, aryl, in which the preferred one may be phenyl having (C 7
-C
1 4 )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
1 4 )alkoxy, phenyl having saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), cyclo(C4-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 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-membered heteromonocyclic 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, 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 1
C
4 )alkoxy having saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen 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 -Cl 4 )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), phenyl having cyclo(C 4
-C
6 )alkyloxy, phenyl which has WO 99/40108 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 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 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, 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 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, 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 8membered 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
(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 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 substituted withphenyl which has (C 1
-C
6 )alkoxy(C 1
-C
6 alkoxy, phenyl substituted with phenyl which has (C 1
-C
6 )alkoxy(C 1
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 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(C 1
-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 saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), phenyl which has (C 1
-C
6 alkoxy having 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 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
C
6 )alkyl, cyclo(C 4
-C
6 )alkyl which has phenyl, indanyl, phenyl substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxgen atom(s) and1 to 3 nitrogen atom(s), phenyl substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having (C 1
-C
6 )alkyl, phenyl substituted with saturated 3 to WO 99/40108 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 1 to 3 nitrogen atom(s), and the most preferred one may be phenyl 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 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, 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 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 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 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 has thiadiazolyl substituted with pentyloxyphenyl, pyrazolyl WO 99/40108 PCT/JP99/00538 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 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 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 substituted with phenyl 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 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, 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 dimethyl.
Suitable example of "aroyl substituted with heterocyclic group which may have one or more suitable substituent may be benzoyl substituted with piperazinyl which has phenyl having octyloxy, benzoyl substituted with piperazinyl which has phenyl having hexyloxy, benzoyl substituted with WO 99/40108 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 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 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 methoxy, benzoyl substituted with oxadiazolyl which has phenyl substituted with phenyl having propyloxy, 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 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, 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 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 phenyloxybutyloxy, benzoyl substituted with oxadiazolyl which WO 99/40108 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 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 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 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 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 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 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 thiadiazolyl having phenyl which has thiadiazolyl substituted WO 99/40108 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 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 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 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 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 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 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 cyclohexyloxy, benzoyl substituted with piperazinyl which has WO 99/40108 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 imidazothiadiazolyl which has phenyl having piperidinopentyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having piperidinohexyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having 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 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, 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 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, 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 with phenyl having propoxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having WO 99/40108 PCT/JP99/00538 methoxyhexyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having methoxyheptyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having methoxyoctyloxy, benzoyl substituted with 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 having pentyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having hexyloxy, benzoyl substituted with thiadiazolyl which has phenyl having cyclohexyl, benzoyl substituted with oxadiazolyl which has phenyl having cyclohexyl, benzoyl substituted with thiadiazolyl which has phenyl substituted with phenyl having propoxy, benzoyl substituted with thiadiazolyl which has phenyl substituted with phenyl having ethoxy, benzoyi substituted with thiadiazolyl which has phenyl substituted with phenyl having methoxybutoxy, and benzoyl substituted with 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 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 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 may be (C 7 -Cl 4 )alkyl, and the more preferred one may be heptyl.
WO 99/40108 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.
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.
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 "aroyl substituted with aryl having lower alkyl" can be referred to aforementioned "lower alkyl", in which the preferred one may be (C 4
-C
6 )alkyl, and the more preferred one may be hexyl.
Suitable example of "aroyl substituted with aryl having 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 "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 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 alkyl" can be referred to aforementioned "lower alkyl", in WO 99/40108 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 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 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 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 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 have one or more higher alkoxy and aryl which may have one or more lower alkoxy, in which the preferred one may be 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 may be pyridyl having 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 -Cl 4 )alkoxy and benzoxazolylcarbonyl which has phenyl having (C 4
-C
6 )alkoxy, WO 99/40108 PCT/JP99/00538 33 in which the preferred one may be benzoxazolylcarbonyl which has pyridyl having octyloxy and benzoxazolylcarbonyl which has phenyl having hexyloxy.
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 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 preferred one may be 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)" 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 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 "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), and the more preferred one may be thiadiazolyl.
WO 99/40108 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 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 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 can be referred 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 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 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.
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 alkanoyl", in which the preferred one may be formyl.
WO 99/40108 PCT/JP99/00538 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 "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 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, and the more preferred one may be phenyl substituted with phenyl having pentyloxy.
Suitable example of "lower alkenoyl" moiety in the term of "lower alkenoyl substituted with heterocyclic group which may have one or more suitable substituent 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 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 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 can be referred to aforementioned "suitable substituent(s)", in which the preferred one may be aryl having lower P:\OPER\Kbm\22998-99 spc.doc-20/11/02 -36alkoxy (lower) alkoxy, and the more preferred one may be phenyl having methoxyhexyloxy.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
*The processes for preparing the polypeptide compound [I] and the starting compound [II] or a salt thereof of the present S 15 invention are explained in detail in the following.
Process 1 The 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 S* or a salt thereof.
Suitable reactive derivative at the carboxy group of the compound [III] may include an acid halide, an acid anhydride, 25 an activated amide, 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 substituted phosphoric acid dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid methanesulfonic acid, etc.], aliphatic carboxylic acid acetic acid, propionic acid, butyric acid, isobutyric acid, pivaric acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.]; or aromatic carboxylic acid benzoic acid, Setc.]; a symmetrical acid anhydride; an activated amide with P:XOPER\Kba.\22998-99 spm.d.-IBIIA/)2 -36A iinidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
[(CH
3 2 N=CH-] ester, vinyl ester, propargyl ester, p-nitropheny. ester, 2, L-dinitrophenyl ester, WO 99/40108 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 thioester, etc.], or an ester with a N-hydroxy compound [e.g.
N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, Nhydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1Hbenzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to 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 The reaction is usually carried out in a conventional solvent such as water, alcohol 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 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; 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); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine, ethoxyacetylene; l-alkoxy-2-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; WO 99/40108 PCT/JP99/00538 38 lower alkyl haloformate ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; (m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 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.
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 4-dimethylaminopyridine, etc.), N-(lower)alkylmorpholine, N,Ndi(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 by reducing a compound [II] or a salt thereof.
Suitable salts of the compounds [Ia] and [II] may be the same as those exemplified for the compound The reaction can be carried out in a conventional manner, namely, chemical reduction or catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of metal tin, zinc, iron, etc.] or metallic compound chromium chloride, chromium acetate, etc.] and an organic or inorganic acid formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic 30 acid, hydrochloric acid, hydrobromic acid, hydride transfer
C-
reagent such as aluminum hydride compound lithium aluminum hydride, lithium hydridotri-t-butoxyaluminate, etc.), borohydride compound sodium borohydride, sodium cyanoborohydride, etc.) or the like etc.].
Suitable catalysts to be used in catalytic reduction are WO 99/40108 PCT/JP99/00538 39 conventional ones such as platinum catalyst platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst spongy palladium, palladium black, palladium oxide, palladium 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 reduced cobalt, Raney cobalt, etc.], iron catalyst reduced iron, Raney iron, etc.], copper catalyst 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 methanol, ethanol, propanol, etc.], acetic acid, diethyl ether, dioxane, 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 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 reduction reaction.
This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2.
Process A The object compound [II] I or a salt thereof can be prepared by reacting the starting compound [IV] or its reactive derivative at the amino group or a salt thereof with the compound [III] or its reactive derivative at the carboxy group WO 99/40108 PCT/JP99/00538 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 solvent, reaction temperature, 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 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 base such as an alkali metal sodium, potassium, etc.], an alkaline earth metal magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene, or the like.
Suitable acid may include an organic acid formic acid, acetic acid, propionoc acid, trichloroacetic acid, trifluoroacetic acid, etc], and an inorganic acid hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
The elimination using Lewis acid such as trihaloacetic acid trichloroaceticacid, trifluoroacetic acid, etc.], or the like preferably carried out in the presence of cation trapping agent anisole, phenol, etc.].
The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,Ndimethylformamide, N,N-dimethylacetamide or any other organic solvent which do not adversely affect the reaction, or the 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 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 diazomethane, phenyldiazomethane, diphenyldiazomethane, trimethylsilyldiazomethane, Bdiazopropionic acid etc.] or a salt thereof to alkylation reaction of the hydroxy group.
This reaction is usually carried out in the solvent such as water, alcohol 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.
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 formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc], and an inorganic acid hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide zinc chloride, zinc bromide, etc.), etc.] and the like.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal sodium, potassium, etc.], an alkali metal hydroxide sodium hydroxide, potassium hydroxide, etc.], an alkali metal hydrogencarbonate sodium hydrogencarbonate, potassium hydrogencarbonate, etc.], alkaline metal carbonate WO 99/40108 PCT/JP99/00538 42 sodium carbonate, potassium carbonate, etc.], tri(lower)alkylamine trimethylamine, triethylamine, diisopropylethylamine, etc.], alkali metal hydride sodium hydride, etc.], alkali metal (lower)alkoxide sodiummethoxide, sodiumethoxide, 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 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, 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 A to may be obtained as its hydrate, and its hydrate 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 are included within the scope of the present invention.
The object compound or a salt thereof includes solvated compound enclosure compound hydrate, etc.)] The object compound or a salt thereof includes both 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.
This application is based on application No. PP1728/98 WO 99/40108 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 compound M[ of the present invention In order to show the usefulness of the polypeptide compound of the present invention, the biological data of the representative compound is explained in the following.
Test (Antimicrobial activity) In vitro antimicrobial activity of the object compound of Example 12 disclosed later was determined by microdilution method as described below.
Test Method: 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.
RPMI1640 medium with L-glutamine, without sodium bicarbonate, and buffered with 165 mMmorpholinepropanesulfonic acid buffer (pH 7.0) was used as a test medium. Inoculum suspension of 106 CFU/ml were prepared by a hemocytometric procedure, and diluted to obtain an inoculum size of approximately X 103 to 2.5 X 103 CFU/ml. Microplates were incubated at 35 0
C
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 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 WO 99/40108 PCT/JP99/00538 44 polypeptide compound of the present invention has an antimicrobial activity (especially, antifungal activity) The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object polypeptide compound or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is 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.
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; 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 agents; perfumes or buffer; or any other commonly may be used as additives.
The object polypeptide compound or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired 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 therapeutically effective amount of the object polypeptide WO 99/40108 PCT/JP99/00538 compound 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 per kg weight of human being in the case of intramuscular administration, a daily dose of 0.1-20 mg of the object polypeptide compound per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the object polypeptide compound per kg weight of human being is generally given for treating or 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 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 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 administration. Insufflation is also a desirable method, especially where infection may have spread to ears and other body cavities.
Alternatively, parenteral administration may be employed using drip intravenous administration.
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) and 1,6-dibromohexane (481 g) in N,N-dimethylformamide (500 WO 99/40108 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 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-(6bromo-n-hexyloxy)benzoate (186 g) as a white solid.
NMR (CDC1 3 1.46-1.55 (4H, 1.78-1.97 (4H, m), 3.38-3.46 (2H, 3.88 (3H, 4.01 (2H, t, J=6.3Hz), 6.90 (2H, d, J=8.9Hz), 7.98 (2H, d, J=8.9Hz) MASS 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 NMR (DMSO-d 6 5) 1.2-1.6 (6H, 1.6-2.0 (4H, m), 3.53 (2H, t, J=6.7Hz), 3.81 (3H, 4.04 (2H, t, J=6.4Hz), 7.03 (2H, d, J=8.9Hz), 7.90 (2H, d, J=8.9Hz) MASS 329 331 (M+3) Preparation 3 A solution of methyl 4-(6-bromo-n-hexyloxy) benzoate (186 g) in methanol (1 L) was treated with 28% sodium methoxide in methanol (340 ml) and the solution refluxed for 2 hours. After cooling, the stirred solution was adjusted to pH 2 with 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 hexaneethyl acetate elution) to give methyl 4-(6-methoxy-nhexyloxy)benzoate (127 g) as an oil.
WO 99/40108 PCT/JP99/00538 47 NMR (CDCl 3 0 6 1. 37-1. 68 (6H, mn), 1.74-1. 88 (2H, mn), 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 d, J=8. 9Hz) The following compound was obtained in a manner similar to that of Prep~aration 3.
Preparation 4 Methyl 4- 7 -methoxy-n-heptyloxy)benzoate MR (DMSO-d 6 5) 1.2-1. 6 (8H, mn), 1. 6-1. 9 (2H, in), 3.21 (3H, 3.29 (2H, t, J=6.4Hz), 3.81 s), 4.04 (2H, t, J=6.SHz), 7.03 (2H, d, J=8.9Hz), 7.90 (2H, d, J=8.9Hz) MASS 281 (M+1) Preparation 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 filtration, washed thoroughly with water then dried under hi-vacuum at 50 0 C to give 4-(6-methoxy-nhexyloxy)benzohydrazide (15.63 g) as a white solid.
MR (DMSO-d 6 6) 1.29-1.58 (6H, in), 1.65-1.78 (2H, in), 3.21 3.30 (2H, t, J=6.4Hz), 4.00 (2H, t, J=6.4Hz), 4.40 (2H, 6.96 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.8Hz), 9.59 (1H, s) MASS (in/z) :267 (M+1) The following compound was obtained in a manner similar to that of Preparation Preparation 6 4- (7-Methoxy-n-heptyloxy) benzohydrazide NMR (DMSO-d 6 6) 1.2-1.6 (8H1, mn), 1.6-1.9 (2H, mn), 3.21 (3H, 3.30 (2H, t, JTh6.41{z), 4.00 (2H, t, J=6.4Hz), 4.40 (2H, 6.96 (2H, d, J=8.711z), 7.78 (2H, d, J=8.9Hz), 9.59 (11H, s) WO 99/40108 PCT/JP99/00538 48 MASS :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 0 0 -5 0 C was treated portionwise with 4-methoxycarbonylbenzoyl chloride (83.75 g) over 30 minutes. After a further 1 hour at 0 0 and 2 hours at room temperature, tlc indicated complete reaction and the reaction mixture was poured into water (7 The resulting precipitate was collected by 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 1.40-1.80 (8H, 3.22 (3H, s), 3.31 (2H, t, J=6.4Hz), 3.90 (3H, 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, 10.64 (1H, s) The following compound was obtained in a manner similar to that of Preparation 7.
Preparation 8 N-[4-(7-Methoxy-n-heptyloxy)benzoyl]-N'-(4-methoxycarbonylbenzoyl)hydrazine NMR (DMSO-d 6 6) 1.2-1.6 (8H, 1.6-1.9 (2H, m), 3.21 (3H, 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, 10.63 (1H, s) MASS :443 (M+1) Preparation 9 A mixture of N-[4-(6-methoxy-n-hexyloxy)benzoyl]-N'- (4-methoxycarbonylbenzoyl)hydrazine (193.4 g) and phosphorus pentasulfide (113.34 g) in tetrahydrofuran (2.5 L) was heated to reflux for 1 hour then cooled to room temperature and poured 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 acetonitrile (500 ml x 5) then dried under hi-vacuum at 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 (CDC1 3 5) 1.40-1.87 (8H, 3.34 (3H, 3.40 (2H, t, J=6.2Hz), 3.96 (3H, 4.03 (2H, t, 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, The following compound was obtained in a manner similar to that of Preparation 9.
Preparation Methyl 4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,3,4thiadiazol-2-yl]benzoate NMR (CDC1 3 5) 1.3-2.0 (10H, 3.34 (3H, 3.38 (2H, t, J=6.4Hz), 3.96 (3H, 4.03 (2H, t, 6.99 (2H, d, J=8.8Hz), 7.95 (2H, d, J=8.8Hz), 8.07 (2H, d, J=8.4Hz), 8.43 (2H, d, J=8.4Hz) MASS :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 sodium hydroxide (25.3 water (250 ml), methanol (1 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 6Nhydrochloric acid and the precipitate collected by filtration, washed thoroughly with water, followed by acetonitrile, then dried under hi-vacuum at 50"C to give 4-[5-[4-(6-methoxyn-hexyloxy)phenyl]-l, 3 ,4-thiadiazol-2-yl]benzoic acid (167 g) as a yellow powder.
NMR (DMSO-d 6 5) 1.27-1.85 (8H, 3.22 (3H, s), 3.32 (2H, t, J=6.4Hz), 4.06 (2H, t, J=6.3Hz), 7.12 WO 99/40108 PCT/JP99/00538 (2H, d, J=8.8Hz), 7.97 (2H, d, J=8.7Hz), 8.12 (4H, 13.28 (1H, br s) The following compound was obtained in a manner similar to that of Preparation 11.
Preparation 12 4-[5-[4-(7-Methoxy-n-heptyloxy)phenyl]-1,3,4thiadiazol-2-yl]benzoic acid IR (KBr) 2939.0, 2867.6, 2642.0, 1712.5, 1604.5, 1440.6, 1402.0, 1253.5 cm- 1 MASS 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'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, washed with water (1 L x acetonitrile (1 L x isopropyl ether (250 ml x then dried under hi-vacuum to give 4- [5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2yl]benzoic acid benzotriazol-1-yl ester (56.92 g) as a yellow powder.
-i IR (KBr) :1778 cm- 1 NMR (CDC1 3 5) 1.44-1.89 (8H, 3.35 (3H, 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, 7.98 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.2Hz), 8.24 (2H, d, J=8.5Hz), 8.41 (2H, d, 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]-1,3,4thiadiazol-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, -i 1253.5 cm-1 NMR (CDC1 3 6) 1.3-2.0 (10H, 3.34 (3H, 3.39 (2H, t, J=6.4Hz), 4.03 (2H, t, J=6.5Hz), 7.01 (2H, d, J=8.8Hz), 7.4-7.7 (3H, 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 :544 (M+1) Preparation 4-[5-(4-Pentyloxyphenyl)isoxazol-3-yl]benzoic acid benzotriazol-l-yl ester Preparation 16 To 3-hydroxybenzoic acid methyl ester (25 g) and potassium carbonate (25 g) in N,N-dimethylformamide (300 ml) were added 1-bromopentane (25 ml) and the mixture was stirred for 7 hours at 80*C. The reaction 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 3-amyloxybenzoic acid methyl ester (35 g).
IR (KBr) 2954, 2870, 1724, 1587 cm 1 NMR (CDC1 3 6) 0.94 (3H, t, J=7.0Hz), 1.43 (4H, m), 1.80 (2H, 3.91 (3H, 3.99 (2H, t, J=6.6Hz), 7.09 (1H, ddd, J=7.8, 1.7 and 1.7Hz), 7.32 (1H, t, 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 :223 (M+1) Preparation 17 To 3-amyloxybenzoic acid methyl ester (35 g) in methanol (200 ml) was added 1N-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 acid (30 mg).
WO 99/40108 PCT/JP99/00538 52 IR (KBr) 2954, 2848, 2570, 1691, 1600, 1591 cm-1 NMR (DMSO-d 6 6) 0.90 (3H, t, J=7.0Hz), 1.40 (4H, m), 1.73 (2H, 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 (1H, dd, J=1.5 and 1.2Hz), 7.52 (1H, ddd, J=7.7, and 1.2Hz) MASS :209 (M+1) Preparation 18 To a solution of 1-hydroxybenzotriazole (24 g) and 3amyloxybenzoic acid (29.5 g) in dichloromethane (500 ml) was added l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (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 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 6) 0.95 (3H, t, J=7.0Hz), 1.45 (4H, m), 1.84 (2H, 4.05 (2H, t, J=6.5Hz), 7.30 (1H, d, J=9.4Hz), 7.43-7.56 (4H, 7.74 (1H, t, 8.10 (1H, d, J=8.5Hz), 8.53 (1H, d, MASS :326 (M+l) Preparation 19 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 precipitate was collected by filtration to give 1-(4-nbutyloxybenzoyl)thiosemicarbazide (11.51 g).
NMR (DMSO-d 6 6) 0.93 (3H, t, J=7.0Hz), 1.2-1.5 (2H, 1.6-1.8 (2H, 4.02 (2H, t, J=6.5Hz), 6.98 (2H, d, J=8.8Hz), 7.56 (1H, 7.83 (1H, 7.84 (2H, d, J=8.8Hz), 9.26 (1H, 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 1-(3-Amyloxybenzoyl)thiosemicarbazide NMR (DMSO-d 6 6) 0.90 (3H, t, J=6.8Hz), 1.39 (4H, m), 1.73 (2H, 4.01 (2H, t, J=6.4Hz), 7.10 (1H, d, 7.30-8.00 (5H, 9.33 (1H, 10.34 (1H, 8.53 (1H, d, MASS :282 (M+l) Preparation 21 To a slurry of 1-(4-n-butyloxybenzoyl)thiosemicarbazide g) in toluene (213.3 ml) at 40 0 C, was added dropwise over minutes, methanesulfonic acid (6.92 ml). The mixture was stirred under refluxing for 12 hours. After cooling to 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 (4-n-butyloxyphenyl)-1,3,4-thiadiazole (4.314 g).
NMR (CDC1 3 5) 0.94 (3H, t, J=7.0Hz), 1.2-1.6 (2H, 1.6-1.9 (2H, 4.01 (2H, t, J=6.5Hz), 7.00 (2H, d, J=8.8Hz), 7.28 (2H, 7.66 (2H, d, J=8.8Hz) The following compound was obtained in a manner similar 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 0.90 (3H, t, J=7.0Hz), 1.39 (4H, 1.73 (2H, 4.01 (2H, t, J=6.5Hz), 7.00 (1H, d, J=8.5Hz), 7.25-7.42 (5H, m) MASS :264 (M+1) Preparation 23 To a suspension of 2 -amino-5-(4-n-butyloxyphenyl)- 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) 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- [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (2.15 g).
IR (KBr) 1714.4, 1602.6, 1278.6, 1255.4, 1178.3 cm 1 The following compound was obtained in a manner similar to that of Preparation 23 Preparation 24 4-[2-(3-Amyloxyphenyl)imidazo[2,1b] [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) 2869.6, 1704.8, 1573.6, 1278.6 cm-1 MASS :436 (M+1) Preparation To a solution of 4- [2-(4-butyloxyphenyl) imidazo [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (2.05 g) in the mixture of methanol (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 IN HC1 and the resulting precipitate was collected by filtration to give butyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid (1.544 g).
The following compound was obtained in a manner similar to that of Preparation Preparation 26 4-[2-(3-Amyloxyphenyl)imidazo[2,1-b][l,3,4]thiadiazol-6-yl]benzoic acid WO 99/40108 PCT/JP99/00538 IR (KBr) 2935.1, 2867.6, 1685.5, 1608.3, 1484.9, 1288.2 cm 1 NMR (DMSO-d 6 5) 0.91 (3H, t, J=7.0Hz), 1.39 (4H, m), 1.75 (2H, 4.07 (2H, t, J=6.5Hz), 7.19 (1H, m), 7.42-7.49 (3H, 8.00 (4H, 8.89 (1H, s) MASS 408 (M+1) The Starting Compound used and the Object Compounds (27) to (30) obtained in the following Preparations 27 to 30 are 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 WO 9940108PCT/JP99/00538 Preparation No.
Formula 6- NaO 3 s' I
H
2 0
I
WO 99/40108 WO 9940108PCT/JP99/00538 PreparationI No Formula NaO 3 NaO 3
S
I
WO 99/40108 WO 9940108PCT/JP99/00538 PreparationFo ua No.
NaO 3
S
HO OH
(CH
2 3
CH
3 WO 99/40108 WO 99/0 108PCT/JP99/00538 Preparation No..
Formnul a 4.
HQ OH
HO.,
Nf
HN
H2N, -0H NaO 3
S'
HO OH HO 0
(CH
2 4
CH
3 NaO, WO 99/40108 PCT/JP99/00538 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 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 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 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 NMR (DMSO-d 6 5) 0.96 (3H, d, J=6.6Hz), 1.05 (3H, d, J=5.8Hz), 1.78-5.53 (35H, 6.71-8.84 (16H, m) MASS 1068.90 (M-Na Preparation 28 To a solution of Starting Compound (54.4 g) and 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 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 6) 0.96 (3H, d, J=6.8Hz), 1.03 (3H, d, J=5.6Hz), 1.60-2.00 (3H, m), 2.05-2.49 (4H, 3.18 (1H, t, J=ll.lHz), WO 99/40108 PCT/JP99/00538 61 3.60-4.48 (17H, 4.68-5.36 (10H, 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, 6.97 (1H, 7.04 (1H, d, J=1.6Hz), 7.27-7.46 (6H, 7.74-7.78 (3H, 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-6yl]benzoic acid (420 mg) in N,N-dimethylformamide (20 ml) was added l-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) 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 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% acetonitrile aq. The fractions containing the Object Compound were combined and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give Object Compound (29) (891 mg).
NMR (DMSO-d 6 6) 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, 2.1-2.7 (4H, 3.25 (1H, m), 3.6-4.5 (16H, 4.7-5.3 (10H, 5.53 (1H, d, J=5.8Hz), 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d,=8.2Hz), 6.86 (1H, 7.05 (1H, 7.14 (2H, d, J=8.9Hz), 7.2-7.5 (3H, 7.90 (2H, d, J=8.9Hz), 7.9-8.0 (4H, 8.10 (1H, d, J=7.7Hz), 8.30 (1H, d, J=6.8Hz), 8.70 (1H, d, J=6.8Hz), 8.86 (1H, s) WO 99/40108 PCT/JP99/00538 62 MASS :1356 (M+Na The following compound was obtained in a manner similar to that of Preparation 29.
Preparation IR (KBr) 3359, 1673.9, 1648.8, 1257.4 cm-1 NMR (DMSO-d 6 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, 1.6-2.7 (9H, 3.19 (1H, m), 3.6-4.6 (15H, 4.7-5.3 (11H, 5.53 (1H, d, J=5.9Hz), 6.73 (1H, d, J=8.3Hz), 6.83 (1H, d, J=8.3Hz), 6.88 (1H, 7.06 (1H, 7.14 (2H, d, J=8.9Hz), 7.2-7.4 (3H, 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, 8.86 (1H, s) MASS 1325 (M+Na Elemental Analysis Calcd. for C 57
H
70
N
11
O
22
S
2 Na.8H 2 O C 45.87, H 5.81, N 10.32 Found C 46.04, H 5.77, N 10.28 Preparation 31 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 g).
NMR (CDC1 3 6) 3.94 (3H, 6.93 (2H, d, J=8.4Hz), 7.27 (1H, 7.53 (2H, d, J=8.6Hz), 7.60 (2H, d, J=8.4Hz), 8.08 (2H, d, J=8.4Hz) MASS :229 (M +1) Preparation 32 A solution of 4-(4'-hydroxyphenyl)benzoic acid (4.98 g), methyliodide (5 ml), and sodium carbonate (7.19 g) in N,Ndimethylformamide (50 ml) was stirred for 17 hours at room temperature. The reaction mixture was partitioned between 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 (5.45 g).
-i IR (KBr) 1718 cm1 NMR (CDC1 3 5) 3.86 (3H, 3.93 (3H, 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) MASS 243 Preparation 33 A mixture of methyl 4-[5-[4'-[4"-[3-(piperizin-1-yl)propyloxy]phenyl]phenyl]-1,3,4-oxadiazol-2-yl]benzoate (1.13 IN sodium hydroxide aqueous solution (3.5 ml), 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)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 6) 1.56 (2H, 1.78 (4H, 2.19 (2H, 3.17 (6H, 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, 8.27 (2H, d, MASS :484 free Preparation 34 A solution of methyl pyrazole-4-carboxylate (10 g) in N,N-dimethylformamide (100 ml) was treated with potassium carbonate (10.95g) and l-bromodecane (19.31g) and the mixture was stirred for 16 hours at room temperature. Ethyl acetate was added and the solution was washed with water 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 l-decylpyrazole-4-carboxylate (19.4 g) as a white solid.
NMR (CDC13, 6) 0.84-0.90 (3H, 1.25 (14H, br s), 1.83-1.90 (2H, 3.82 (3H, 4.15 (2H, t, J=7Hz), 7.87 (1H, 7.90 (1H, s) MASS 267 (M Preparation 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 850C.
After cooling, the reaction was quenched with water and the 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 6) 2.14-2.26 (2H, 3.87 (3H, s), 4.12-4.29 (4H, 6.89-6.98 (3H, 7.08 (2H, d, J=8.8Hz), 7.25-7.33 (2H, 7.70 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.4Hz) MASS 363 (M Preparation 36 A solution of methyl 4-(4'-hydroxyphenyl)benzoate (5 g) in N,N-dimethylformamide (50 ml) was treated with potassium carbonate (6.06 g) and allyl bromide (2.46 ml), then heated at 600C 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 ether, then dried to give methyl (allyloxy)phenyl]benzoate (5.55 g) as a solid.
mp 148-149°C NMR (CDC1 3 5) 3.93 (3H, 4.29-4.61 (2H, 5.28- 5.49 (2H, 5.99-6.18 (1H, 7.00 (2H, d, J=8.8Hz), 7.56 (2H, d, J=8.8Hz), 7.61 (2H, d, WO 99/40108 PCT/JP99/00538 8.07 (2H, d, MASS :269 (M Preparation 37 A solution of 4-(4'-hydroxyphenyl)benzoic acid (4 g) and IN sodium hydroxide (41 ml) in dimethyl sulfoxide (40 ml) was heated for 30 minutes at 850C, 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, washed with water, and dried to give 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 3.34 (1H, br s), 4.04-4.10 (4H, 6.91-6.95 (3H, 7.05 (2H, d, J=7.9Hz), 7.24-7.30 (2H, 7.66-7.76 (4H, 7.98 (2H, d, J=7.8Hz) Preparation 38 A mixture of 4-[4'-(4-phenoxybutyloxy)phenyl]benzoic acid (5 l-hydroxybenzotriazole (2.24 g) and l-ethyl-3- (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 collected, washed with water, and dried to give N-(tertbutoxycarbonyl)-N'-[4-[4'-(4phenoxybutyloxy)phenyl]benzoyl]hydrazine (6 g) as a solid.
IR (KBr) 1650.8, 1492.6, 1290.1, 1249.6 cm-1 NMR (DMSO-d 6 6) 1.44 (9H, br 1.90 (4H, br s), 4.04-4.10 (4H, 6.88-6.96 (3H, 7.05 (2H, d, J=8.7Hz), 7.24-7.32 (2H, 7.69 (2H, d, J=8.8Hz), 7.75 (2H, d, J=8.5Hz), 7.92 (2H, d, J=8.2Hz), 8.91 (1H, 10.21 (1H, s) Preparation 39 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 hydrogen carbonate solution. The precipitate was collected, washed with water, and dried to give phenoxybutyloxy)phenyl]benzoylhydrazine (5 g).
IR (KBr) 3282.3, 1604.5 cm 1 NMR (DMSO-d 6 5) 1.89 (4H, br 4.04-4.09 (4H, m), 4.55 (2H, br), 6.83-6.96 (3H, 7.04 (2H, d, J=8.6Hz), 7.24-7.28 (2H, 7.64-7.72 (4H, m) 7.88 (2H, d, J=8.3Hz), 9.79 (1H, s) MASS :377 (M Preparation A solution of 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 (-100 ml) was added to the reaction mixture and the precipitate was collected, washed with water and dried to give N-[4-[4'-(8-methoxy-noctyloxy)phenyl]benzoyl]-N'-(4-methoxycarbonylbenzoyl)hydrazine (1.10 g).
IR (KBr) 3220.5, 2933.2, 2856.1, 1724.0, 1679.7, 1654.6 cm 1 NMR (DMSO-d 6 6) 1.20-1.60 (10H, 1.60-1.80 (2H, 3.21 (3H, 3.21-3.33 (2H, 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, d, J=8.3Hz), 8.04 (2H, d, J=8.5Hz), 8.11 (2H, d, 10.60 (1H, 10.70 (1H, s) MASS :533 (M Preparation 41 A suspension of N-(4-methoxybenzoyl)-N'-(4methoxycarbonylbenzoyl)hydrazine (10 g) and di-phosphorus WO 99/40108 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 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)-1,3,4thiadiazol-2-yl]benzoate (8.15 g).
IR (KBr) 2952.5, 2840.6, 1714.4, 1606.4, 1278.6, 1251.6 cm-1 NMR (CDC1 3 5) 3.89 (3H, 3.96 (3H, 7.01 (2H, d, J=8.9Hz), 7.97 (2H, d, J=8.9Hz), 8.07 (2H, d, J=8.7Hz), 8.16 (2H, d, J=8.7Hz) MASS :327 (M 4 +l) Preparation 42 To a solution of borontribromide (2.0M in dichloromethane, 103 ml) was added dropwise methyl 4-[5-(4-methoxyphenyl)- 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 dried under reduced pressure at 60 0 C to give 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 (6.56 that was used crude in the next reaction.
Preparation 43 To a suspension of a mixture of methyl hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and hydroxyphenyl)-1, 3 ,4-thiadiazol-2-yl]benzoic acid (600 mg), potassium carbonate (531 mg) and N,N-dimethylformamide (3 ml) was added 4-phenoxybutylbromide (880 mg) and the mixture was stirredat 100 0 C (bath temperature) for2 hours. After cooling, WO 99/40108 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 ml), ethanol (20 ml) and 10% sodium hydroxide aqueous solution (1.39 ml). The mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water (100 ml), 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 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]-1,3,4thiadiazol-2-yl]benzoic acid (685 mg).
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 hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (2.0 g), potassium carbonate (14.6 g) andN,N-dimethylformamide was added 1,5-dibromopentane (10 ml) and the mixture was stirred at 100 0 C (bath temperature) for 1.5 hours. 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 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 potassium carbonate (2.10g) andN,N-dimethylformamide ml), and the mixture was stirred at 1000C (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 with water. To this compound was added tetrahydrofuran WO 99/40108 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 collected by filtration, washed with water, dried under reduced pressure to give 4-[5-[4-(5-phenoxy-npentyloxy)phenyl]-l,3,4-thiadiazol-2-yl]benzoic acid (2.47 that was used crude in the next reaction.
MASS :461 (M+1) Preparation To a suspension of a mixture of methyl hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (3.12 g), potassium carbonate (22.07 g) and N,N-dimethylformamide ml) was added 1,5-dibromopentane (15 ml) and the mixture was stirred at 100 0 C (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 removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried to give a crude powder (3.71 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 reaction mixture was added sodium methoxide (28% in methanol) 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 acetonitrile and dried under reduced pressure to give 4- [5-[4-(5-methoxy-n-pentyloxy)phenyl]-l,3,4-thiadiazol-2yl]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, 1253.5 cm 1 WO 99/40108 PCT/JP99/00538 NMR (DMSO-d 6 1.3-1.7 (4H, 1.7-2.0 (2H, m), 3.23 (3H, 3.36 (2H, 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) MASS :399 (M +1) Preparation 46 To a solution of piperidine (2.98 g) and methyl 6chloronicotinate (5.00 g) in N,N-dimethylformamide (75ml) was added potassium carbonate (12.08 g) The mixture was stirred 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 as a white solid.
IR (KBr) 2941, 2850, 1701, 1608, 1552, 1508, 1435, 1415 cm-1 NMR (CDC1 3 5) 1.5-1.8 (6H, 3.6-3.7 (4H, m), 3.86 (3H, 6.57 (1H, d, J=9.1Hz), 7.98 (1H, dd, J=9.1 and 2.4Hz), 8.78 (1H, d, MASS :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 (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 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give 6-(1piperidyl)nicotinoylhydrazine (3.44 as a white solid.
IR (KBr) 3300, 2931, 2846, 1649, 1608, 1554, 1502, 1417, 1348, 1242 cm 1 NMR (CDC1 3 6) 1.5-1.8 (6H, 3.4-3.8 (6H, 6.61 WO 99/40108 PCT/JP99/00538 71 (1H, d, J=8.9Hz), 7.51 (1H, br 7.85 (1H, dd, and 2.5Hz), 8.54 (1H, d, MASS :221 Preparation 48 To a solution of N-[6-(l-piperidyl)nicotinoyl]-N'-(4methoxycarbonylbenzoyl)hydrazine (2.00 g) inpyridine was added phosphorus pentasulfide (1.74 The mixture was refluxed for 4 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water (150 ml) and the mixture was adjusted to pH 11 with lN 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 [6-(1-piperidyl)pyridin-3-yl]-1,3,4-thiadiazol-2yl]benzoate (1.59 as a yellow solid.
IR (KBr) 2933, 2848, 1720, 1604, 1433, 1279, 1109 cm-1 NMR (CDC1 3 6) 1.6-1.8 (6H, 3.6-3.8 (4H, 3.96 (3H, 6.73 (1H, d, J=9.1Hz), 8.06 (2H, d, J=8.7Hz), 8.14 (1H, dd, J=9.2 and2.9Hz), 8.16 (2H, d, J=8.6Hz), 8.70 (1H, d, J=2.2Hz) MASS :381 Preparation 49 To a refluxing suspension of methyl piperidyl)pyridin-5-yl]-1,3,4-thiadiazol-2-yl]benzoate (1.50 g) in a mixed solvent of tetrahydrofuran (75 ml) and ethanol (15 ml) was added dropwise 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 was added water (100 ml) and the pH was adjusted to 1 with 1N hydrochloric acid (15 ml). The mixture was stirred for minutes at ambient temperature and the resulting precipitates were filtered, washed with water and dried to give [6-(l-piperidyl)pyridin-3-yl]-1,3,4-thiadiazol-2yl]benzoic acid hydrochloride (1.36 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, 3.6-3.7 (4H, m), 6.99 (1H, d, J=9.1Hz), 8.08 (1H, dd, J=9.1 8.11 (4H, 8.71 (1H, d, J=2.4Hz) MASS :367 (free) Preparation 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 methylene chloride (60 ml) was added triethylamine (0.57 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.43 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 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 piperidyl)pyridin-3-yl]-1,3,4-thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester (1.18 as a yellow solid.
IR (KBr) 2931, 2854, 1778, 1600, 1547, 1512, 1431, 1358, 1242, 993 cm i NMR (CDC1 3 5) 1.6-1.8 (6H, 3.6-3.8 (4H, 6.75 (1H, d, J=9.1Hz), 7.4-7.7 (3H, 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 :484 (M +1) Preparation 51 A solution of methyl 4- (4'-hydroxyphenyl)benzoate (2.02 n-butylbromide (3 ml) and sodium carbonate (3.6 g) in N,N-dimethylformamide was stirred for 17 hours at 80°C. The reaction mixture was cooled to room temperature and 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- (4'-butyloxyphenyl)benzoate (2.45 g).
IR (KBr) :2956, 2935, 2873, 1722 cm- 1 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 (2H, di, J=8.8Hz), 7.78 (2H, d, J=8.SHz), 8.00 (2H, d, MASS :285 The following compounds [Preparations 52 to -UA] were obtained in a manner similar to that of Preparation 51.
Prep2aration 52 Methyl 4- (4 '-n-pent yloxyphenyl) benzoate IR (KBr) :2958, 2935, 2866, 1722 cm'1 NMR (DMSO-dr 6 6) :0.91 (3H, t, J=7.OHz), 1.39 (4H, in), 1.74 (2H, in), 3.87 (3H, 4.02 (2H, t, J=6.4Hz), 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, MASS z) 2 99 (M Preparation 53 Methyl 4- (4 '-n-hexyloxyphenyl) benzo ate IR (KBr) :2954, 2933, 2866, 1724 cm- 1 MR (DMSO-d 6 65) :0.87 in), 1.20-1.87 (8H, in), 3.87 (3H, 4.02 (2H, in), 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) MASS 313 Preparation 54 Methyl 4- (4 t -n-heptyloxyphenyl)benzoate IR (KBr) :2956, 2931, 2856, 1724 cmrC1 NNR (DmSO-d 6 6) :0.86 (3H, in), 1.20-1.80 (10H, in), 3.87 (3H, 4.05 (2H, in), 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 MASS :327 Preparation A solution of methyl bromopropoxy)phenyl]benzoate (1.5 potassium carbonate (1.2 g) and cis-2,6--dimethylmorpholine (990.6 mg) in N,Ndimethylformamide was stirred for 15 hours at room temperature, then diluted with ethyl acetate and washed with water dried over magnesium sulfate, evaporated, then purified by silica gel chromatography (20:1 dichioromethane-ethanol elution) to give methyl 6dimethylmorpholino)propoxylphenylllbenzoate (755 mg).
NMR (CDCl 3 6) :1.18 (6H, d, J=6.3Hz), 1.70-1.90 (2H, in), 2.00-2.14 (2H, in), 2.50-2.65 (2H, in), 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) MASS 384 (M The following compound was obtained in a manner similar to that of Prep~aration Preparation 56 Methyl 4- (piperizin-l-yl) propyloxy] phenyl] benzoate IR :2933, 2852, 2771, 1718 cm- 1 NMR (CDC1 3 6) 1.47 (2H, in), 1.64 (4H, in), 2.04 (2H, tt, J=6.3 and 6.3Hz), 2.51 (6H, in), 3.93 (3H, s), 4.07 (2H, t, J=6.3Hz), 6.98 (2H, d, J=8.8Hz), 7.56 (2H, d, J=8.8Hz), 7.61 (2H, di, J=8.6Hz), 8.07 (2H, d, J=8.6Hz) MASS (in/z) :354 (M Preparation 57 A mixture of N-[4-(4'-allyloxyphenyl)benzoyl]-N'-(4iethoxycarbonylbenzoyl)hydrazine (1.5 g) and phosphorus WO 99/40108 PCT/JP99/00538 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 50 0 C under vacuum to give methyl 4-[5-[4'-[4"-allyloxyphenyljphenyl]-1,3,4oxadiazol-2--yllbenzoate as a solid.
IP. (KBr) :1720.2, 1650.8, 1284.4, 1255.4 cm- 1 NI4R (DMSO-d 6 6) :3.98 (3H, 4.61 (2H, d, J=5.3Hz), 5.30-5.50 (2H, mn), 6.03-6.17 (1H, mn), 7.04 (2H, d, J=8.8Hz), 7.61 (2H1, d, J=8.8Hz), 7.74 (2H, d, 8.20 (2H, d, J=8.5Hz), 8.23 (4H, s) MASS :413 The following compounds [Preparations 58 to 68] were obtained in a manner similar to that of Preparation 57.
Preparation 58 Methyl 4-[5-[4'-(4"-methoxyphenyl)phenyl]-1,3,4oxadiazol-2-yl] benzoate IR (KBr) :1716 c- NMR (CDCl 3 6) :3.88 (3H, 3.98 (3H, 7.02 (2H, d, J=8.8Hz), 7.61 (2H1, d, J=8.8Hz) MASS 387 Preparation 59 Methyl 4- (4"-butyloxyphenyl) phenyl] -1,3,4oxadiazol-2-yl] benzoate IR (KBr) :2956, 2933, 2871, 1720 cmJ 1 NMR (CDCl 3 6) :1.00 (3H, t, J=7.3Hz), 1.54 (2H1, qt, J=7.3 and 7.0Hz), 1.82 (21H, tt, J=7.0 and 3.98 (3H, 4.03 (2H, t, J=7.OHz), 7.00 (2H, d, J=8.7Hz), 7.60 (2H, d, J=8.7Hz), 7.73 (2H, d, J=8.4Hz), 8.22 (6H, m) MASS 429 Preparation Methyl 4-[5-[414"-n-peltyloxyphenyl)phenyl]-1,3,4oxadiazol-2-yl] benzoate IR (KBr) :2956, 2931, 2870, 1720 cm- 1 WO 99/40108 PCT/JP99/00538 76 NIAR (CDCl 3 6) 0. 995 (3H, t, J=7. OHz) 1 .43 (4H, in), 1 .83 (2H, tt, J=7 .OHz) 3. 98 (3H, s) 4 .02 (2H, t, J=7.OHz), 7.00 (2H, d, J=8.7Hz), 7.60 (2H, d, J=8.7Hz), 7.73 (2H, d, JP=8.4Hz), 8.23 (2H, mn) MASS 443 (M Preparation 61 Methyl 4-[5-[4'-(4"-n-hexyloxyphenyl)phenyl]-1,3,4oxadiazol-2-yl] benzoate IR (KBr) :2954, 2933, 2870, 1722 cmf 1 MR (CDCl 3 5) :0.92 (3H, t, J=6.7Hz), 1.39 (6H, in), 1.82 (2H, tt, J=6.9Hz), 3.98 (3H, 4.02 (2H, t, 7.00 (2H, d, J=8.6Hz), 7.60 (2H, d, J=8.6Hz), 7.73 (2H, di, J=8.3Hz), 8.22 (6H, mn) MASS (in/z) 457 Prep~aration 62 Methyl (4"-n-heptyloxyphenyl)phenyl]-1,3,4oxadiazol-2-yl] benzoate IR (KBr) :2954, 2931, 2856, 1722 cmf 1 MR (CDC1 3 5) :0.90 (3H, br), 1.20-2.00 (10H, br), 3.98 O3H, 4.02 (2H, br), 7.00 d, J=7.6Hz), 7.59 (2H, d, J=7.6Hz), 7.73 (2H, di, J=6.8Hz), 8.20 (6H, in) MASS 471 Preparation 63 Methyl 4-[5--[4'-[4"l-[3-(piperizin-1yl)propyloxylphenyl]phenyl]-1,3,4-oxadiazol-2-yl]benzoate IR (KBr) :2931, 2852, 2804, 2769, 1720 cmJ' MR (CDC1 3 6) :1.51 (2H, mn), 1.74 (4H, in), 2.14 (2H, mn), 2. 64 (6H,in) 3. 98 (3H, s) 4. 10 (2H, t, J=6.2Hz) 7.00 (2H, di, J=8.8Hz), 7.60 (2H, di, J=8.7Hz), 7.73 (2H, di, J=8.2OHz), 8.20 (2H, d, J=8.5Hz), 8.23 (4H,
S)
MASS (in/z) 498 Preparation 64 Methyl 4-[5-(1-n-decylpyrazol-4-yl)-1,3,4-oxadiazol- WO 99/40108 PCT/JP99/00538 77 2-yl] benzoate NMR (CDCl 3 6) 0. 84-0. 91 (3H, mn), 1. 26-1. 32 (14H, mn), 1.80-2.00 (2H, mn), 3.97 (3H, 4.21 (2H, t, J=7.lHz), 7.26 (1H, 8.09 (1H, 8.26 (4H, s) MASS (in/z) 411 (Me) Preparation Methyl (3-phenoxypropyloxy)phenyllphenyl]-1,3,4-oxadiazol-2-yllbenzoate IR (KBr) 1718.3, 1600.6, 1490.7, 1280.5, 1245.8 cmJ 1 NMR (CDCl 3 6) :2.26-2.35 (2H, mn), 3.98 (3H, s), 4.16-4.27 (4H, in), 6.91-7.05 (5H, mn), 7.26-7.33 (2H, in), 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) MASS (in/z) 507 Preparation 66 Methyl 4-[5-[4'-[4"-(4-phenoxybutyloxy)phenyllphenyl]-1,3, 4-oxadiazol-2-yllbenzoate IR (KBr) :1720.2, 1602.6 cin' NMR (CDCl 3 6) 2. 02 (4H, br s) 3.93 (3H, s) 3. 97- 4. 06 (4H, mn), 6. 83-7. 04 (6H, mn), 7.26-7. 33 (1H, in), 7.60 (2H, d, J=8.7Hz), 7.89 (2H, d, J=8.7Hz), 8.18-8.23 (6H, mn) MASS (in/z) 521 (Mi) Preparation 67 Methyl 4- (8-iethoxy-n-octyloxy)phenyl]phenyl] 4-oxadiazol-2-yl]benzoate IR (KBr) :1720.2 cirJ 1 NMR (CDCl 3 6) :1.20-1.95 (12H, mn), 3.34 (3K, s), 3.38 (2H, t, J=7Hz), 3.98 (3K, 4.02 (2K, t, 7.00 (2K, d, J=8.7Hz), 7.59 (2K, d, J=8.7Hz), 7.73 (2H, d, J=8.5Hz), 8.19 (2K, d, 8.22 (4K, s) MASS (in/z) 515 (M Preiparation68 WO 99/40108 PCT/JP99/00538 78 Methyl 4-[5-[4'-[4"-[3-(2,6-dimethylmorphino)propyloxy]phenyl]phenyl]-1,3,4-oxadiazol-2-yl]benzoate NMR (CDC1 3 5) 1.26 (6H, d, J=6.3Hz), 2.32-2.60 (4H, 3.15-3.30 (2H, 3.43 (2H, d, J=11.lHz), 3.98 (3H, 4.10-4.20 (2H, 4.30-4.50 (2H, 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 528 (M The following compound was obtained in a manner similar to that of Preparation 9.
Preparation 69 Methyl 4-[5-(l-n-decylpyrazol-4-yl)-1,3,4-thiadiazol- 2-yl]benzoate NMR (DMSO-d 6 5) 0.84 (3H, br 1.23 (14H, br s), 1.70-1.90 (2H, 3.90 (3H, 4.15-4.23 (2H, m), 8.09 (1H, 8.13 (4H, 8.58 (1H, s) MASS 427 (M The following compound was obtained in a manner similar to that of Preparation 1.
Preparation Methyl 4-[4'-(3-bromopropyloxy)phenyl]benzoate NMR (DMSO-d 6 5) 2.22-2.32 (2H, 3.69 (2H, t, J=6.6Hz), 3.87 (3H, 4.15 (2H, t, J=6Hz), 7.08 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.7Hz), 7.79 (2H, 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 NMR (DMSO-d 6 5) 1.32 (6H, 1.71 (2H, 1.91 (2H, 4.45 (1H, 7.00 (2H, d, J=8.8Hz), 7.57 (2H, 7.84 (2H, d, J=8.7Hz), 9.27 (1H, 10.21 (1H, s) MASS 294 (M +l) The following compound was obtained in a manner similar WO 99/40108 PCT/JP99/00538 79 to that of Preparation 21.
Preparation 72 (4-cyclohexyloxyphenyl) 4-thiadiazole IR (KBr) 3272.6, 3114.5, 2937.1, 28-56.1, 1604.5, 1519.6, 1465.6 cm- 1 NMR (DMSO-d 6 5) :1.17-1.48 (6H, in), 1.73 (2H, mn), 1.92 (2H, in), 4.40 mn), 7.00 (2H, d, J=8.8Hz), 7.27 (2H, 7.64 (211, di, J=8.8Hz) MASS :276 The following compound was obtained in a manner similar to that of Preparation 23.
Preparation 73 4-12-(4-Cyclohexyloxyphenyl)iinidazo[2,1-bl thiadiazol-6-yllbenzoic acid ethyl ester trifluoroacetate IR (KBr) 2931.3, 2861.8, 1714.4, 1702.8, 1502.3, 1280.5, 1257.4 cmJ 1 MASS 448 The following compound was obtained in a manner similar to that of Preparation Preparation 74 4-[2-(4-Cyclohexyloxyphenyl)inidazo[2,1-b] thiadiazol-6-yl]benzoic acid IR (KBr) 2931.3, 1679.7, 1606.4, 1473.3, 1421.3, 1290.1, 1249.6 cirJ 1 NMR (DMSO-d 6 :1.43 (6H1, mn), 1.74 (2H, in), 1.94 (211, 4.50 (1H, mn), 7.14 (2H1, di, J=8.8Hz), 7.88 (2H, d, J=8.8Hz), 8.00 (4H, 8.86 (1H1, s) MASS :420 (M The following compounds [Preparations 75 to BA.] were obtained in a manner similar to that of Preparation Preparation 4- (4'-Methoxyphenyl) benzoylhydrazine IR (KBr) :3292, 3205, 1655, 1622 cirC 1 MR (CDCl 3 5) :1.59 (2H1, br), 3.86 (3H, 6.99 (2H1, d, J=7.9Hz), 7.38 (1H, br), 7.55 (2H, di, WO 99/40108 PCT/JP99/00538 J=7.9Hz), 7.62 (2H, d. J=7.3Hz), 7.79 (2H, d, J=7. .3Hz) MASS 243 Preparation 76 4- (4 '-Butyloxyphenyl) benzoylhydrazine IR (KBr) 3340, 3277, 3194, 2956, 2918, 2870, 1655, 1610 cnJ 1 MR (CDC1 3 6) :0.99 (3H, t, J=7.3Hz), 1.53 (4H, mn), 1. 80 (2H, tt, J=6. 4and 6. 4Hz) 4. 02 (2H, t, J=6. 4Hz) 6.98 (2H, d, J=8.8Hz), 7.38 (1H, 7.54 (2H, di, J=8.8Hz), 7.62 (2H, di, J=8.4Hz), 7.79 (211, di, J=8. 4Hz) MASS 285 (M+1) Prep~aration 77 4- -n-Pentyloxyphenyl) benzoylhydrazine IR (KBr) 3288, 3205, 3059, 2958, 2937, 2868, 1655, 1622, 1601 cm- 1 MR (CDC1 3 6) :0.94 (3H, t, J=6.8Hz), 1.44 (4H, mn), 1.60 (2H, br), 1.82 (2H, in), 4.00 (2H, t, J=6.8Hz), 6.98 (2H, t, J=8.5Hz), 7.38 (1H, br), 7.54 (2H, di, 7.62 (2H, d, J=8.lHz), 7.79 (2H, di, J=8.lHz) MASS 299 Preparation 78 4- (4 '-n-Hexyloxyphenyl) benzoylhydrazine IR (KBr) 3288, 3207, 3057, 2954, 2935, 2868, 1655, 1626, 1606 cm- 1 MR (CDC1 3 6) :0.91 (3H, in), 1.36 (6H, mn), 1.81 (2H, mn), 4.01 (2H, mn), 6.98 (2H, di, J=8.OHz), 7.20 (1H, br), 7.54 (2H, di, J=8.OHz), 7.62 (2H, di, J=7.9Hz), 7.78 (2H, di, J=7.9Hz) MASS 313 (M Preparation 79 4- -n-Heptyloxyphenyl)benzoylhydrazine IR (KBr) :3286, 3205, 3061, 2956, 2931, 2856, 1654, WO 99/40108 PCT/JP99/00538 81 1623, 1608 crn- NM (CDC1 3 6) 0.90 (3H, 1.32 (8K, 1.81 (2H, 4.00 (2K, 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), 7.77 (2H, d, J=8.4Hz) MASS 327 (M+1) Preparation 4-[4'-[3-(Piperazin-1-yl)propyloxy]phenyl]benzoylhydrazine IR (Kr) 3275, 3105, 3041, 2956, 2933, 2870, 2852, 2814, 2767, 1643 cm-i NMR (CDC1 3 6) 1.47 (2K, 1.63 (4H, 2.03 (2H, tt, J=6.3Hz), 2.50 (6H, 4.06 (2H, t, J=6.3Hz), 6.98 (2H, d, J=8.8Hz), 7.41 (1H, 7.54 (2H, d, J=8.8Hz), 7.62 (2H, d, J=8.SHz), 7.79 (2H, d, MASS 354 (14+1) Preparation 81 1-n-Decyl-4-pyrazolylcarbonylhydrazine NvR (DMSO-d 6 6) 0.82-0.95 (3H, 1.22 (14K, br s), 1.62-1.81 (2H, 4.08 (2H, t, J=6.9Hz), 4.29 (2H, d, J=4Hz), 7.82 (1H, 8.12 (1H, 9.28 (1H, br
S)
MASS 267 Preparation 82 4-[4'-(3-Phenoxypropyloxy)phenyl]benzoylhydrazine NMR (DMSO-d 6 6) 2.16-2.26 (2H, 4.11-4.23 (4H, 4.54 (2H, 6.89-6.98 (3K, 7.06 (2K, d, J=8.8Hz), 7.25-7.33 (2H, 7.67 (2K, d, J=8.7Hz), 7.70 (2H, d, J=8.4Hz), 7.89 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS 363 Preparation 83 4-[4'-Allyloxyphenyllbenzoylhydrazine NNR (DMSO-d 6 6) 4.51 (2K, 4.60-4.65 (2K, i), WO 99/40108 PCT/JP99/00538 82 5.25-5.47 (2H, 5.98-6.17 (1H, 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 269 Preparation 84 4-[4'-[3-(2,6-Dimethylmorpholino)propyloxylphenyl]benzoylhydrazine NMR (DMSO-d 6 6) 1.04 (6H, d, J=6.3Hz), 1.58 (2H, t, J=l0.6Hz), 1.86-1.92 (2H, 2.40 (2H, t, J=7Hz), 2.75 (2H, d, J=l0.2Hz), 3.51-3.58 (2H, 4.05 (2H, t, J=6.2Hz), 4.50 (2H, 7.02 (2H, d, J=B.8Hz), 7.64-7.71 (4H, 7.88 (2H, d, J=B.4Hz), 9.79 (1H, s) MASS 384 The following compounds [Preparations 85 to 2-6 were obtained in a manner similar to that of Preparation 7.
Preparation 1-[4-(4'-Methoxyphenyl)benzoyl]-2-(4-iethoxycarbonylbenzoyl)hydrazine IR (KBr) 3228, 2956, 2840, 1720, 1680, 1655 cm-i NMR (DMSO-d 6 6) 3.82 (3H, 3.90 (3H, 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), 10.72 (1H, s) MASS 405 (M+1) Preparation 86 1-[4-(4'-Butyloxyphenyl)benzoyl)-2-(4iethoxycarbonylbenzoyl)hydrazine IR (KBr) 3242, 3088, 3028, 2956, 2933, 2872, 1724, 1682, 1655, 1605 cm 1 NMR (DMSO-d 6 6) 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, 4.03 (2H, t, J=6.4Hz), 7.05 (2H, d, 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, 10.72 (1H, s) MASS 447 (M+1) Preparation 87 1-[4-(4'-Pentyloxyphenyl)benzoyl]-2-(4methoxycarbonylbenzoyl)hydrazine IR (KBr) 3226, 3030, 2958, 2931, 2870, 1724, 1680, 1655, 1605 cm- 1 NMR (DMSO-d 6 6) 0.91 (3H, t, J=6.7Hz), 1.40 (4H, m), 1.74 (2H, 3.90 (3H, 4.03 (2H, t, J=6.SHz), 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), 10.72 (1H, s) MASS 461 (M+1) Preparation 88 1-[4-(4'-n-Hexyloxyphenyl)benzayl]-2-(4methoxycarbonylbenzoyl)hydrazine IR (KBr) 3242, 3219, 3091, 3028, 2956, 2933, 2866, 1724, 1680, 1655, 1605 cm- 1 NMR (DMSO-d 6 6) 0.89 (3H, t, J=6.2Hz), 1.35 (6H, m), 1.74 (2H, 3.90 (3H, 4.03 (2H, t, J=6.9Hz), 7.05 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.7Hz), 7.79 (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 (in/z) 475 (M+1) Preparation 89 1-[4-(4'-n-Heptyloxyphenyl)benzoyl]-2-(4iethoxycarbonylbenzoyl)hydrazine IR (KBr) 3219, 3091, 3029, 2956, 2931, 2856, 1722, 1679, 1652, 1604 cm- 1 NMR (DMSO-d 6 0.88 (3H, br), 1.29 (8H, br), 1.75 (2H, br), 3.90 (3H, 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, di, J=8.8Hz), 8.45 (2H, br) MASS 489 (M Preparation (Piperidin-1-yl)propyloxylphenyl]benzoyl] (4-methoxycarbonylbenzoyl) hydrazine IR (KBr) 3061, 3026, 2933, 2852, 2805, 2771, 2391, 1724 cmJ' NNR (DMSO-d 6 6) :1.49 (6H, in), 1.88 (2H, tt, J=6.2 and 6.2Hz), 2.36 (6H, in), 3.90 (OH, 4.06 (2H, t, J=6.2Hz), 7.05 (2H, d, J=8.7Hz), 7.70 (2H, di, J=8.7Hz), 7.78 (2H, di, J=8.4Hz), 8.00 (2H, d, J=8.4Hz), 8.05 (2H, di, J=8.5Hz), 8.11 (2H, di, 10.6 (1H, s) MASS (in/z) 516 (M Preparation 91 N- (4-Methoxycarbonylbenzoyl) (-n-decyl-4pyrazolylcarbonyl) hydrazine NNR (DMSO-d 6 5) :0.82-0.89 (3H, mn), 1. 24 (14H, br s) 1. 70-1. 90 (2H, in), 3. 90 (3H, s) 4. 14 (2H, t, J=7Hz) 7.95 (1H, 8.02 (2H, di, J=8.5Hz), 8.10 (2H, di, 8.28 10.18 (1H, 10.50 (1H,
S)
MASS (in/z) 429 Prep~aration 92 (3-Phenoxypropyloxy)phenylllbenzoyl]-N'-(4inethoxycarbonylbenzoyl) hydra zine IR (KBr) 3210.9, 1724.0, 1650.8, 1602.6, 1560.1, 1523.5, 1502.3, 1469.5, 1432.9, 1284.4, 1247.7 cmJ 1 NMR (DMSO-d 6 65) :2.18-2.24 (2H, in), 3.90 (3H, s), 4.13-4.21 (4H, in), 6.95-6.99 (3H, in), 7.09 (2H, di, J=7.9Hz), 7.25-7.33 (2H, in), 7.69-7.81 (4H, in), 7.98-8.09 (6H, in), 10.61 (1H, 10.73 (1H, s) MASS (in/z) :525 WO 99/40108 PCT/JP99/00538 Prepara tion 93 N- (4 '-Allyloxyphenyl)benzoyl] (4inethoxycarbonylbenzoyl) hycirazine IR (KBr) :3228.3, 3023.8, 1724.0, 1679.7, 1654.6, 1604.5, 1554.3, 1513.8, 1492.6, 1434.8 cm- 1 MR (DMSO-d 6 5) 90 (3H, s) 4. 64 (2H, d, J=5. lHz) 5.26-5.47 (2H, mn), 5.98-6.17 (1H, mn), 7.08 (2H, d, J=8.7Hz), 7.72 (2H, d, J=8.7Hz), 7.80 (2H, di, J=8.4Kz), 8.00 d, J=8.5Kz), 8.05 (2H, d, J=8.6Hz), 8.11 (2H, di, J=8.6Hz), 10.60 (1H, s), 10.72 (1H, s) MASS (in/z) 431 Preparation 94 N- (4-Phenoxybutyloxy)phenyl]benzoyl] (4iethoxycarbonylbenzoyl) hydrazine IR (KBr) 3228.3, 1724.0, 1679.7, 1654.6, 1602.6 crtf 1 NMR (DMSO-d 6 6) :1.90 (4H, br 3.90 (3H, s), 4. 05-4.11 (4H, mn), 6. 88-6.96 (3H, mn), 7. 05-7.09 (2H, mn), 7.25-7.28 (2H, m) 7. 69-8. 09 (10H,im) 10. 60 (1H, 10.72 (1H, s) Prep~aration N- 6-Diinethylmorpholino) propyloxy] phenyllbenzoyl] (4-methoxycarbonyibenzoyi) hydrazine IR (KBr) :1720.2, 1681.6, 1645.0, 1604.5 cmrJ 1 NMR (DMSO-d 6 65) :1.05 (6H, d, J=6.3Kz), 1.53-1.64 (2H, in), 1.87-1.93 (2H, mn), 2.41 (2H, t, J=7.lHz), 2.76 (2H, d, J=10.4Hz), 3.52-3.59 (2H, in), 3.90 (3H, 4.00-4.10 (2H, in), 7.05 (2H, d, J=8.7Kz), 7.71 (2H, d, J=8.7Hz), 7.79 (2H, di, J=8.4Hz), 8.00 (2K, di, J=8. 6Hz) 8. 02-8. 13 (4K, in), 10. 60 (1H, s) 10. 72 (1H, s) MASS (in/z) 546 Preparation 96 (1-Piperidyl)nicotinoyl]-N'- (4-iethoxycarbonyl- 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 6) 1.4-1.7 (6H, 3.6-3.7 (4H, m), 3.90 (3H, 6.92 (1H, d, J=9.0Hz), 7.9-8.2 8.65 (1H, 10.34 (1H, 10.62 (1H, s) MASS 383 (M +1) The following compounds [Preparations 97 to 108] were obtained in a manner similar to that of Preparation 11.
Preparation 97 4-[5-[4'-[4"-(8-Methoxy-n-octyloxy)phenyl]phenyl]- 1,3,4-oxadiazol-2-yl]benzoic acid NMR (DMSO-d 6 6) 1.20-1.60 (10H, 1.60-1.80 (2H, 3.21 (3H, 3.25-3.50 (3H, 3.90-4.10 (2H, 6.95-7.10 (2H, 7.50-7.80 (4H, 7.80-8.00 (2H, 8.10-8.30 (4H, m) MASS :501 (M Preparation 98 4-[5-[4'-(4"-Methoxyphenyl)phenyl]-1,3,4-oxadiazol-2yl]benzoic acid IR (KBr) 2960, 2904, 2839, 2675, 2543, 1684, 1604 cm 1 NMR (DMSO-d 6 6) 3.83 (3H, 7.08 (2H, d, 7.91 (2H, d, J=8.5Hz), 8.17 (2H, d, J=8.5Hz), 8.20 (2H, d, J=8.5Hz), 8.28 (2H, d, MASS :373 (M +1) Preparation 99 4-[5-[4'-(4"-Butyloxyphenyl)phenyl]-1,3,4-oxadiazol- 2-yl]benzoic acid IR (KBr) :2958, 2935, 2871, 1687 cm- 1 NMR (DMSO-d 6 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, 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 415 (M +1) Preparation 100 4-[5-[4'-(4"-Pentyloxyphenyl)phenyl]-1,3,4-oxadiazol- 2-yl]benzoic acid IR (KBr) 2958, 2933, 2865, 2673, 2546, 1685 cm 1 NMR (DMSO-d 6 6) 0.91 (3H, t, J=7.OHz), 1.40 (4H, 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, J=8.8Hz), 7.91 (2H, d, J=8.5Hz), 8.15 (2H, d, J=8.4Hz), 8.20 (2H, d, J=8.lHz), 8.27 (2H, d, MASS (in/z) 429 (M+1) Preparation 101 4-[5-[4'-(4"-Hexyloxyphenyl)phenyll-1,3,4-oxadiazol- 2-yl]benzoic acid IR (KBr) 2954, 2933, 2864, 2675, 2546, 1686 cm-l NMR (DMSO-d 6 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), 7.07 (2H, d, J=8.8Hz), 7.74 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.OHz), 8.16 (2H, d, J=8.6Hz), 8.20 (2H, d, J=8.OHz), 8.27 (2H, d, J=8.6Hz) MASS 433 (M +1) Preparation 102 4-[5-[4'-(4"-n-Heptyloxyphenyl)phenyl]-1,3,4oxadiazol-2-yl]benzoic acid IR (KBr) 2956, 2931, 2856, 2671, 2545, 1686 cm- 1 MASS 457 (14+1) Preparation 103 4-[5-(l-n-Decylpyrazol-4-yl)-1,3,4-oxadiazol-2-yl]benzoic acid NMR (DMSO-d 6 5) 0.75-0.95 (3H, 1.23 (14H, br s), 1.83 (2H, br 3.33 (1H, br s, CO 2 4.22 (2H, t, J=6.8Hz), 8.14 (1H, 8.17 (4H, 8.65 (1H,
S)
WO 99/40108 PCT/JP99/00538 88 MASS :397 (M Preparation 104 4-[5-[l-n-Decylpyrazol-4-yl]-1,3,4-thiadiazol-2-yl]benzoic acid NMR (DMSO-d 6 5) 0.80-0.90 (3H, 1.23 (14H, br s), 1.70-1.90 (2H, 3.34 (1H, br 4.19 (2H, t, J=6.9Hz), 8.08 (1H, 8.10 (4H, 8.58 (1H, s) Preparation 105 4- [5-[4'-[4"-(3-Phenoxypropyloxy)phenyl]phenyl]- 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 1 NMR (DMSO-d 6 5) 2.18-2.24 (2H, 4.13-4.25 (4H, 6.90-6.99 (3H, 7.11 (2H, d, J=8.8Hz), 7.26-7.33 (2H, 7.75 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.5Hz), 8.15-8.30 (6H, 13.20-13.60 (1H, br) MASS :493 Preparation 106 4- [5-[4'-[4"-Allyloxyphenyl]phenyl] -1,3,4-oxadiazol- 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 5) 4.65 (2H, d, J=5Hz), 5.27-5.48 (2H, 5.99-6.15 (1H, 7.10 (2H, d, J=8.7Hz), 7.75 (2H, d, J=8.6Hz), 7.91 (2H, d, J=8.3Hz), 8.15-8.30 (6H, 12.38 (1H, br s) MASS :399 (M Preparation 107 4-[5-[4'-[4"-(4-Phenoxybutyloxy)phenyl]phenyl]-1,3,4oxadiazol-2-yl]benzoic acid IR (KBr) 1733.7, 1697.1, 1650.8, 1602.6 cm 1 NMR (DMSO-d 6 5) 1.91 (4H, br 3.33 (1H, br s), 4.05-4.12 (4H, 6.88-6.96 (2H, 7.07-7.11 (2H, 7.25-7.28 (2H, 7.66-8.00 (5H, 8.14-8.36 (6H, m) WO 99/40108 PCT/JP99/00538 89 Prelparation 108 4- 6-Dimethylmorpholino) propyloxy] phenyllphenylll-1,3, 4-oxadiazol-2-yllbenzoic acid MASS :514 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-2yllbenzoic acid benzotriazol-1-yl ester IR (KBr) :1782 c- NMR (CDCl 3 5) :3.89 (3H, 7.03 (2H, d, J=8.7Hz), 7.53 (3H, in), 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, J=8.7Hz) MASS 490 Prep~aration 110 4-[5-[4'-(4"-Butyloxyphenyl)phenylll-1,3,4-oxadiazol- 2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) :2956, 2933, 2872, 1776 cmJ 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, in), 7.61 (2H, d, J=8.7Hz), 7.76 (2H, 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 532 Preparation 111 4-[5-[4'-(4"1-n-Pentyloxyphenyl)phenyl]-1,3,4oxadiazol-2-yl]benzoic acid benzotriazol-1-yl ester IR (KBr) :2956, 2935, 2868, 1779 cm- 1 NMR (CDCl 3 5) :0.95 O3H, t, J=6.9Hz), 1.44 (4H, in), 1.77 (2H, in), 4.03 (2H, t, J=6.5Hz), 7.02 (2H, d, J=8.7Hz), 7.45-7.57 (3H, in), 7.60 (2H, d, J=8.7Hz), WO 99/40108 PCT/JP99/00538 7.75 (2H, di, J=8.4Hz), 8.14 (1H, di, J=8.2Hz), 8.22 (2H, di, J=8.4Hz), 8.22 (2H, d, J=8.4Hz), 8.40 (2H, di, J=8.7Hz), 8.47 d, J=8.7Hz) MASS 546 Preparation 112 4-[5-[4'-(4"-n-Hexyloxyphenyl)pheriyl]-1,3,4oxadiazol-2-yllbenzoic acid benzotriazol-1-yl ester IR (KBr) :2953, 2931, 2866, 1776 cm'1 NNR (CDC1 3 6) :0.92 (3H, t, J=6.7Hz), 1.36-1.49 (6H, in), 1.82 (2H, in), 4.03 (2H, t, J=6.5Hz), 7.02 (2H, J=8.8Hz), 7.45-7.57 (3H, in), 7.61 (2H, di, J=8.8Hz), 7.76 (2H, di, J=8.4Hz), 8.14 (2H, di, J=8.2Hz), 8.22 d, J=8.4Hz), 8.41 (2H, d, J=8.8Hz), 8.48 (2H, di, J=8.8Hz) MASS (in/z) 560 Preparation 113 4-ES- (4"-n-Heptyloxyphenyl)phenyl]l ,3,4oxaciiazol-2-yllbenzoic acid benzotriazol-1-yl ester IR (KBr) :2954, 2929, 2856, 1776 cmC' NMR (CDC1 3 5) :0.91 (3H, in), 1.34 (8H, mn), 1.75 (2H, in), 4.03 (2H, t, J=6.5Hz), 7.02 (2H, t, J=8.7Hz), 7.47-7.57 (3H. in), 7.61 d, J=8.7Hz), 7.76 (2H, di, J=8.3Hz), 8.14 (1H, di, J=8.2Hz), 8.22 (2H, di, J=8.3Hz), 8.41 (2H, di, J=8.SHz), 8.48 (2H, di, MASS (in/z) 574 Preparation 114 4-15- (1-n-Decylpyrazol-4-yl) 4-oxadiazol-2-yl] benzoic acid benzotriazol-1-yl ester IR (KBr) :1783.8, 1623.8, 1234.2, 989.3 crEJ' NNR (CDC1 3 6) :0.84-0.91 (3H, in), 1.26-1.34 (14H, in), 1.80-2.00 (2H, mn), 4.23 (2H, t, J=7.lHz), 7.44-7.63 (3H, in), 8.11-8.15 (3H, in), 8.35 (2H, di, J=8.7Hz), 8.45 (2H, di, J=8.7Hz) MASS (in/z) :514 (M WO 99/40108 PCT/JP99/00538 91 Preparation 115 4-[5-(l-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- 1 NMR (CDC1 3 5) 0.84-0.91 (3H, 1.26-1.34 (14H, m), 1.94 (2H, br 4.21 (2H, t, J=7.lHz), 7.43-7.63 (3H, 7.99 (1H, 8.09 (1H, 8.10-8.15 (1H, 8.22 (2H, d, J=8.5Hz), 8.40 (2H, d, MASS 530 (M Preparation 116 4-[5-[4'-[4"-(3-Phenoxypropyloxy)phenyl]phenyl]- 1,3,4-oxadiazol-2-yllbenzoic acid benzotriazol-1-yl ester IR (KBr) 1778.0, 1602.6, 1490.7, 1471.4, 1238.1 cmf 1 NMR (CDC1 3 5) 2.27-2.34 (2H, 4.16-4.26 (4H, m), 6.91-7.05 (5H, 7.26-7.33 (2H, 7.44-7.62 (SH, 7.74 (2H, d, J=7.9Hz), 8.13 (1H, d, 8.21 (2H, d, J=7.9Hz), 8.37-8.48 (4H, m) MASS 610 (M Preparation 117 4-[5-(4'-[4"-Allyloxyphenyl]phenyl]-1,3,4-oxadiazol- 2-yllbenzoic acid benzotriazol-1-yl ester IR (KBr) 1776.1, 1602.6, 1488.9, 1232.3 cmJ' NMR (CDC1 3 5) 4.61 (2H, d, J=5.2Nz), 5.30-5.50 (2H, 6.00-6.19 (1H, 7.04 (2H, d, J=8.7Hz), 7.44-7.63 (4H, 7.75 (2H, d, J=8.4Hz), 8.11-8.30 (4H, 8.38-8.49 (4H, m) MASS 516 Preparation 118 4-[5-[4'-[4"-(4-Phenoxybutyloxy)phenyl phenyl]-1,3,4oxadiazol-2-yllbenzoic acid benzotriazol-1-yl ester IR (KBr) 1776.1 cm-1 NMR (CDC1 3 5) 2.02 (4H, br 4.06-4.11 (4H, in), 6.83-7.04 (5N, 7.26-7.33 (1H, 7.48-7.63 (6H, 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 624 Preparation 119 (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-i NMR (CDC1 3 6) 1.30-1.70 (10H, 1.70-1.90 (2H, m), 3.34 (3H, 3.38 (2H, t, J=6.4Hz), 4.02 (2H, t, J=6.5Hz), 7.02 (2H, d, J=8.7Hz), 7.45-7.63 (5H, 7.76 (2H, d, J=8.5Hz), 8.12-8.31 (3H, 8.41 (2H, d, J=8.8Hz),. 8.48 (2H, d, J=8.8Hz) MASS 618 Preparation 120 4-15-[4'-(4-Phenoxybutyloxy)phenyl]-1,3,4-thiadiazol- 2-yl]benzoic acid benzotriazol-1-yl ester IR 3058.5, 2956.3, 2873.4, 1778.0, 1602.6, 1236.1 cm NMR (CDC1 3 6) 2.0-2.1 (4H, 4.0-4.2 (4H, m), 6.9-7.0 (3H, 7.03 (2H, d, J=8.8Hz), 7.3-7.4 (2H, m) 7.4-7.6 (3H, 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 (in/z) 564 (M+1) Preparation 121 4-[5-[4'-(5-Phenoxy-n-pentyloxy)phenyl]-1,3,4thiadiazol-2-yllbenzoic acid benzotriazol-1-yl ester IR (KBr) 2946.7, 2871.5, 1785.8, 1600.6, 1255.4, 1234.2 cm- 1 NMR (CDC1 3 5) 1.5-2.1 (6H, 3.9-4.2 (4H, i), 6.8-7.1 (5H, 7.2-7.4 (2H, 7.4-7.7 (3H, i), 7.98 (2H, d, J=8.8Hz), 8.13 (1H, d, J=8.2Hz), 8.25 (2H, d, J=8.6H), 8.41 (2H, d, J=8.6Hz) MASS (in/z) 578 Preparation 122 WO 99/40108 PCT/JP99/00538 93 4-[5-[4'-(5-Methoxy-n-pentyloxy)phenyl]-, 3,4thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester NMR (CDC1 3 6) 1.5-2.1 (6H, 3.54 (3H, 3.43 (2H, t, J=6.1Hz), 4.06 (2H, t, J=6.3Hz), 7.02 (2H, d, J=8.8Hz), 7.4-7.7 (3H, 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, MASS :516 (M +1) Preparation 123 4-Cyclohexyloxybenzoic acid benzotriazol-1-yl ester IR (KBr) 2939, 2854.1, 1776.1, 1602.6, 1508.1 cm-1 NMR (CDC1 3 6) 1.25-1.67 (6H, 1.85 (2H, 2.01 (2H, 4.43 (1H, 7.03 (2H, d, 7.38-7.54 (3H, 8.08 (1H, d, J=8.2Hz), 8.19 (2H, d, MASS :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 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)-3thiosemicarbazide (57 g).
Preparation 125 To a slurry of 1-(4-methoxybenzoyl)-3-thiosemicarbazide (57 g) in toluene (300 ml), was added methanesulfonic acid 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 sulfonate salt was filtered and dried. The salt was placed in water, and 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 (4-methoxyphenyl)-l,3,4-thiadiazole (31.1 g).
WO 99/40108 PCT/JP99/00538 94 IR (KBr) 3251, 3114.5, 1610.3, 1525 cm- 1 NMR (DMSO-d 6 5) 3.80 (3H, 7.00 (2H, d, 7.28 (2H, 7.69 (2H, d, MASS 208 Preparation 126 A mixture of 4-bromobenzenethiol (6 1,7dibromoheptane (16.37 and potassium carbonate (8.77 g) in dimethylformamide (30 ml) was stirred at room temperature for hours. The reaction mixture was pulverized with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-bromo-4-(7bromoheptylthio)benzene (7.62 g).
IR (KBr) 1465.6, 1089.6, 800.3 cm- 1 NMR (CDC1 3 5) 1.37-1.88 (10H, 2.89 (2H, t, J=7.2Hz), 3.40 (2H, t, J=6.8Hz), 7.14-7.21 (2H, 7.36-7.43 (2H, m) Preparation 127 To a solution of l-bromo-4-(7-bromoheptylthio)benzene 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 HC1 aq. and extracted with ethyl acetate. The organic layer was 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 nhexane/ethyl acetate (50:1) to give 1-bromo-4-(7methoxyheptylthio)benzene (3.59 g).
IR (KBr) 1471.4, 1118.5, 1093.4 cm- 1 NMR (CDC1 3 6) 1.30-1.67 (10H, 2.88 (2H, t, J=7.3Hz), 3.33 (3H, 3.36 (2H, t, J=6.2Hz), 7.13-7.20 (2H, 7.35-7.42 (2H, m) MASS 317.1 WO 99/40108 PCT/JP99/00538 Preparation 128 To a solution of 4-(4-chlorophenyl)-4-hydroxypiperidine g) in dichloromethane (50 ml) was added di-tert-butyl dicarbonate (5.7 After stirring for 5 hours at room 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 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-tertbutoxycarbonyl-4-(4-chlorophenyl)-4-hydroxypiperidine (7.58 g).
IR (Film) 2976, 2926, 1668 cm- 1 NMR (CDC1 3 5) 1.47 (9H, 1.6-1.8 (3H, 1.9-2.1 (2H, 3.1-3.3 (2H, 3.9-4.1 (2H, 7.2-7.5 (4H, m) APCI MS 212 (M+H)+-101 Preparation 129 To a solution of l-tert-butoxycarbonyl-4-(4chlorophenyl)-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 at room temperature and for 2 hours at 60 0 C. To the reaction mixture was added iodomethane (4.0ml) at 60°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 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 l-tert-butoxycarbonyl-4-(4chlorophenyl)-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, 1.7-2.1 (4H, 2.97 (3H, 3.0-3.3 (2H, 3.9-4.1 (2H, 7.2-7.4 (4H, m) APCI MS 226 (M+H)+-101 Preparation 130 To a solution of 2-indanol (4 g) and triethylamine (5.8 ml) in dichloromethane (40ml) was added dropwise with stirring methanesulfonylchloride (2.8 ml) in an ice-bath. The mixture was then stirred for 1.5 hours. The reaction mixture 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- 2-yl ester (6.29 g).
IR (KBr) 3029.6, 1328.7, 1162.9 cm- 1 NMR (CDC1 3 6) 3.02 (3H, 3.19-3.44 (4H, 5.48-5.58 (1H, 7.18-7.28 (4H, m) MASS(m/z) 119.2(M-OMs+1) Preparation 131 To a solution of 4-(5-amino-1,3,4-thiadiazol-2yl)benzoic acid methyl ester trifluoroacetic acid salt (8 g) in water was added lN sodium hydroxide and the mixture was adjusted to pH 8. The precipitate was collected by filtration to give 4-(5-amino-l,3,4-thiadiazol-2-yl)benzoic acid (5.05 g).
Preparation 132 A mixture of 1-(4-nitrophenyl)-lH-pyrazol-4-carboxylic acid methyl ester (19.44 Fe powder, NH 4 C1, methanol and
H
2 0 was heated for 30 minutes at 80 0 C and 3 hours at 100°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 l-(4-aminophenyl)-1Hpyrazol-4-carboxylic acid methyl ester (9.84 g).
WO 99/40108 PCT/JP99/00538 97 IR (KBr) 1701, 1521, 1248 cm- 1 NMR (CDC1 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) MASS 218(M++1) Preparation 133 Amixture of 1-(4-formylphenyl) -H-pyrazol-4-carboxylic acid methyl ester (1.00 methanol (10 ml) and tetrahydrofuran (25 ml) was treated with sodium borohydride at 0°C. 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)-lH-pyrazol- 4-carboxylic acid methyl ester (1.04 g).
IR (KBr) 1724, 1558, 1521, 1443, 1392, 1255 cm- 1 NMR (CDC1 3 6) 3.88 (3H, 4.76 (2H, 7.48 (2H, d, J=8.7Hz), 7.69 (2H, d, J=8.7Hz), 8.10 (1H, s), 8.41 (1H,s) MASS 233(M +1) Preparation 134 A solution of l-(4-formylphenyl)-lH-pyrazol-4carboxylic 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, 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 with lN HCI and the resulting precipitate was collected by filtration to give 1-(4-hydroxyphenyl)-1H-pyrazol-4carboxylic acid methyl ester (0.51 g).
IR (KBr) 1718, 1691, 1554, 1523, 1250 cm- 1 NMR (CDC1 3 5) 3.87 (3H, 6.92 (2H, d, J=9.0Hz), 7.55 (2H, d, J=9.0Hz), 8.07 (1H, 8.30 (1H,s) WO 99/40108 PCT/JP99/00538 98 MASS 219(M+1) Preparation 135 A solution of 4-(4-hydroxypiperidin-l-yl)benzoic acid ethyl ester (5.4 silver oxide (5.31 g) and 3bromocyclohexene (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 filtration and dried. The residue was purified by silica gel chromatography (3:2 hexane-ethyl acetate elution) to give 4-[4-(2-cyclohexenyloxy)piperidin-l-yl]benzoic acid ethyl ester (3.84 g).
NMR (CDC1 3 5) 1.36 (3H, t, J=7.1Hz), 1.40-2.15 3.00-3.20 (2H, 3.50-3.75 (3H, 3.90-4.05 (1H, 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++1) Preparation 136 To a solution of 4-[4-(2-cyclohexenyloxy)piperidin-lyl]benzoic acid ethyl ester (3.82 g) in methanol (80 ml) was added 10% palladium on carbon (1.0 and hydrogen gas at atmosphere pressure for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure to give 4- (4-cyclohexyloxypiperidin-lyl)benzoic acid ethyl ester (2.38 g).
NMR (CDC1 3 5) 1.10-1.32 (4H, 1.36 (3H, t, J=7.1Hz), 1.40-2.00 (9H, 2.90-3.15 (2H, 3.20-3.45 (1H, 3.50-3.75 (3H, 4.32 (2H, q, J=7.1Hz), 6.86 (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[2,1b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (1.0 g) in dichloromethane (10 ml) WO 99/40108 PCT/JP99/00538 99 was added borone tribromide (1.OM solution in 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 filtration and dried to give 4-[2-(4-hydroxyphenyl)imidazo- [1,3,4]thiadiazol-6-yl]benzoic acid (893 mg).
IR (KBr) 3209, 1689.3, 1604.5, 1484.9 cm- 1 NMR (DMSO-d 6 6) 6.97 (2H, d, J=8.5Hz), 7.81 (2H, d, 8.00 (4H, 8.84 (1H,s) MASS 338(M+H Preparation 138 To a solution of 5-(4-pentyloxyphenyl)-1,3,4thiadiazol-2-yl-amine (20 g) in pyridine (200 ml) was added 4-methoxycarbonylbenzoylchloride (15 g) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried to give pentyloxyphenyl)-1,3,4-thiadiazol-2-yl]terephthalamic acid methyl ester (30.3 g).
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, 1.6-1.9 (2H, 3.90 (3H, 4.05 (2H, t, 7.09 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.8Hz), 8.12 (2H, d, J=8.4Hz), 8.25 (2H, d, J=8.4Hz), MASS 426(M+H Preparation 139 To a solution of N-tert-butoxycarbonyl-4-piperidinone (3.3 g) and l-(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 ml) and sodium cyanoborohydride (1 g) in several portions, the reaction mixture was stirred at ambient temperature for 2 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, and the filtrate was evaporated under reduced pressure and chromatographed (Silica gel 60 (Trademark prepared by Merck)) eluting with hexane/ethyl acetate to afford 1tert-butoxycarbonyl-4-[4-(4-cyclohexylphenyl)piperazin-1yl]piperidine (1.35 g).
NMR (CDC1 3 5) 1.3-1.6 (6H, 1.45 (9H, 1.6-2.0 (8H, 2.3-2.6 (2H, 2.6-3.0 (6H, 3.0-3.3 (4H, 4.17 (2H, d, J=13Hz), 6.86 (2H, d, J=8.7Hz), 7.11 (2H, d, J=8.7Hz) MASS 428(M+H Preparation 140 To a solution of cyclohexylphenyl)piperazin-1-yl]piperidin-1yl]benzonitrile (1.95 g) in acetic acid (10 ml) was added concentrated hydrogen chloride (20 ml) and the mixture was 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)piperazinl-yl]piperidin-l-yl]benzoic acid (959 mg).
IR (KBr) 3400, 2927, 2620, 2514, 1714, 1608, 1513, 1452, 1274, 1226, 1182, 1010 cm- 1 NMR (DMSO-d 6 6) 1.2-1.5 (5H, 1.6-1.9 (7H, 2.2 (2H, 2.4 (1H, 2.84 (2H, t, J=8.5Hz), 3.20 (4H, d, J=8.5Hz), 3.4-3.8 (5H, 4.08 (2H, d, J=12.5Hz), 6.93 (2H, d, J=8.8Hz), 7.03 (2H, d, J=8.8Hz), 7.12 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.8Hz), 11.13 (1H, s) MASS 448(M+H+) Preparation 141 Amixture of 1-(4-formylphenyl) -H-pyrazol-4-carboxylic acidmethyl ester 1-phenyl piperazine (4.21 acetic WO 99/40108 PCT/JP99/00538 101 acid (3.7ml), sodium cyanoborohydride (1.55 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 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 1-[4-(4-phenylpiperazin-l-yl-methyl)phenyl]-lH-pyrazol-4carboxylic acid methyl ester (3.90 g).
IR (KBr) 1702, 1600, 1560, 1271 cm- 1 NMR (DMSO-d 6 5) 2.4-2.6 (4H, 3.14 (3H, t, J=4.8Hz), 3.58 (2H, 3.81 (3H, 6.76 (1H, t, J=7.2Hz), 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, 9.11 (1H, s) MASS 377(M +1) Preparation 142 To an ice-cooled solution of methyl 4-(4hydroxyphenyl)benzoate (3.00 g) and Nphenyltrifluoromethanesulfonide (4.84 g) in tetrahydrofuran ml) was added triethylamine (1.98 ml), then the solution was stirred at this temperature for 1 hour and at ambient 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 a crude oil.
This oil was purified on a silica gel column chromatography eluting successively with the following solvents: (1)2.5% ethyl acetate in n-hexane, 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.
IR (KBr) 1713, 1691, 1606, 1522, 1495, 1420 cm- 1 WO 99/40108 PCT/JP99/00538 102 NMR (CDC1 3 5) 3.95 (3H, 7.31-7.46 (2H, 7.56-7.75 (4H, 8.08-8.20 (2H, m) MASS 361(M++1) Preparation 143 To a suspension of 4-piperazin-l-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 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-l-yl)benzoic acid ethyl ester (0.38 g).
IR (KBr) 1697.1, 1606.4, 1349.9, 1238.1 cm- 1 NMR (CDC1 3 6) 1.37 (3H, t, J=7.1Hz), 2.67-2.72 (4H, 2.88-3.40 (9H, 4.33 (2H, q, J=7.1Hz), 6.85-6.90 (2H, 7.12-7.23 (4H, 7.91-7.96 (2H, m) MASS 351.3(M+1) Preparation 144 To a solution of 2-amino-4'-bromoacetophenone hydrochloride (5.0 4-heptyloxybenzoic acid (4.72 g) and 1-hydroxybenzotriazole (2.7 g) in dichloromethane (50 ml) was added l-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, IN 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 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- NMR (CDC1 3 6) 0.80-1.10 (3H, 1.20-1.60 (8H, m), 1.75-1.95 (2H, 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 432, 434 Preparation 145 A solution of 2-(4-heptyloxyphenyl)-5-(4bromophenyl)thiazole (2.06 g) in dry tetrahydrofuran (60 ml) was cooled to -60 0 C, and a solution of n-butyllithium (1.56M in n-hexane, 4.05 ml) was added slowly to maintain the reaction 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) and 0.5Nhydrochloric acid (80ml), then extracted with dichloromethane (700 ml) The organic layer was washed 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 heptyloxyphenyl)thiazol-2-yl]benzoic acid (1.68 g).
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 6) 0.70-1.00 (3H, 1.10-1.60 (8H, m), 1.60-1.90 (2H, 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, J=8.7Hz), 8.00 (2H, d, J=8.2Hz), 8.39 (1H, s) APCI-MS 396 The following compound was obtained in a manner similar to that of Preparation 19.
Preparation 146 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 6) 0.91 (3H, t, J=6.9Hz), 1.28-1.52 (4H, 1.68-1.86 (2H, 3.91 (3H, 4.08 (2H, t, 7.14 (2H, d, J=8.8Hz), 7.98 (2H, d, J=8.8Hz), 8.01-8.24 (8H, 10.82 (2H, s) MASS 545 Preparation 147 To a solution of l-tert-butoxycarbonyl-4-(4chlorophenyl)-4-methoxypiperidine (0.72 g) in ethyl acetate ml) was added 4N HC1 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 was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 4-(4-chlorophenyl)-4-methoxypiperidine (0.39 g).
IR (Film) 2943, 2827, 1541 cm- 1 NMR (CDC1 3 5) 1.7-2.1 (4H, 2.17 (1H, 2.9-3.2 (7H, 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 dihydrochloride IR (KBr) 2940.9, 2508.9, 1498.4, 1249.6 cm- 1 NMR (CDC1 3 6) 1.51-1.83 (6H, 3.34 (3H, 3.40 (2H, t, J=6.2Hz), 3.93 (2H, t, J=6.4Hz), 4.00-4.40 (8H, 6.84-6.89 (2H, 7.36-7.40 (2H, m), 7.58-7.62 (2H, 7.87-7.92 (2H, 9.90-10.15 (1H, m) MASS 355 (M+1) Preparation 149 To a solution of 4-hydroxyacetophenone (10 g) and pyridinium hydrobromide perbromide (23.5 g) in acetic acid WO 99/40108 PCT/JP99/00538 105 ml) was added hydrogenbromide (30% in acetic acid solution) 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 dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to afford 2-bromo-l-(4-hydroxyphenyl)ethanone (1.72 g).
NMR (CDC1 3 6) 4.40 (2H, 5.78 (1H, 6.92 (2H, d, J=8.8Hz), 7.94 (2H, d, J=8.8Hz) MASS 217 The following compound was obtained in a manner similar to that of Preparation 149.
Preparation 150 2-Bromo-l-(4-pentyloxyphenyl)ethanone NMR (CDC1 3 6) 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, 6.94 (2H, d, J=9.0Hz), 7.96 (2H, d, MASS 287 (M+H Preparation 151 A solution of 1-(4-aminophenyl)-lH-pyrazol-4-carboxylic acid methyl ester (3.0 g) inN,N-dimethylformamide (30 ml) was treated with potassium carbonate (5.72 sodium iodide (4.14 g) and 1,5-dibromopentane, and the mixture was stirred for hours at room temperature and 6 hours at 80 0 C, during which period additional N,N-dimethylformamide (20 ml), dibromopentane (1.14 g) and potassium 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 was purified by silica gel chromatography (dichloromethane elution) to give 1-(4-piperidylphenyl)-lH-pyrazol-4carboxylic acid methyl ester (1.34 g).
IR (KBr) 1720, 1521, 1248 cm- 1 NMR (CDC13, 5) 1.5-1.8 (6H, 3.21 (4H, t, J=5.3Hz), 3.86 (3H, 6.98 (2H, d, J=9.1Hz), 7.53 (2H, d, WO 99/40108 PCT/JP99/00538 106 J=9.1Hz), 8.06 (1H, 8.29 (1H, s) MASS 286 The following compound was obtained in a manner similar to that of Preparation 151.
Preparation 152 1-(4-Pyrrolidinylphenyl)-lH-pyrazol-4-carboxylic acid methyl ester IR (KBr) 1720, 1541, 1525, 1246 cm- 1 NMR (CDC1 3 5) 2.0-2.1 (4H, 3.2-3.4 (4H, 3.86 (3H, 6.59 (2H, dd, J=6.9 and 2.1Hz), 7.49 (2H, dd, J=6.9 and 2.1Hz), 8.05 (1H, 8.25 (1H, s) MASS 294 (M'+23) Preparation 153 To a suspension of cyclohexane-l-4-dicarboxylic acid 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 (1.78 g).
NMR (CDC1 3 5) 1.38-1.64 (4H, 2.09-2.32 (5H, m), 2.64-2.77 (1H, 3.68 (3H, s) Preparation 154 Thionyl chloride (8.47 ml) was added dropwise to methanol (54 ml) at 10 0 C. To the solution was added trans-1,4cyclohexane dicarboxylic acid (4 g) and the mixture was stirred for 24 hours at ambient temperature. The reaction mixture was evaporated under reduced pressure to give cyclohexane-1,4dicarboxylic acid dimethyl ester (4.68 g).
IR (KBr) 1729.8, 1195.6 cm- 1 NMR (CDC1 3 5) 1.34-2.15 (8H, 2.23-2.34 (2H, m), 3.67 (6H, s) MASS 201 (M+1) The following compounds [Preparations 155 to 1571] were obtained in a manner similar to that of Preparation 154.
WO 99/40108 PCT/JP99/00538 107 Preparation 155 acid dimethyl ester IR (KBr) :1722.1, 1261.2, 1101.2 cm- 1 NMR (CDC1 3 6) :2.57 (6H, 3.91 (6H1, 7.76 (2H, s) MASS :223 (M+1) Preparation 156 2,4-Hexendioic acid dimethyl ester IR (KBr) :1702.8, 1612.2, 1249.6 cm- 1 NMR (CDC1 3 6) 3.71 (6H, 6.49 (2H, dd, J=3.1 and 11.5Hz), 7.40 (2H, dd, J=3.1 and 11.5Hz) MASS :171 (M+1) Preparation 157 Naphthalene-1,4-dicarboxylic acid dimethyl ester NMR (CDC1 3 6) :4.03 (6H, s) 7. 65 (2H, q, J=3. 3Hz) 8. 09 (2H, 8.83 (2H, q, J=3.3Hz) MASS 245 (M+1) The following compounds [Preparations 158 to .L-.ZI were obtained in a manner similar to that of Preparation 153.
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, 7.73-7.87 (2H1, m) 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, 2.60 (3H, 3.93 (3H, 7.78 (1H, 8.03 (1H, s) Preparation 160 5-Chlorocarbonyl-2,4--pentenoic acid methyl ester IR (KBr) :1745.3, 1714.4, 1243.9 cm- 1 NMR (CDC 13, 6) 3. 70 (3H, s) 6. 29- 6. 64 (2H, m) 7.2 4 64 (2H, m) WO 99/40108 PCT/JP99/00538 108 Preparation 161 4-Chlorocarbonylnaphtalene-l-carboxylic acid methyl ester IR (KBr) :1762.6, 1724.0, 1257.4 cm- 1 NMYR (CDC1 3 6) :3.98 (3H, 7.68-7.77 (2H, in), 8.14 (2H, 8.66-8.82 in) Preparation 162 6-Chlorocarbonylnaphtalene-2-carboxylic acid methyl ester IR (KBr) :1743.3, 1714.4, 1290.1 cm-1 NMR (ODC1 3 6) 3.94 (3H, s) 8. 04-8. 08 (2H, in), 8.21-8.27 (2H, in), 8.68-8.71 (2H, mn) Preparation 163 To asolution of 4-piperidin-1-yl-benzonitrile (3 g) and thiosemicarbazide (1.8 g) in toluene (30 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred at 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-(4piperidin-1-yl-phenyl)-Ijl,3,4]thiadiazol-2-yl-amine (3.58 g).
IR (KBr) 2933, 2838, 1604, 1502, 1463, 138 6, 1349 1245, 1126, 1043, 821 cm- 1 NMR (DMSO-d 6 6) 1.57 (6H, mn), 3.24 (4H, in), 6.96 (2H, d, J=8.8Hz), 7.19 (211, 7.54 (2H, d, J=8.8Hz) MASS (in/z) 261 The following compounds (Preparations 164 to 169) were obtained in a manner similar to that of Preparation 163.
Preparation 164 5- (4-Morpholinylphenyl)- 4]thiadiazol-2-yl-amine IR (KBr) 3274, 3106, 1604, 1508, 1465, 1378, 1324, 1267, 1238, 1122 cm- 1 NNR (DMSO-d 6 6) 3.19 t, J=4.811z), 3.74 (411, t, J=4.8Hz), 7.00 (2H, d, J=8.8Hz), 7.22 (2H, 7.59 (2H, d, J=8.811z) WO 99/40108 PCT/JP99/00538 109 MASS :263 (M+H 4 Preparation 165 (cis-2, 6-Dimethylmorpholin-4-yl)phenylthiadiazol-2-yl-amine IR (KBr) :3272, 3106, 1608, 1525, 1469, 1376, 1346, 1245, 1176, 1145, 1081 cm- 1 NM'R (DMSO-d 6 5) :1.16 (6H, di, J=6.2Hz), 2.31 (2H, t, J=11. 5Hz) 3. 6-3. 8 (4H, in), 7. 00 (2H, d, J=8. 8Hz) 7.21 (2H, 7.58 (2H, d, J=8.8Hz) MASS :291 Preparation 166 (4-Thiomorpholinophenyl) 3, 4]thiadiazol-2-ylamine IR (KBr) :3340, 3270, 3129, 1604, 1506, 1467, 1384, 1295, 1230, 1195 cirC 1 NMR (DMSO-d 6 5) :2.64 (411, t, J=5.OHz), 3.66 (4H, t, 6.97 (2H, d, J=8.8Hz), 7.21 (2H, 7.57 (211, d, J=8.8Hz), MASS :279 Prelparation 167 (4-Ethylpiperazinyiphenyl) [1,3,4]thiadiazol-2yl- amine IR (KBr) :3278, 3120, 2967, 2829, 1685, 1608, 1517, 1467, 1388, 1240, 1203, 1130 cm- 1 NMR (DMSO-d 6 6) :1.04 (3H, t, J=7.2Hz), 2.41 (2H, q, J=7.2Hz), 2.51 (4H, mn), 3.23 (4H, mn), 6.99 (2H, d, J=8.8Hz), 7.21 (2H, 7.57 (2H, di, J=8.8Hz) MASS :290 Preparation 168 (4-Cyclohexylpiperazinylphenyl) thiadiazol-2-yl-amine IR (KBr) :3016, 2950, 2865, 1743, 1672, 1606, 1513, 1456, 1430, 1402, 1201, 1133 cm- 1 NNR (DMSO-d 6 5) :1.0-1.6 (SH, mn), 1.63 (1H, d, J=lOHz), 1.85 (2H, d, J1lOHz), 2. 09 (2H, d, J~10Hz), 2.8- WO 99/40108 PCT/JP99/00538 110 3.3 (5H, 3.55 (2H, 3.99 (2H, d, J=10Hz), 7.09 (2H, d, J=8.8Hz), 7.65 (2H, d, J=8.8Hz) MASS 344 (M+H Preparation 169 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 6) 3.88(3H, 7.19 (2H, 7.90 (2H, d, J=8.5Hz), 8.04 (2H, d, MASS 236 Preparation 170 To a mixture of 4-methoxycarbonylphenylboronic acid (2.01 g) and l-bromo-4-ethoxymethylbenzene (2.00 g) in a mixed solvent of ethylene glycol dimethyl ether (20ml) and 2Maqueous sodium carbonate solution (6 ml) was added tetrakis(triphenylphosphine)palladium (0.54 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 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 g) eluting successively with the following solvents: (l)n-hexane ethyl acetate=50:1, n-hexane ethyl acetate=10:l. The fractions containing the object compound were concentrated and dried to give methyl ethoxymethylphenyl)benzoate as a white solid (1.85 g).
NMR (CDC1 3 6) 1.27 (3H, t, J=7.0Hz), 3.58 (2H, q, 3.94 (3H, 4.56 (2H, 7.44 (2H, d, J=8.7Hz), 7.54-7.61 (4H, 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 NMR (CDC1 3 6) 3.41 (3H, 3.55-3.70 (4H, 3.94 WO 99/40108 PCT/JP99/00538 111 (3H, 4.63 (2H, 7.45 (2H, d, J=8.3Hz), 7.56-7.74 (4H, 8.07-8.20 (2H, m) MASS 301 Preparation 172 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 (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 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 (3.10 g) as a pale yellow oil.
NMR (DMSO-d 6 5) 3.25 (3H, 3.43-3.60 (2H, 4.46 (2H, 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.
Preparation 173 Ethyl 4-(4-propoxypiperidin-l-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, 1.80-1.98 (2H, m), 3.00-3.20 (2H, 3.39 (2H, t, J=6.5Hz), 3.41-3.76 (3H, 4.23 (2H, q, J=7.1Hz), 6.97 (2H, d, J=9.1Hz), 7.76 (2H, d, MASS 292 (M+1) Preparation 174 Ethyl 4-(4-benzyloxypiperidin-l-yl)benzoate NMR (DMSO-d 6 5) 1.28 (3H, t, J=7.1Hz), 1.45-1.66 (2H, 1.85-2.02 (2H, 3.00-3.21 (2H, 3.55-3.78 (3H, 4.23 (2H, q, J=7.1Hz), 4.55 (2H, 6.98 (2H, d, J=9.1Hz), 7.23-7.43 (5H, 7.76 (2H, d, MASS 340 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 NMR (DMSO-d 6 6) 0.85 (3H, 1.1-1.6 (10H, 3.44 (2H, t, J=6.4Hz), 3.81 (3H, 4.49 (2H, 7.45 (2H, d, J=8.5Hz), 7.91 (2H, d, J=8.5Hz), 8.15 (1H, 9.11 (1H, s) MASS 331 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 at ambient temperature for 4 hours. After concentration, to the residue was added ethyl acetate (50 ml) and n-hexane 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 column chromatography on silica gel (80 g) eluting with a mixed 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 (CDC1 3 6) 1.22-1.66 (6H, 1.72-1.90 (2H, m), 1.95-2.10 (2H, 3.93 (3H, 4.22-4.37 (1H, m), 6.89-7.03 (2H, 7.47-7.76 (4H, 8.00-8.13 (2H, m) MASS 311 The following compound was obtained in a manner similar to that of Preparation 176.
Preparation 177 4-Cyclohexyloxybenzoic acid methyl ester NMR (CDC1 3 6) 1.20-2.10 (10H, 3.88 (3H, s), 4.20-4.40 (1H, 6.85-6.95 (2H, 7.90-8.00 (2H, m) WO 99/40108 PCT/JP99/00538 113 APCI MASS (positive) 235.2 Preparation 178 To an ice-cooled solution of ethyl 4-(piperazin-lyl)benzoate (2.00 g) and 4-methylcyclohexanone (1.05 ml) in 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 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% gradient solution) to give ethyl 4-[4-(cis-4methylcyclohexyl)piperazin-l-yl]benzoate (0.80 g) as a pale green solid and ethyl 4-[4-(trans-4methylcyclohexyl)piperazin-l-yl]benzoate (0.64 g) as a pale green solid. Trans-product was confirmed by X-ray crystal analysis.
Ethyl 4-[4-(cis-4-methylcyclohexyl)piperazin-lyl]benzoate IR (KBr) 1697, 1608, 1520, 1446 cm- 1 NMR (DMSO-D 6 6) 0.89 (3H, d, J=6.8Hz), 1.28 (3H, t, J=7.1Hz), 1.23-1.52 (6H, 1.52-1.76 (3H, m), 2.07-2.25 (1H, 2.47-2.63 (4H, 3.20-3.40 (4H, 4.23 (2H, q, J=7.1Hz), 6.96 (2H, d, J=9.1Hz), 7.78 (2H, d, J=8.9Hz) MASS 331 Ethyl 4-[4-(trans-4-methylcyclohexyl)piperazin-lyl]benzoate IR (KBr) 1709, 1608, 1518, 1444 cmi NMR (DMSO-D 6 6) 0.85 (3H, d, J=6.8Hz), 0.80-1.02 (2H, 1.28 (3H, t, J=7.1Hz), 1.09-1.56 (3H, m), 1.56-1.88 (4H, 2.08-2.34 (1H, 2.50-2.67 (4H, WO 99/40108 PCT/JP99/00538 114 3.18-3.34 (4H, 4.23 (2H, q, J=7.1Hz), 6.95 (2H, d, J=9.1Hz), 7.77 (2H, d, J=8.9Hz) MASS 331 The following compound was obtained in a manner similar to that of Preparation 178.
Preparation 179 Ethyl 4-[4-(4,4-dimethylcyclohexyl)piperazin-1yl]benzoate NMR (CDC1 3 5) 0.91 (6H, 1.07-1.55 (6H, 1.36 (3H, t, J=7.1Hz),1.64-1.82 (2H, 2.10-2.30 (1H, 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 345 Preparation 180 To a mixture of cesium carbonate (1.90 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 (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 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-dimethylmorpholinophenyl)]benzoate (525 mg) as a pale yellow solid.
IR (KBr) 1720, 1603, 1497, 1446 cm- 1 NMR (CDC1 3 6) 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, 3.72-3.94 (2H, 3.93 (3H, 6.98 (2H, d, J=8.9Hz), 7.51-7.70 (4H, 8.02-8.14 (2H, m) WO 99/40108 PCT/JP99/00538 115 MASS 326 The following compound was obtained in a manner similar to that of Preparation 180.
Preparation 181 Methyl 4-[4-(4-cyclohexylpiperazin-lyl)phenyl]benzoate IR (KBr) 2929, 2852, 2829, 1714, 1603, 1529, 1498, 1439 cm- 1 NMR (CDC1 3 5) 1.00-1.41 (5H, 1.51-2.05 (5H, m), 2.24-2.43 (1H, 2.69-2.84 (4H, 3.22-3.36 (4H, 3.93 (3H, 7.00 (2H, d, J=8.9Hz), 7.48-7.68 (4H, 8.00-8.12 (2H, m) MASS 379 (M +1) Preparation 182 To a suspension of 2-amino-5-(4-methoxyphenyl)-1,3,4thiadiazole (7.2 g) in ethanol (50 ml) was added ethyl 4bromoacetylbenzoate (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 filtration and dried. To a suspension of the powder in xylene 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 4-[2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid ethyl ester trifluoroacetic acid salt (13.7 g).
IR (KBr) 2360.4, 1746.3, 1604.5, 1483.0 cm 1 MASS 380 The following compounds [Preparations 183 to 1901 were obtained in a manner similar to that of Preparation 182.
Preparation 183 4-[2-(4-Piperidin-l-yl-phenyl)imidazo[2,1b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt WO 99/40108 PCT/JP99/00538 116 IR (KBr) 2940, 2584, 2474, 1702, 1608, 1523, 1471, 1409, 1367, 1280 cm-1 MASS 433 ((M-TFA)+H Preparation 184 4-[2-(4-Morpholin-4-yl-phenyl)imidazo[2,1b][l,3,4]thiadiazol-6-yllbenzoic acid ethyl ester trifluoroacetic acid salt IR 2669, 1706, 1606, 1473, 1274, 1236, 1176, 1118, 1020, 929 cm- 1 MASS 435 ((M-TFA)+H Preparation 185 4-[2-(cis-2,6-Dimethylorpholin-4-ylphenyl)imidazo[2,1-b] [1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) 2979, 1710, 1606, 1473, 1371, 1278, 1241, 1176, 1106 cm- 1 MASS z) 463 (M-TFA) Preparation 186 4-[2-(4-Thiomorpholin-4-yl-phenyl)imidazo[2,1b][l,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) 2979, 1708, 1604, 1504, 1471, 1274, 1193, 1105 cm-l MASS 451 ((M-TFA)+H 4 Preparation 187 4-[2-[4-(4-Ethylpiperazin-1-yl)phenyl]imidazo[2,1b][1,3,4]thiadiazol-6-yllbenzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) 2983, 2931, 2674, 2605, 1702, 1606, 1471, 1405, 1282, 1241, 1201 cm- 1 NMR (DMSO-d 6 5) 1.23-1.38(6H, 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, 8.86 (1H, s) MASS 462 ((M-TFA)+H WO 99/40108 PCT/JP99/00538 117 Preparation 188 4-[2-[4-(4-Cyclohexylpiperazin-lyl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt IR (KBr) 2935, 2586, 1708, 1604, 1571, 1488, 1409, 1367, 1278, 1199, 1106 cm- 1 MASS 516 ((M-TFA)+H Preparation 189 4-[6-(4-Hydroxyphenyl)imidazo[2,1b][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, 7.72 (2H, d, 7.91 (2H, d, J=8.5Hz), 8.12 (4H, 8.61 (1H, s) MASS 352 ((M-TFA)+H Preparation 190 4-[6-(4-Pentyloxyphenyl)imidazo[2,1b][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester trifluoroacetic acid salt IR (KBr) 2952, 2869, 1720, 1612, 1494, 1471, 1436, 1405, 1280, 1251, 1182, 1110 cm- 1 MASS 422 ((M-TFA)+H Preparation 191 A solution of methyl 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 1Nhydrochloric 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 (0.5 ml) and refluxed for 4 hours. After cooling to room temperature, the reaction mixture was poured into cold water and the WO 99/40108 PCT/JP99/00538 118 resulting precipitate was collected by filtration, wash 'ed thoroughly with water and dried to give methyl methoxybutoxy)phenyllbenzoate (1.16 g) as a white solid.
IR (KBr) :2949, 2873, 1720, 1603, 1529, 1498, 1439 cm- 1 NMR (DMSO-d 6 6) :1.5S4-1.85 (4H, mn), 3.24 (3H, s) 3. 38 (2H, t, J=6.2Hz) 3. 87 (3H, s) 4. 04 (2H, t, J=6.l1Hz) 7.05 (2H, t, J=8.8Hz), 7.69 (2H, d, J=8.7Hz), 7.78 (2H1, d, J=8.4Hz), 8.00 (2H, d, J=8.4Hz) MASS :315 The following compounds [Preparations 192 to 194] were obtained in a manner similar to that of Prep~aration 191.
Preparation 192 Methyl 4- (3-methoxypropoxy)phenyllbenzoate IR (KBr) :2953, 2875, 1724, 1603, 1529, 1495, 1435crrC 1 NMR (DMSO-d 6 6) 96 (2H, in), 3. 26 (3H, s) 3. 49 (2H, t, J=6.3Hz), 3.87 (3H, 4.08 t, J=6.4Hz), 6. 98-7.14 (2H, in), 7. 64-7. 86 mn), 7. 96-8.10 (2H, in) MASS :301 Preparation 193 1-Bromo-4-ethoxymethylbenzene NNR (DMSO-d 6 6) :1.15 O3H, t, J=7.OHz), 3.47 (2H, q, 4.42 7.28 (2H, d, 7.46-7.61 (2H, in) Prep~aration 194 Methyl 4- (3-ethoxypropoxy)phenyl~benzoate NNR (DMSO-d 6 6) :1.11 t, J=7.OHz), 1.96 (2H, in), 3.43 (2H, q, J=7.OHz), 3.52 (2H, t, J=6.3Hz), 3.87 O3H, s) 4. 08 (2H, t, J=6. 3Hz) 7. 06 (2H, d, J=8. 8Hz) 7.70 (2H, d, J=8.8Hz), 7.78 (2H, d, J=8.5Hz), 8.00 (2H, d, J=8.51Iz) MASS (in/z) :315 (M 4 +1) Preparation 195 To a suspension of 4-[2-(4-hydroxyphenyl)iinidazo[2,1b] [1,3,4]thiadiazol6yllbenzoic acid ethyl ester (500 mg) WO 99/40108 PCT/JP99/00538 119 and potassium carbonate (2 g) inN,N-dimethylformamide 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 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 and diisopropyl ether and dried to give piperidin-l-yl-butyloxy)phenyl]imidazo[2,1b] [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 MASS 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-l-ylpentyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid ethyl ester IR (KBr) 2935, 1708, 1608, 1471, 1274, 1176, 1101cm- 1 MASS 519 Preparation 197 4-[2-[4-(6-Piperidin-l-ylhexyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid ethyl ester IR (KBr) 2933, 1710, 1608, 1471, 1274, 1176, 1103 cm- 1 MASS 533 Preparation 198 4-[2-[4-(5-Morpholin-4-ylpentyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid ethyl ester IR (KBr) 2940, 1708, 1608, 1471, 1276, 1176 T 1116cm 1 WO 99/40108 PCT/JP99/00538 120 MASS 521 Preparation 199 4-[2-[4-[5-(cis-2,6-Dimethylmorpholin-4yl)pentyloxy]phenyl]imidazo[2,1-b] [1,3,4]thiadiazol-6yl]benzoic acid ethyl ester IR (KBr) 2937, 1708, 1608, 1471, 1409, 1369, 1307, 1278, 1176 cm- 1 MASS 549 (M+H Preparation 200 4-[2-[4-[6-(cis-2,6-Dimethylmorpholin-4yl)hexyloxy]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid ethyl ester IR (KBr) 2937, 1710, 1606, 1544, 1471, 1403, 1305, 1270, 1257, 1176 cm- 1 MASS 563 Preparation 201 4-[2-[4-(5-Thiomorpholin-4-ylpentyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid ethyl ester IR (KBr) 2939, 1706, 1608, 1471, 1274, 1176, 1108 cm- 1 MASS 537 Preparation 202 To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester (1 g) and 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 and methanol. To a suspension 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 precipitate was collectedby filtration, washed with water, methanol and diisopropyl ether and dried to give (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 452 The following compounds [Preparations 203 to 205] were obtained in a manner similar to that of Preparation 202.
Preparation 203 4-[2-[4-(6-Methoxyhexyloxy)phenyl]imidazo[2,1b][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 MASS 466 (M+H Preparation 204 4-[2-[4-(7-Methoxyheptyloxy)phenyl]imidazo[2,1b][1,3,4]thiadiazol-6-yl]benzoic acid methyl ester IR (KBr) 2933, 2858, 1714, 1608, 1591, 1533, 1469, 1419, 1305, 1259, 1178, 1112 cm- 1 MASS 480 (M+H 4 Preparation 205 4-[2-[4-(8-Methoxyoctyloxy)phenyl]imidazo[2,1b][1,3,4]thiadiazol-6-yl]benzoic acid methyl ester IR (KBr) 2931, 2856, 1712, 1610, 1591, 1533, 1471, 1419, 1305, 1259, 1178, 1112 cm-1 MASS 494 Preparation 206 A mixture of piperazin-1-carboxylic acid tert-butyl ester (0.64 4-bromo-4'-(5-methoxypentyloxy)biphenyl (1 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 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 methoxypentyloxy)biphenyl-4-yl]piperazin-1-carboxylic 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, 1.49-1.90 (6H, 3.14-3.19 (4H, 3.34 (3H, 3.41 (2H, t, J=6.2Hz), 3.57-3.62 (4H, 3.99 (2H, t, J=6.4Hz), 6.91-6.99 (4H, 7.44-7.49 (4H, m) MASS 455 (M+1) The following compound was obtained in a manner similar to that of Preparation 206.
Preparation 207 4-[4-[4-(7-Methoxyheptylthio)phenyl]piperazin-lyl]benzoic acid IR (KBr) 1681.6, 1585.2, 1423.2, 1230.4 cm- 1 NMR (DMSO-d 6 5) 1.20-1.55 (10H, 2.80 (2H, t, J=6.7Hz), 3.20 (3H, 3.24-3.43 (10H, m), 6.82-6.86 (2H, 6.94-6.98 (2H, 7.23-7.27 (2H, 7.69-7.73 (2H, m) MASS 443.2 (M+1) Preparation 208 l-tert-Butoxycarbonyl-4-[4-(4cyclohexylphenyl)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 separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-(4cyclohexylphenyl)-4-piperidylpiperazine (3.83 g).
Preparation 209 To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1b] [1,3,4]thiadiazol-6-yl]benzoic acid (4.0g) in ethanol 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 ether and dried to give WO 99/40108 PCT/JP99/00538 123 hydroxyphenyl) imidazo[2,1-b] [l,3,4]thiadiazol-6yllbenzoic acid ethyl ester (2.09 g).
IR (KBr) 3215, 1679.7, 1608.3, 1473.3, 1288.2 cm- 1 MR (DMSO-d 6 6) :1.34 (3H, t, J=7.lHz), 4.32 (2H, q, J=7.lHz), 6.96 (2H, d, J=8.5Hz), 7.89 (2H, d, 8.02 (4H, 8.84 (1H, 10.40 (1H, s) MASS :366 The following compound was obtained in a manner similar to that of Preparation 209.
Preparation 210 4-Cyclohexylbenzoic acid methyl ester NMR (CDCl 3 6) :1.10-1.55 (5H, in), 1.65-1.95 (5H, mn), 2.45-2.65 (1H, in), 3.89 (3H, 7.26 (2H, d, J=8.2Hz), 7.95 (2H, d, J=8.2Hz) APCI MASS: 219 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 0 N N, N,
N-N
211 NJI N 0OMe 212 213 0 s- O(CH2)6CH3
OW
N-N
NN, N,
N-N
214 0 0 N
N-N
2150 216q, N, N-N 216 0
O>
WO 99/40108 WO 9940108PCT/JP99/00538 12 Preparation No. Formula N Noki 0K 2187 N N 2 1 9.
220 N-N-
NJIN
0 222 0N% 0 AK s \.jI (H2)60C3 WO 99/40108 WO 9940108PCT/JP99/00538 1 26 Preparation No. Formula 0 223
H
3
C
224 NYN 0 s a (H)0H
CH
3
N-N
k, O-o(CH2)60H3 2250 0 NIN N- N- N(C 2 CH 226NN. QJQ0 H CH 0 227 S3NOJKH2J- 3 CN 2280 WO 99/40108 PCT/JP99/00538 127 Preparation No. Formula
NN-N
NN
229 S3
OE
230 0 -N N NN 0 0 ~~0Me 231 NN% 232 o~OM c 0 233 .00-0Et 234 0
S
N
O~~
0 /NN~ WO 99/40108 PCT/JP99/00538 128 Preparation No. Formula 0 235 6 N -N ,JKNyS yQ$Q0 236 6 N 237 M 0(CH 2 )6CH 3 0 NcN'N II .S 0 238 N-N N-N ar 0 N N 23N-N 64
N-N
WO 99/40108 PCT/JP99/00538 129 Preparation No. Formula N O)Ll, N--&O-CA3, 241 X
N-N
N N0 N
N-G
242
N-N
0
M
24N-N N N 7 Me 245
N
244 j -O c
N-N
246 NN Q WO 99/40108 PCT/JP99/00538 130 Preparation No. Formula 248 N- N 251, N-N HOMe
N
248
CN.
WININ, 0/ 249 0" NO N N N'"OE 250S N QCH2) OCH3H20CH N NN 0j~ 252 N N WO 99/40108 WO 9940108PCT/JP99/00538 1 3 1 Preparation No. Formula 2S3
N-N
OHCa 254
N>
CO
2 Me
O
2 N 01 255 K)'-e 257 259 NC-~ NJ WO 99/40108 WO 99/0 108PCT/JP99/00538 1 32 Preparation No. Fo rmul a 260 NC {N NEt 261 EtOOC-0 NO OH 262 EOC0
N-
263 EtOOC Q-N N~ 264 ~EtOOC-- -O
O
264 2656e O Z~ 26EtOOC -Q0-N \2N-09 WO 99/40108 WO 9940108PCT/JP99/00538 1 33 Preparation No. Formula 267 EtOOC-O-N(: Me 268 NC-QNJNQ 269 N-GN D N-CN-J 2700 N N-0-0JO(CH 2 5
CH
3 271 4k MeO 14 272 Me 2 CO 01, 273 MeO 2 C -0 -0 -0N, B
L
WO 99/40108 WO 99/01 08PCT/JP99/00538 134 Preparation No. Formula 274 M0cO 275
MCO
2 CO
D
276
MCO
2 C000 e 277 MeO 2
CN
v
O(CH)
3
H
3 278 MeO 2 C j-jj" 279 EtO-NN 2
CC
2 NH-N
(CH
2 6
CH
3 0 WO 99/40108 WO 9940108PCT/JP99/00538 13 Preparation No. Formula
N-
21H 2 NHN N N
N
0 282
H
2
N}IN
0 283
H
2 NHNy-..
N/--O-H
1 0 284
H
2 NHNy-aNO- 0 285
H
2 NHN 0 0 0 WO 99/40108 WO 9940108PCT/JP99/00538 1 36 Preparation No. Formula 288
H
2
NHN
0 0 29H2NN N N-s) 0 290 F
H
2 NHN /0 NN-0j 0 291 H
NI
292 H 2 NHN /N 0 0 293 H 2 H V e NNMe WO 99/40108 WO 9940108PCT/JP99/00538 1 37 Preparation No. Formula 0 294H 2
NHN
0 295 H2NHN JC 0 0 296
H
2 NHN JX O 0 297 H2NHN 0 298
H
2 NHN e 299-
H
2 NHN WO 99/40108 WO 9940108PCT/JP99/00538 1 38 Preparation No. Formula 0 300 H 2 NHN N-K 0
N
0 301
H
2 NHN NIII'D-->-d 0 302
H
2 NHN Q Et 0 303 e
H
2 NHN A- 0 304 H 2 NHN W 0 305 H 2 NH-N J&O-' WO 99/40108 WO 9940108PCT/JP99/00538 1 39 Preparation No. Formula 0 306 ~H2NHN i 0 307-
H
2 NHN /\/O'OMe 0 309 H 2 NHN Om 00 310 MeoI HN H N-N,,N 0--CHC 0 0 WO 99/40108 WO 9940108PCT/3P99/00538 140 Preparation No. Formula 0 3 2MeO IH H r NO S N-N N J O 0 0 0 313 MeO -I H H IN-&N N -N j- N j 0 0 0 314 Mo I HH N 6 H1 3 N N o o 0 315 MeO H
"N
o 0 0 316 MeO HH
NC
N-NI /N 0 0 0 317 MeO HH
N-N
0 0 WO 99/40108 PCT/JP99/00538 14 1 WO 99/40108 WO 9940108PCT/JP99/00538 1 42 Preparation No. Formula 0 324
MOH
0 0 o 0 0 325 Me0)'(JH'N o0 0 0 327 Me N 011'N.
0 328 e
NN
o 0 0 0 0 329 MeO"\j NN" N N<)
HH
WO 99/40108 WO 9940108PCT/JP99/00538 14 3 Preparation No. Formula 330 N N N N o 0) 0 0 o 0 0 r, 1 332 NGNN t 0 0 0 332 MejOJHNN o 0 0 ~~OMe MeG -OJH HAaO- 0 0 0 MeojIIGoIY -a WO 99/40108 WO 9940108PCTI.JP99/00538 144 Preparation No. Formula 0e>\ 0 0 337
O~~M
Me0'-1 0 0 338 0 JeON- 1 O0,WiI /e 0 0 0 339 N 8 341 H 3
CO
2 QI-H 0(CH 2 4
CH
3 00 WO 99/40108 WO 99/0 108PCT/JP99/00538 1 Preparation No. Formula
H
3
C
342 H 3
CO
2 C /\HN-NH 260 0 0
CH
3 343 H 3
CO
2 C N~ oCH)0H 00
H
3
CO
2 C H_ OC02H 344 00 345 H 3
C
2 C 1 Or 00 0 346 MeO
N%/
s "c N-&--0(CH2 6
CH
3
I
N-N
0 347 -N-N M +0Oj WO 99/40108 WO 9940108PCT/JP99/00538 1 46 Preparation No. Formula 0 348 NN 0 349- N-N MeO 0 350 Me 13 N-N CH 1 351
H
3
CO
2 C 2 6
CH
3
H
3
C
N- N 352 H 3
CO
2 C )._a)-O(CHAO 6
CH
3
CH
3 N-N 353 \30C -l11
O(CH
2 6 0CH 3 WO 99/40108 WO 9940108PCT/JP99/00538 14 7 Preparation No. Formula 354 ~H 3
CO
2 C J:O Br S
O(CHCH
3 356 S,
N
MeOOC-jy rf
N-N
357N
N-N
358 359 N MeOOC\/ N\/V,
N-N
WO 99/40108 WO 9940108PCT/JP99/00538 1 48 Preparation No. Formula 360 MeOOC.~-O S>QO(CH2)CH3
N-N
361 MeOOC N /N S
N-N
362 MeOOCO 4 SI
N-N
363 -M MeOOCN N-DX
N-N
364MCO\S\UOiI 0 365 MeOOC-QP---a\/
IO-
WO 99/40108 WO 9940108PCT/JP99/00538 1 49 Preparation No. Formula
I'
367 MeQOC/S\ NN
N
368 MeO
N-N
369 Me~- I, 1K Nil"(--
N-N
370 MeOOC-N(S
N-
371 MeOOC-QK(
N
N-N
WO 99/40108 WO 9940108PCT/JP99/00538 150 Preparation No. Formula 372 MOOC\/-<S
N
N K) 375 MeOC
/OE
N-
376 MOC-Oc,<Sy\
O
N-N
377 MeOC-KIIiS
N-N
WO 99/40108 WO 99/01 08PCT/JP99/00538 1 51 Preparation No. Formula 378 MeOOC-O I s/ OB
N-N
379 MeOOC~
N-N
380 MeOOC..I"I s SYf,& O-O"-'QMe 381 MeOOC( O,,.OMe
N-N
N-N OMe 383 H OOC -O S C
,N
N
N-N
WO 99/40108 WO 9940108PCT/JP99/00538 152 Preparation No. Formula 34HOOC N N 38 N- N N 385 HOOC,.(D
N-
N-N
36HOOC S, 1\r\a~CA
N-N
37HOOC-O-Q/=O- H O O S 386 S
N-N
387 Meo- 3&
C-
WO 99/40108 PCT/JP99/00538 3 WO 99/40108 WO 9940108PCT/JP99/00538 154 Preparation No. Formula N-N -I 396 HO- 398 OC
OOOCN
*2HCI N-N WO 99/40108 WO 9940108PCT/JP99/00538 155 Preparation No. Formula 402
N-N
*2HCI 403 HOOC
S
N-N
HC1 404 O C Z\ I'
S
N
HCI
SP- Me 406
N-N
*HCI
407 N-N WO 99/40108 WO 9940108PCT/JP99/00538 6 Preparation No. Formula
-N-N
408 HNC\
HCI
409 HOOcS/O
N-N
N-N OMe 410 HO-
S-
411 *2HC1 HO-OC N N 412
N-N
*2HCI 413 LS a 413 *2HC1 WO 99/40108 WO 99/01 08PCT/JP99/00538 7 Preparation No. Formula 414 HOOC /J
N
416 HOOC I~
N-N
417 HOOC-~j--
N-N
47HOOC 0
N-N
419
HOOC
N N WO 99/40108 WO 9940108PCT/JP99/00538 8 Preparation No. Formula 420 HOOC s O
N-N
421 HOOC O~
-N-N
HOC-J--1Q\..QN Oe 422 OCCS3 423
OCOOH
.HCI
424 HO l- N-Q J HCI 425
N-
WO 99/40108 PCT/JP99/00538 159 Preparation No. Formula
N-N
426
HO
2 CCH2)4 H02C sS
H
3
C
N-N
427 HO 2 C I\ a/ O(CHAOCH 3
CH
3 428 H02CN-N 428 O(CH) 6
CH
3
N-NN
H0 2 C 1 o NN iCHH2)2 429 430 H02C 431 H02C O(CH2)-N WO 99/40108 WO 9940108PCT/JP99/00538 1 Preparation No. Formula 432 H0 2 2 )FNZo 436 H 2 C (H-N WO 99/40108 WO 9940108PCT/JP99/00538 16 1 Preparation No. Formula 438 H0 2 C 439 HO 2 C N2I)S>MO 440H0CS _OC27 e 441 H0 2 C /NN>Kj0W 442
N-N
443
HO
2 C- WO 99/40108 WO 99/01 08PCT/JP99/00538 1 62 Preparation No. Formula
/NN
444 HO 2 C N~ N S 445 H0 2 C a >0 S N N 446 H0 2 C /N N-Et 447 __CC 448HOCG A\\/OC)CH H02/ O(CH 2
)CH
3 WO 99/40108 WO 9940108PCT/JP99/00538 1 63 Preparation No. Formula 450H02\C O(CH 2 5
CH
3 451
HO
2 C N /O(CH 2 4
CH,
452 H 453H 3
CO
2 C-Y7&CO 2
H
H
3
C
454H 3
CO
2 C \/C0 2
H
CH
3 455
H
3
CO
2 C2H
H
3
CO
2 C CO 2
H
456 457 MC2 WO 99/40108 PCT/JP99/00538 164 The following compounds [Prenarations 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, mn), 1.45-2.10 (8H, in), 3.0-3.80 (6H, mn), 6.97 (2H, d, J=9.OHz), 7.40-7.65 (3H, in), 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 Preparation 212 IR (KBr) :3008, 2935, 1792, 1770, 1600 cm- 1 NMR (CDC1 3 6) :3.97 (3H, 7.07 (2H, d, 7.43-7.56 (3H, in), 8.10 (1H, d, J=8.5Hz), 8.23 (2H, d, MASS :270 Preparation 213 IR (KBr) :1776, 1234, 1095 cm-i NMR (CDC1 3 6) :0.89 (3H, in), 1.1-2.0 (10H, mn), 3.52 (2H, t, J=6.6Hz), 4.57 (2H, 7.4-7.6 (4H, in), 7.75 (2H, d, J=8.5Hz), 8.14 (2H, d, J=8.lHz), 8.22 (1H, 8.26 (2H, d, J=8.7Hz), 8.43 (2H, d, J=8.7Hz), 8.59 (1H, s) MASS :594 Preparation 214 NMR (CDCl 3 6) :1.20-1.60 (5H, in), 1.70-2.05 (5H, in), 2.50-2.75 (1H, in), 7.25-8.50 (12H, in) ESI MASS (positive) :502.3 (M++Na) Preiparation 215 NNR (CDC1 3 6) :1.10-2.20 (10H, mn), 4.30-4.50 (1H, mn), 7.04 (2H, d, J=9.lHz), 7.40-8.50 (10H, m) APOI MASS (positive) 5 18.3 (M++Na) Preparation 216 NNR (CDCl 3
+CD
3 OD, 6) :1.70-2.15 (4H, in), 2.70-2.90 (1H, in), 2. 90-3.20 (2H, mn), 4. 00-4.15 (2H, mn), 7. 08 (2H, d, J=9. lHz) 7. 10-7 .40 (5H, in), 7. 40-7. 70 (3H, mn), 7.90-8.55 (7H, in) WO 99/40108 PCT/JP99/00538 165 APCI MASS 543 Preparation 217 NMR (CDC1 3
+CD
3 0D, 5) 1.70-2.10 (4H, 2.60-3.15 (3H, 3.90-4.15 (2H, 6.90-7.15 (2H, m), 7.15-7.40 (6H, 7.40-8.45 (9H, m) Preparation 218 NMR (CDC1 3 6) 1.20-2.15 (10H, 4.25-4.50 (1H, m), 7.05 (2H, d, J=6.9Hz), 7.35-7.65 (3H, 8.00-8.50 (7H, m) APCI MASS (positive) 502.2 (M'+Na) Preparation 219 NMR (CDC1 3 6) 1.15-2.00 (10H, 2.45-2.75 (1H, m), 7.30-8.50 (12H, m) APCI MASS (positive) 466.2 Preparation 220 IR (KBr) 2978, 2937, 2873, 1772, 1599, 1498, 1439 cm- 1 NMR (CDC1 3 6) 1.27 (3H, t, J=7.0Hz), 3.65 (2H, q, 3.84 (2H, t, J=4.8Hz), 4.20 (2H, t, 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, 8.28 (2H, d, J=8.6Hz), 8.43 (2H, d, J=8.7Hz) MASS 564 Preparation 221 IR (KBr) 1778.0, 1600.6, 1230.4, 1182.2 cm- 1 NMR (CDC1 3 6) 1.10-1.74 (10H, 2.82 (2H, t, J=7.2Hz), 3.33 (3H, 3.33-3.65 (10H, 6.88-7.02 (4H, m), 7.32-7.58 (5H, 8.07-8.18 (3H, m) Preparation 222 IR (KBr) 1810.8, 1600.6, 1257.4, 1178.3 cm- 1 NMR (DMSO-d 6 6) 1.30-2.40 (18H, 3.21 (3H, s), 3.28-3.35 (2H, 4.05 (2H, t, J=6.6Hz), 7.05-7.10 (2H, 7.40-8.18 (6H, m) MASS 536 (M+1) WO 99/40108 PCT/JP99/00538 166 Preparation 223 IR (KBr) 1776.1, 1677.8, 1251.6, 1197.6 cm- 1 NMR (DMSO-d 6 6) 0.91 (3H, t, J=6.9Hz), 1.23-1.55 (4H, 1.60-1.90 (2H, 4.00-4.10 (2H, m), 7.03-7.09 (2H, 7.39-8.17 (12H, m) MASS 552 Preparation 224 IR (KBr) 1795.4, 1606.4, 1442.5, 1259.3, 1220.7 cm- 1 NMR (DMSO-d 6 6) 1.44-1.95 (8H, 2.71 (3H, s), 2.75 (3H, 3.35 (3H, 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, 7.84 (1H, 7.96-8.15 (3H, m), 8.34 (1H, s) MASS 558 (M+1) Preparation 225 IR (KBr) 1697.1, 1604.5, 1251.6 cm- 1 NMR (CDC1 3 6) 1.40-2.00 (8H, 3.35 (3H, s), 3.40 (2H, t, J=6.4Hz), 4.04 (2H, t, J=6.4Hz), 6.97-7.02 (2H, 7.20-8.07 (9H, 8.50-8.54 (1H, m) MASS 506 (M+1) Preparation 226 IR (KBr) 1778.0, 1602.6, 1238.1 cm 1 NMR (CDC1 3 6) 1.07 (3H, t, J=7.4Hz), 1.77-1.94 (2H, 4.00 (2H, t, J=6.6Hz), 7.00-7.05 (2H, m), 7.46-9.56 (16H, m) MASS 568 (M+1) Preparation 227 IR (KBr) 1778.0, 1604.5, 1257.4, 1172.5 cm 1 NMR (CDC1 3 6) 1.40-1.90 (8H, 3.35 (3H, 3.41 (2H, t, J=6.3Hz), 4.05 (2H, t, J=6.3Hz), 7.00-7.04 (2H, 7.44-9.04 (12H, m) MASS 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 6) :1.00 (3H, t, J=7.3Hz), 1.40-1.96 (4H, m) 4. 04 (2H, t, J=6.5SHz) 7. 02 (2H, d, J=8 .7Hz) 7.36-7. 66 mn), 7. 73 (2H, d, J=8. 4Hz) 8. 00-8.21 (3H, mn), 8. 28 (211, d, J=8. 6Hz) 8. 44 (211, d, J=8. 7Hz) MASS :548 (M+1) Prep aration 229 IR (KBr) :2870, 1778, 1649, 1601, 1529, 1500, 1471, 1439 citC 1 NMR (CDC1 3 6) :1.70-2.00 (4H, in), 3.37 (311, s), 3.47 (2H, t, J=6.lHz), 4.06 (2H, t, J=6.1Hz), 7.01 (211, d, J=8.7Hz), 7.42-7.68 (3H, mn), 7.60 (2H, d, J=8.811z), 7.72 (2H, d, J=8.5Hz),8.06-8.20 (1H, mn), 8.28 (2H, d, J=8.7Hz), 8.43 (2H, di, J=8.6Hz) MASS :578 Pre-paration 230 NMR (CDC1 3 6) :1.29 O3H, t, J=7 .0 Hz) 3. 60 (2H, q, J=7.OHz), 4.58 (2H, 7.40-7.64 (5H, in), 7.65 (2H,d, J=8.2Hz), 7.76 (2H, d, J=8.4Hz), 8.09-8.20 (3H, mn), 8.29 (21, d, J=8.7Hz) 8.44 (2H, d, J=8.71z) MASS :534 Preparation 231 IR (KBr) :2978, 2937, 2873, 1772, 1599, 1498, 1439 cm- 1 NMR (CDC1 3 6) :3.42 (3H, mn), 3.55-3.74 (4H1, mn), 4.65 (2H, s) 7.43-7. 63 (5H, mn), 7 .65 d, J=8.211z) 7.76 (2H, d, J=8.5Hz), 8.08-8.17 (3H1, mn), 8.28 (211, d, J=8.7Hz), 8.43 (2H, di, J=8.6Hz) MASS (in/z) :564 Preparat-ion 232 NMR (CDC1 3 6) :3.41 (3H, s) 3. 54-3. 68 (211, m) ,3.68-3. (2H, m) 3. 90 (2H, t, J=4. 9Hz) 4. 22 (2H, t, J=4 .9Hz) 7.04 (211, d, J=8.811z) 7. 44-7 .68 (3H, mn), 7.55 (211, WO 99/40108 PCT/JP99/00538 168 d, J= 9. lHz) 7. 72 (2H, di, J= 8 .5Hz) 8. 05- 8. 20 (3H, mn), 8.27 (2H, d, J=8.6Hz), 8.43 (2H, d, J=8.7Hz) MASS :594 (M 4 +1) Preparation 233 IR (KBr) :2976, 2868, 1778, 1601, 1527, 1500, 1471, 1439 cm- NNR (CDC1 3 6) :1.22 (3H, t, J=7.OHz), 2.10 (2H, mn), 3.52 (2H, q, J=7.OHz), 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 (5H, in), 7.72 (2H, d, J=8.5Hz), 8.04-8.20 (1H, in), 8.10 (2H1, d, J=8.4Hz), 8.28 (2H, di, J=8.6H-z), 8.43 (2H, d, J=8.6Hz) Prep~aration 234 IR (KBr) :2926, 2877, 1768, 1601, 1527, 1500, 1439, 1417 cm-i NMR (CDC1 3 5) :2.09 (2H, mn), 3.38 (3H, 3.59 (2H1, t, J=6.lHz), 4.13 (2H, t, J=6.3Hz), 7.03 (2H, di, J=8.8Hz), 7.44-7.66 (5H, in), 7.72 (2H, d, 8.08-8.18 (3H, in), 8.28 (2H, di, J=8.7Hz), 8.44 (2H1, di, J=8.7Hz) MASS (in/z) :564 Preparation 235 IR (KBr) :1776, 1655, 1601, 1529, 1498, 1439 cmi NNR (CDC1 3 6) 49 (3H, s) 3. 80 (2H, in), 4. 20 (2H, mn), 7.05 (2H, di, J=8.8Hz), 7.40-7.64 (4H, mn), 7.72 (2H, d, J=8.4Hz) 7.98-8.18 (4H, in), 8.28 (2H, d, J=8.6Hz), 8.44 (2H, di, J=8.7Hz) MASS (in/z) :550 Preparation 236 IR (KBr) :1776, 1603, 1527, 1497, 1439 cnV- 1 NMR (CDC1 3 6) :1.19-2.14 (10H, mn), 4.23-4.40 (1H, mn), 7.02 (2H, d, J=8.8Hz), 7.41-7.67 (5H, in), 7.72 (2H, di, J=8.SHz), 8.02-8.21 (3H, in), 8.28 (2H, di, J=8.7Hz), 8.43 (2H, di, J=8.7Hz) MASS (in/z) :574 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, 1 10-1.60 (8H, m), 1.60-2.00 (2H, 4.03 (2H, t, J=6.5Hz), 6.98 (2H, d, J=8.8Hz), 7.40-7.70 (3H, 7.81 (2H, d, 7.93 (2H, d, J=8.8Hz), 8.12 (2H, d, J=8.1Hz), 8.17 (1H, 8.31 (2H, d, APCI MASS 513 Preparation 238 IR (KBr) 1776, 1603, 1524, 1441, 1414 cm- 1 NMR (CDC1 3 5) 1.03-1.43 (5H, 1.54-2.14 (5H, m), 2.24-2.50 (1H, 2.65-2.86 (4H, 3.23-3.47 (4H, 6.98 (2H, d, J=8.7Hz), 7.41-7.68 (3H, 7.92 (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 566 Preparation 239 IR (KBr) 1772, 1574, 1234 cm- 1 NMR (CDC1 3 5) 2.6-2.75 (4H, 3.2-3.3 (4H, m), 3.65 (2H, 6.8-7.0 (3H, 7.1-7.3 (2H, m), 7.4-7.6 (4H, 7.74 (2H, d, J=8.5Hz), 8.14 (2H, d, J=8.1Hz), 8.21 (1H, 8.26 (2H, d, J=8.6Hz), 8.43 (2H, d, J=8.6Hz), 8.59 (1H, s) MASS 640 Preparation 240 IR (KBr) 1780, 1520, 1236, 982 cm- 1 NMR (CDC1 3 5) 1.5-1.8 (6H, 3.42 (4H, t, J=5.6Hz), 7.02 (2H, d, J=9.1Hz), 7.4-7.7 (5H, 8.14 (2H, d, J=10.5Hz), 8.25 (2H, d, J=8.6Hz), 8.42 (2H, d, J=8.6Hz), 8.47 (1H, s) MASS 549 Preparation 241 IR (KBr) 1776, 1571, 1252 cm- 1 NMR (CDC1 3 5) 0.8-1.0 (3H, 1.2-1.8 (8H, m), WO 99/40108 PCT/JP99/00538 170 4.02 (2H, t, J=6.5Hz), 7.01 (2H, d, 7.4-7.7 (5H, 8.1-8.3 (4H, 8.43 (2H, d, J=8.6Hz), 8.51 (1H, s) Preparation 242 IR (KBr) 2927, 2854, 1599, 1531, 1498, 1444 cm- 1 MASS 642 (M +1) Preparation 243 IR (KBr) 1782, 1597, 1533, 1502, 1444, 1421 cm- 1 NMR (CDC1 3 5) 1.30 (6H, d, J=6.3Hz), 2.40-2.58 (2H, 3.49-3.63 (2H, m) 3.72-3.94 (2H, 7.01 (2H, d, J=8.8Hz), 7.42-7.65 (5H, 7.73 (2H, d, 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) MASS 589 Preparation 244 IR (KBr) 1778, 1603, 1441, 1414 cm-i NMR (CDC1 3 5) 0.92 (6H, 1.10-1.84 (8H, m), 2.16-2.35 (1H, 2.68-2.87 (4H, 3.30-3.46 (4H, 6.98 (2H, d, J=9.0Hz), 7.40-7.65 (3H, 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 594 (M +1) Preparation 245 IR (KBr) 1784, 1603, 1520, 1441, 1414 cm- NMR (CDC1 3 5) 1.66-2.14 (4H, 3.07-3.28 (2H, m), 3.56-3.84 (3H, 4.60 (2H, 6.98 (2H, d, 7.23-7.67 (8H, 7.91 (2H, d, J=8.9Hz), 8.13 (1H, d, J=8.2Hz), 8.23 (2H, d, J=8.6Hz), 8.40 (2H, d, J=8.6Hz) MASS 589 Preparation 246 IR (KBr) 1780, 1603, 1522, 1441, 1414 cm- 1 NMR (CDC13, 6) 0.95 (3H, d, J=6.9Hz), 1.37-2.15 (9H, 2.25-2.44 (1H, 2.68-2.92 WO 99/40108 PCT/JP99/00538 171 (4H, 3.27-3.50 (4H, 6.98 (2H, d, 7.37-7.67 (3H, 7.93 (2H, d, J=8.9Hz), 8.08-8.18 (1H, 8.24 (2H, d, J=8.6Hz), 8.40 (2H, d, J=8.6Hz) Preparation 247 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, 1.13-2.05 (7H, 2.20-2.48 (1H, m),2.62-2.90 (4H, 3.23-3.53 (4H, 6.97 (2H, 7.38-7.66 (3H, 7.92 (2H, d, J=8.8Hz), 8.06-8.17 (1H, 8.24 (2H, d, J=8.6Hz), 8.40 (2H, d, J=8.7Hz) Preparation 248 IR (Nujol) 1782, 1603 cm- 1 NMR (CDC1 3 5) 1.9-2.3 (4H, 3.03 (3H, 3.2-3.5 (2H, 3.6-3.9 (2H, 7.03 (2H, d, J=8.9Hz), 7.36 (4H, 7.4-7.7 (3H, 7.93 (2H, d, J=8.9Hz), 8.13 (1H, d, J=8.2Hz) (+)APCI MASS 623 Preparation 249 IR (KBr) 2923, 2848, 2823, 1766, 1602, 1515, 1450, 1378, 1259, 1222, 1186, 1153, 1089, 1014, 971 cm- 1 NMR (CDC1 3 6) 1.2-1.5 (5H, 1.6-1.9 (7H, m), 2.07 (2H, 2.43 (1H, 2.6-2.9 (5H, 3.02 (2H, t, J=8.5Hz), 3.26 (4H, m) 4.07 (2H, d, J=13Hz), 6.8-7.1 (4H, 7.12 (2H, d, J=8.6Hz),7.3-7.6 (3H, 8.0-8.2 (3H, m) MASS 462 Preparation 250 IR (KBr) 1780, 1682, 1655, 1601, 1549, 1498, 1429 cm- NMR (CDC1 3 5) 1.62-1.95 (2H, 2.01 (2H, m), 2.70-3.18 (3H, 4.64 (2H, 6.80 (1H, d, J=9.1Hz), 7.18-7.40 (5H, 7.40-7.65 (3H, m), 8.00-8.25 (2H, 8.25 (2H, d, J=8.6Hz), 8.41 (2H, d, J=8.6Hz), 8.76 (1H, d, J=2.3Hz) MASS 560 WO 99/40108 PCT/JP99/00538 172 Preparation 251 IR (KBr) :1781.9, 1602.6, 1228.4 cm-1 MR (CDC1 3 6) :1.54-1.87 (6H, in), 3.35 (3H, s), 3.38-3. 68 (10H,m) 4 .00 (2H, t, J=6.4Hz) 6.93-7.05 (6H, in), 7.39-7.53 (7H, in), 8.08-8.18 (3H, m) Preparation 252 IR (KBr) :1776.1, 1600.6, 1232.3 cm- 1 MR (CDC13, 6) :2.73-2.78 (4H, in), 2.93-3.73 (9H, mn), 6. 94-6. 98 (2H, in), 7. 14-7. 58 (7H, mn), 8. 07-8. 15 (3H,
M)
MASS (in/z) :440 (M+1) Preparation 253 IR (KBr) :1778, 1599, 1576, 1527, 1498, 1473, 1439 cin' MR (CDC1 3 5) :1.47 (3H, t, J=7.OHz), 4.11 (2H, q, J=7. OHz) 7. 02 (2H, d, J=8. 9Hz) 7.42-7. 80 (7H, m) 8.10-8.56 (7H, m) MASS :520 The following compounds [Preparations 254 to 270] were obtained in a manner similar to that of Preparation 46.
Preparation 254 IR (KBr) :1702.2, 1702.8 cm- 1 MR (DMSO-d 6 6) :3.83 (3H, 8.06 (2H, di, J=8.7Hz), 8.20 (2H, di, J=8.7Hz), 8.24 (1H, 9.31 (1H, 10.04 (1H, s) MASS (mn/z) :231 Preparation 255 IR (KBr) :1722, 1562, 1514, 1346, 1279 cm- 1 MR (ODC1 3 6) :3.90 (3H, 7.92 (2H, d, J=9.2Hz), 8.16 (1H, 8.38 (2H, di, J=9.2Hz), 8.86 (1H, s) MASS (in/z) :246 Preparation 256 IR (KBr) :2937, 2856, 2819, 2213, 1608, 1517, 1448, 1384, 1349, 1247, 1224, 1180, 1122 cm- 1 MR (CDC1 3 6) :1.66 (6H, in), 3.32 (4H, t, 6.83 (2H, di, J=9.lHz), 7.46 (2H, di, J=9.lHz) WO 99/40108 PCT/JP99/00538 173 MASS 187 (M+H Preparation 257 NMR (CDC1 3 6) 3.28 (4H, t, J=4.9Hz), 3.85 (2H, d, J=4.9Hz), 6.87 (2H, d, J=9.OHz), 7.52 (2H, d, J=9.OHz) MASS 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), 3.6-3.9 (2H, 6.85 (2H, d, J=9.0Hz), 7.50 (2H, d, MASS 217 (M+H Preparation 259 NMR (CDC1 3 6) 2.69 (2H, t, J=5.lHz), 3.77 (2H, t, J=5.lHz), 6.81 (2H, d, J=9.OHz), 7.49 (2H, d, MASS 205 Preparation 260 NMR (CDC1 3 6) 1.13 (3H, t, J=7.2Hz), 2.47 (2H, q, J=7.2Hz), 2.58 (4H, t, J=S.lHz), 3.35 (4H, t, 7.22 (2H, d, J=8.8Hz), 7.49 (2H, d, J=8.8Hz) MASS 216 Preparation 261 NMR (CDC1 3 6) 1.36 (3H, t, J=7.1Hz), 1.55-1.75 (2H, 1.80-2.10 (4H, 3.00-3.15 (2H, m), 3.60-4.00 4.31 (2H, q, J=7.lHz), 6.82 (2H, d, J=9.lHz), 7.90 (2H, d, J=9.lHz) APCT MASS (positive) 250.3 Preparation 262 NMR (CDC1 3 6) 1.37 (3H, t, J=7.lHz), 1.60-2.10 (4H, 2.55-2.80 (1H, 2.95 (2H, dt, J=3.lHz, J=12.3Hz), 3.90-4.05 (2H, 4.32 (2H, q, J=7.lHz), 6.90 (2H, d, J=9.lHz), 7.10-7.35 (4H, 7.93 (2H, d, J=9.lHz) WO 99/40108 PCT/JP99/00538 174 APCI MASS :310.3 Preparation 263 MR (DMSO-d 6 5) :1.29 (3H, t, J=7.1Hz), 3.21-3.34 (4H, mn), 3.40-3.53 (4H, mn), 4.24 (2H, q, J=7.lHz), 6.81 (1H, t, J=7.2Hz), 7.00 (2H, di, J=7.9Hz), 7.05 (2H, d, J=9.OHz), 7.25 (2H, t, J=7.9Hz), 7.81 (2H, d, J==8.9Hz) MASS (rn/z) :311 Preparation 264 MR (DMSO-d 6 5) :1.28 (3H, t, J=7.lHz), 1.26-1.54 (2H, in), 1.64-1.90 (2H, in), 2.90-3.16 (2H, in), 3.58-3.84 (3H, mn), 4.23 (2H, q, J=7.lHz),4.75 (1H, brs), 6.95 (2H, d, J=9.lHz), 7.76 (2H, di, J=9.OHz) MASS (in/z) :250 Preparation 265 IR (KBr) :2939, 2843, 1703, 1601, 1552, 1497, 1439, 1414 cm-1 MR (DMSO-d 6 5) :1.59 (2H, mn), 1.87 (2H, in), 2.78-3.15 (3H, mn), 3.79 (3H, 4.62 (2H, in), 6.92 (1H, di, J=9.lHz), 7.21 (5H, in), 7.94 (1H, dd, J=9.1 and 2.3Hz), 8.65 (1H, di, J=2.3Hz) MASS :297 (M 4 +1) Preparation 266 IR (KBr) :1707, 1610, 1516, 1444 cin 1 MR (DMSO-d 6 6) :1.04-1.30 (5H, in), 1.28 (3H, t, J=7.lHz), 1.47-1.86 (5H, in), 2.16-2.34 (1H, in), 2.52-2.64 (4H, in), 3.19-3.34 (4H, mn),4.23 (2H, q, J=7.lHz), 6.95 (2H, di, J=9.OHz), 7.77 d, J=8. 9Hz) MASS (in/z) :317 Preparation 267 IR (Nujol) :1699, 1606 cm-1 MR (CDC1 3 6) :1.37 (3H, t, J=7.lHz), 1.9-2.2 (4H, in), 3. 01 O3H, s) 3.2-3. 4 (2H, in), 3. 6-3. 8 (2H, mn), 4.33 (2H, q, J=7.lHz) WO 99/40108 PCT/JP99/00538 175 (+)APCI MASS :374 Preparation 268 1K :2927, 2850, 2212, 1602, 1517, 1442, 1394, 1253, 1178, 1143, 927, 823 cm- 1 NMR (CDC1 3 6) :1.2 (5H, in), 1. 65 (1H, in), 1. 85 (4H, m), 2.30 2.70 (4H, t, J=5.lHz), 3.32 (4H, t, 6.85 (2H, d, J=9.OHz), 7.48 (2H, di, J=9.OHz) MASS :270 Preparation 269 Preparation 270 IR (KBr) :1708.6, 1288.2, 1230.4 cm-i NI4R (CDC1 3 6) :1.38 (3H, t, J=7.lHz), 1.50-1.87 (6H, in), 3.34 (3H, 3.37-3.53 (10H, in), 4.00 (2H, t,J=6.4Hz), 4.34 (2H, q, J=7.lHz), 6.90-7.04 (6H, m),7.45-7.51 (4H, mn), 7.94-7.98 (2H, m) MASS :503 (M+1) The following compounds [Preparations 271 to 279] were obtained in a manner similar to that of Preparation 16.
Prep~aration 271 IR (KBr) :1724, 1558, 1521, 1257 cm-i NMR4 (CDCl 3 6) 91 (3H, t, J=6. 9Hz) 1. 3-1. 9 (8H, m) 3.87 (3H, 3.99 (2H, t, J=6.5Hz), 6.98 (2H, di, J=9.01-z), 7.58 (2H, di, J=9.OHz), 8.30 (1H, 8.53 (1H, s) MASS :303 Preparation 272 NMR4 (OD1 3 6) :1.44 (3H, t, J=7.OHz), 4.08 qt, J=7.OHz), 6.98 d, J=8.81{z), 7.56 (2H, di, J=8.8Hz), 7.62 (2H, d, J=8.6Hz), 8.07 (2H, di, J=8. 6Hz) MASS :257 Prep~aration 273 1K (KBr) :2947, 2875, 1722, 1603, 1527, 1495, 1435 cm 1 i WO 99/40108 PCT/JP99/00538 176 NMR (CDC1 3 6) 1.88-2.18 (4H, 3.51 (2H, m), 3.93 (3H, 4.05 (2H, 6.98 (2H, d, J=8.6Hz),7.50-7.70 (4H, 8.08 (2H, d, J=8.2Hz) MASS 363 (M 365 Preparation 274 NMR (CDC13, 6) 3.40 (3H, 3.60 (2H, 3.73 (2H, 3.89 (2H, 3.93 (3H, 4.20 (2H, 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) MASS 331 Preparation 275 NMR (CDC1 3 6) 1.26 (3H, t, J=7.0Hz), 3.62 (2H, q, 3.76-3.87 (2H, 3.93 (3H, 4.12- 4.24 (2H, 6.96-7.08 (2H, 7.52-7.70 (4H, m), 8.02-8.14 (2H, m) MASS 301 (M +1) Preparation 276 IR (KBr) 2949, 2877, 1722, 1695, 1603, 1529, 1497, 1435 cm- 1 NMR (CDC1 3 6) 3.47 (3H, 3.78 (2H, 3.93 (3H, 4.18 (2H, 6.95-7.08 (2H, m), 7.48-7.68 (4H, 8.00-8.12 (2H, m) MASS 287 (M +1) Preparation 277 IR (KBr) 2954, 2873, 1718, 1610, 1544, 1494, 1471, 1280, 1249, 1110 cm 1 MASS 408 ((M-TFA)+H Preparation 278 IR (KBr) 2935, 2867, 1720, 1610, 1544, 1494, 1471, 1436, 1405, 1332, 1280, 1249, 1176, 1110 cm- 1 MASS 436 Preparation 279 IR (KBr) 2950, 2867, 1708, 1608, 1525, 1471, 1409, 1305, 1259, 1274, 1176, 1103 cm 1 MASS 450 (M+H 4 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 TB. (KBr) :1653, 1626, 1574, 1524 cm-1 NMR (DMSO-d 6 6) :0.85 (3H, mn), 1.1-1.6 (10H-, mn), 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, 9.48 (1H, brs) MASS :331 Preparation 281 TB. (KBr) :1657, 1603, 1570, 1516, 1313 cm- 1 NNR (DMSO-d 6 6) :2.4-2.6 (4H, in), 3.0-3.2 (4H, mn), 3.57 (2H, 4.41 (2H, d, J=4.3Hz), 6.76 (1H, t, J=7.8Hz), 6.92 (2H, d, J=7.8Hz), 7.20 (211, t, 15J=7.8Hz), 7.47 (2H, t, J=8.5Hz), 7.81 (2H, d, 8.12 (1H, 8.88 (1H, s),9.48 (1H, t, J=4.3Hz)' MASS :377 Prep~aration 282 TB. (KBr) :1632, 1562, 1516 cm- 1 NNR (DMSO-d 6 6) :1.5-1.8 (61H, mn), 3.0-3.3 (4H, in), 4.38 (2H, d, J=3.9Hz), 7.03 (2H, d, J=9.lHz), 8.04 (1H, 8.70 (1H, 9.41 (1H, brs) MASS :286 Preparation 283 TB. (KBr) :1649, 1623, 1522 cmtC' NMB. (DMSO-d 6 6) :0.8-1.0 (3H, mn), 1.2-1.8 (8H, mn), 4.00 (2H, t, J=4.OHz), 4.39 (2H, d, J=4.01-z),7.05 (2H, d, J=9.OHz), 7.72 (2H, d, J=9.OHz),8.07 (1H, s), 8.76 (1H, 9.44 (1H, t, J=4.OHz) MASS :303 Preparation 284 TB. (KBr) :1618, 1560, 1525 cm- 1 lNR (DMSO-d 6 65) :1.9-2.1 (4H, mn), 3.1-3.3 (4H, mn), 4.38 (2H1, brs), 6.62 (2H, d, J=9.OHz), 7.58 (2H, di, WO 99/40108 PCT/JP99/00538 178 J=9.OHZ) 8.-02 (1H, s) 8 .64 (1H, s) 40 (1H, brs) MASS (in/z) :294 (M+23) Prepoaration 285 NMR (CDC1 3 6) :1.10-1.40 (5H, mn), 1.40-2.10 (10H, in), 2. 90-3.15 (2H, mn), 3.25-3. 50 (1H, in), 3. 50-3.75 (3H, in), 4.05 (2H, d, J=3.9Hz), 6.88 (2H, d, 7.63 (2H, dd, J=9.0 and APCI MASS (positive) :318.3 Preparation 286 NMR (CDC1 3 6) :1.70-2.10 (4H, in), 2.60-2.85 (1H, in), 2. 85-3. 05 (2H, in), 3. 05-3. 50 (2H, mn), 3. 85-4. 10 (2H, mn), 6. 85-7.00 (2H, 10-7. 40 (5H, in), 7. 68 (2H, di, J=8.8Hz) APCI MASS :296 Preparation 287 NNR (ODC1 3 6) :1.20-2.10 (10H, in), 4.10 (2H, brs), 4.20-4.40 (1H, in), 6.91 (2H, d, J=8.9Hz), 7.49 (1Hi, brs), 7.78 (2H, d, J=8.9Hz) ESI MASS :257.3 (M 4 +Na) Preparation 288 NMR (CDC1 3 6) 10-1.55 (5H, in), 1. 60-2. 00 (5H, in), 2.40-2.65 (1H, in), 7.25 (2H, di, J=8.2Hz), 7.67 (2H, d, J=8.2Hz) APOT MASS :219 Preparation 289 IR (KBr) :2958, 2929, 2850, 2821, 1651, 1628, 1603, 1529, 1487, 1443 cm- 1 NM'R (DMSO-d 6 6) :1.00-1.36 (5H, mn), 1.50-1.92 (SH, in), 2.16-2.38 (1H, in), 2.57-2. 64 (4H, in), 3. 10-3.28 (4H, mn), 4.48 (2H, 7.01 (2H, di, 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 (in/z) :379 Prep~aration 29-0 NMR (DMSO-d 6 6) :3.13-3.54 (8H, mn), 4.38 (2H, 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 297 (M +1) Preparation 291 NMR (DMSO-d 6 5) 0.87 (3H, t, J=7.4Hz), 1.37-1.60 (4H, 1.80-1.98 (2H, 2.90-3.10 (2H, 3.38 (2H, t, J=6.6Hz), 3.38-3.70 (3H, 4.34 and 4.35 (2H, 6.92 (2H, d, J=9.0Hz), 7.68 (2H, d, J=8.9Hz), 9.45 (1H, brs) MASS 278 Preparation 292 IR (KBr) 1666, 1605, 1545, 1495, 1448 cm- 1 NMR (DMSO-d 6 6) 1.17 (6H, d, J=6.1Hz), 2.20-2.38 (2H, 3.59-3.78 (4H, 4.49 (2H, 7.03 (2H, d, J=8.9Hz), 7.61 (2H, d, J=8.8Hz), 7.69 (2H, d, 7.87 (2H, d, J=8.4Hz), 9.77 (lH,-s) MASS 326 Preparation 293 NMR (DMSO-d 6 5) 0.88 (6H, 1.05-1.52 (6H, m), 1.52-1.73 (2H, 2.08-2.26 (1H, 2.52-2.72 (4H, 3.10-3.31 (4H, 4.36 (2H, 6.91 (2H, d, J=8.9Hz), 7.69 (2H, d, J=8.8Hz), 9.46 (1H, s) MASS 331 (M +1) Preparation 294 IR (KBr) 1637, 1606, 1554, 1508, 1456 cm- 1 NMR (DMSO-d 6 6) 1.46-1.70 (2H, 1.87-2.06 (2H, m), 2.92-3.12 (2H, 3.52-3.73 (3H, 4.35 (2H, s), 4.54 (2H, 6.94 (2H, d, J=8.9Hz), 7.20-7.42 7.69 (2H, d, J=8.8Hz), 9.45 (1H, s) MASS 326 (M +1) Preparation 295 NMR (DMSO-d6, 6) 1.16-2.04 (10H, 4.29-4.51 (1H, m), 4.51 (2H, 7.03 (2H, d, J=8.8Hz), 7.64 (2H, d, 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 :311 Preparation 296 IR (KBr) :2912, 2870, 2846, 1608, 1597, 1533, 1493, 1423 cm- 1 NM'R (OD1 3 6) :1.74 (211, in), 1.97 (2H, mn), 2.70-3.12 (3H, in), 3.31 (2H, brs), 4.58 (2H1, mn), 6.69 (1H, d, J=9.OHz) 7.05-7.55 (6H, mn), 7 .88 (1H1, dci, 2.3Hz), 8.56 (1H, d, J=2.3Hz) MASS (in/z) :297 Preparation 297 NMR (DMSO-d 6 6) :1.35 (3H, t, J=7.OHz), 4.07 (2H, q, J=7.OHz), 4.50 (2H, 7.02 (2H1, d, J=8.8Hz),, 7.66(2H, d, J=8.7Hz), 7.70 (2H, d, J=8.4Hz), 7.89 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS (in/z) :257 Preparation 298 IR (KBr) :2956, 2916, 2870, 1612, 1535, 1514, 1493 cirC 1 NMR (DMSO-d 6 6) :1.55-1.87 (4H, mn), 3.24 (3H, s), 3.38 (211, t, J=6.2Hz), 4.03 (2H, J=6.lHz), 4.57 (2H, brs), 7.03 (2H, di, J=8.7 Hz), 7.58-7.78 (4H, mn), 7.89 (211, d, J=8.3Hz), 9.79 (111, s) MASS (in/z) :315 Preparation 299 IR (KBr) :1626, 1606, 1566,, 1524, 1498, 1454 cm- 1 lNR (DMSO-d 6 6) :1.00-1.35 (511, mn), 1.35-1.90 (511, in), 2. 16-2.36 (111, mn), 2. 54-2. 69 m) 3.12-3.28 (411, in), 4.35 (211, 6.91 (2H, d, J=8.9Hz), 7.69 (211, J=8.811z), 9.46 (1H1, s) MASS (in/z) :303 Preparation 300 1K (KBr) :1659, 1626, 1606, 1531, 1498, 1446 cm- 1 lNKR (DMSO-d 6 6) :0.89 (311, d, J=6.811z), 1.32-1.80 (911, inf), 2.10-2.26 (111, mn), 2.50-2.65 (411, m), WO 99/40108 PCT/JP99/00538 181 3.15-3.30 (4H, 4.36 (2H, 6.92 (2H, d, 7.69 (2H, d, J=8.8Hz), 9.46 (1H, s) MASS 317 Preparation 301 IR (KBr) 1660, 1606, 1549, 1506, 1446 cm 1 NMR (DMSO-d 6 6) 0.86 (3H, d, J=6.4Hz), 0.84-1.05 (2H, 1.05-1.54 (3H, 1.60-1.90 (4H, 2.12-2.33 (1H, 2.54-2.65 (4H, 3.11-3.27 (4H, 4.36 (2H, 6.91 (2H, d, J=8.9Hz), 7.69 (2H, d, J=8.8Hz), 9.46 (1H, s) MASS 317 Preparation 302 NMR (DMSO-d 6 6) 1.17 (3H, t, J=7.0Hz), 3.51 (2H, q, 4.50 (2H, 4.52 (2H, 7.42 (2H, d, J=8.2Hz), 7.66-7.80 (4H, 7.92 (2H, d, J=8.9Hz), 9.83 (1H, s) MASS 271 (M+1) Preparation 303 NMR (DMSO-d 6 6) 3.27 (3H, 3.45-3.68 (4H, m), 4.54 (4H, 7.43 (2H, d, J=8.2Hz), 7.66-7.81 (4H, 7.92 (2H, d, J=8.4Hz), 9.83 (1H, s) MASS 301 Preparation 304 NMR (DMSO-d 6 6) 3.25 (3H, 3.44-3.55 (2H, m), 3.55-3.65 (2H, 3.73-3.86 (2H, 4.08-4.20 (2H, 4.52 (2H, 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, 9.80 (1H, s) MASS 331 (M +1) Preparation 305 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=6.4Hz), 4.07 (2H, t, J=6.4Hz), 4.50 (2H, 7.03 (2H, d, J=8.8Hz), 7.66 (2H, d, J=8.7Hz), 7.70 (2H, d, J=8.5Hz), 7.89 (2H, d, J=8.4Hz), 9.79 (1H, s) WO 99/40108 PCT/.IP99/00538 182 MASS :315 Preparation 306 NNR (DI'45-d 6 6) :1.14 (3H1, t, J=7.OHz), 3.51 (2H1, q, J=7. OHz) 3. 66-3. 80 (2H, mn), 4. 07-4. 20 (211, mn), 4 .51 (2H, s) 7. 05 (2H, d, J=8. 8Hz) 7. 67 (2H1, d, J=8. 8Hz), 7.70 (2H, di, J=z8.4Hz), 7.89 (2H, d, J=8.4Hz), 9.79 (1H1, s) MASS (in/z) :301 (M+1) Prep~aration 307 IR (KBr) :2933, 2873, 1608, 1531, 1491 citC1 NMR (DMS0-cl 6 6) 1. 97 (2H1, in), 3. 26 (3H1, s) 3. 49 (2H, t, J=6.3Hz), 4. 07 t, J=6. 4Hz) 4. 50 (211, brs) 7.03 (2H, di, J=8.8Hz), 7.66 (2H, di, J=8.7Hz), 7.70 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.4Hz), 9.79 (1H, s) MASS :301 Preparation 308 IR (KBr) :2927, 2881, 1630, 1606, 1533, 1489 cin 1 NNR (DMSO-d 6 6) 32 (311, 3. 67 (2H, mn), 4.14 (3H, 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 (1H1, s) MASS (in/z) :287 (M4+1) Preparation 309 IP. (Nujol) :3292, 1603 cin' NI4R (DMSO-c1 6 6) :1.8-2.2 (4H1, mn), 2.92 (3H, 3.0-3.2 (2H1, mn), 3.6-3.8 (2H, in), 4.36 (2H, 6.98 (2H, d, J=8.81z), 7.44 (411, 7.71 (211, di, J=8.8Hz), 9.46 (1H, s) (+)APCI MASS :360 (M+11)' 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 NMR (DMSO-d 6 6) :0.86 (3H, t, J=6.9Hz), 1.1-1.6 WO 99/4010S PCT/JP99/00538 183 mn), 3. 45 (2H, t, J=6. 4Hz) 3. 90 (3H, S) 4. 50 (2H, 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) MASS :493 Preparation 311 IR (KBr) :1718, 1614, 1279 cm- 1 NNR (DMSO-d 6 5) :2.4-2.6 (4H, mn), 3.0-3.2 (411, mn), 3.59 3.90 (3H, 6.77 (1H, t, J=7.7Hz), 6.92 (2H, d, J=7.7Hz), 7.20 (2H, t, J=7.7Hz), 7.50 (2H, t, J=8.5Hz), 7.86 (2H, di, J=8.5Hz), 8.04 (2H, t, J=8.6Hz), 8.11 (2H, di, J=8.6Hz), 8.26 (1H, s), 9.02 (1H, 10.37 (1H, 10.70 (1H, s) MASS :539 Preparation 312 NNR (DMSO-d 6 5) :1.10-2.00 (14H, mn), 2.95-3.15 (2H, mn), 3.40-3.75 (4H, in), 3.90 (3H, 7.00 d, J=8.9Hz),, 7.80 (2H, di, J=8.8Hz), 8.03 (2H, di, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.25 (1H1, s), 10.58 (111, s) APCI MASS (positive) :480.3 Prep~aration 313 IR (KBr) :1724, 1635, 1570, 1520, 1279 cm-1 NT4R (DMSO-d 6 5) :1.5-1.7 (6H, mn), 3.1-3.3 (4H, mn), 3.90 (3H, 7.05 (2H, d, J=9.lHz), 7.66 (2H, di, J=9.lHz), 8.04 (2H, d, J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 8.85 (1H, 10.30 (1H, 10.68 (1H, s) MASS (in/z) :448 (M+1) Preparation 314 IR (KBr) :1716, 1603, 1552, 1521, 1470, 1284, 1257 cm- 1 NIMR (DMSO-d 6 5) :0.89 (3H, t, J=6.8Hz), 1.2-1.8 (8H-, mn), 3.90 4.02 (2H, t, J=6.4Hz), 7.08 (2H, di, J=9.OHz), 7.77 (2H, d, J=9.OHz), 8.04 (2H, di, WO 99/40108 PCT/JP99/00538 184 J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 8.91 (1H, 10.33 (1H, 10.69 (1H, s) MASS 465 (M+1) Preparation 315 NMR (DMSO-d 6 5) 1.60-1.95 (4H, 2.65-3.00 (3H, m), 3.90 (3H, 4.04 (2H, 7.05 (2H, d, J=8.9Hz), 7.10-7.40 (5H, 7.83 (2H, d, J=8.9Hz), 8.00-8.15 (4H, 10.27 (1H, 10.59 (1H, s) APCI MASS 458 Preparation 316 IR (KBr) 1720, 1645, 1560, 1525, 1281 cm- 1 NMR (DMSO-d 6 5) 1.9-2.1 (4H, 3.2-3.4 (4H, m), 3.90 (3H, 6.64 (2H, d, J=9.0Hz), 7.63 (2H, d, 8.04 (2H, d, J=8.7Hz), 8.11 (2H, d, J=8.7Hz), 8.15 (1H, 8.78 (1H, 10.28 (1H, s), 10.67 (1H, s) MASS 456 (M++23) Preparation 317 NMR (DMSO-d 6 5) 1.10-2.10 (10H, 3.90 (3H, s), 4.35-4.55 (1H, 7.04 (2H, d, J=8.8Hz), 7.88 (2H, d, J=8.8Hz), 8.00-8.15 (4H, 10.41 (1H, 10.64 (1H, s) APCI MASS 397 (M +1) Preparation 318 NMR (DMSO-d 6 6) 1.15-1.60 (5H, 1.60-1.90 (5H, m), 2.50-2.70 (1H, 3.90 (3H, 7.37 (2H, d, J=8.3Hz), 7.85 (2H, d, J=8.2Hz), 8.00-8.15 (4H, m), 10.48 (1H, 10.68 (1H, s) APCI MASS 381 (M+1) Preparation 319 IR (KBr) 2927, 2852, 1722, 1684, 1645, 1603, 1495, 1446 cm-1 NMR (DMSO-d 6 6) 1.00-1.36 (5H, 1.51-1.91 2.20-2.38 (1H, 2.56-2.72 (4H, 3.12-3.28 (4H, 3.90 (3H, 7.03 (2H, d, J=8.9Hz), 7.64 WO 99/40108 PCT/JP99/00538 185 (2H, di, J=8. 7Hz) 7.77 (2H, d, J=8.5Hz) 7. 97 (2H, d, J=8. 4Hz) 8. 00-8. 16 (4H, in), 10. 57 (1H, s) 10. 71 (1H, s) MASS (in/z) :541 Preparation 320 NNR (DMSO-d 6 :3.21-3.54 (8H, in), 3.90 (3H, s) 6. 82 (1H, t, J=7.2Hz), 7.01 (2H, di, J=7.9Hz), 7.08 (2H, d, J=8.9Hz), 7.25 (2H, t, J=7.9Hz), 7.85 (2H, di, J=8.8Hz), 8.04 (2H, d, J=8.6Hz), 8.09 (2H, d, J=8.6Hz), 10.31 (1H, 10.60 (1H, s) MASS :459 Preparation 321 NNR (DMSO-d 6 6) :0.88 (3H, t, J=7.4Hz), 1.41-1.63 (4H, mn), 1.84-2.01 (2H, in), 2.96-3.16 (2H, mn), 3.40 (2H, t, J=6.6Hz), 3.40-3.76 (3H, mn), 3.90 (3H, 7.00 (2H, di, J=8.9Hz), 7.80 (2H, di, J=8.8Hz), 8.00-8.16 (4H, mn), 10.25 (1H, 10.58 (1H, s) MASS (in/z) :440 Preparation 322 NMR (DMSO-d 6 6) :1.18 (6H, di, J=6.lHz), 2.18-2.43 (2H, in), 3.51-3.83 (4H, mn), 3.90 (3H, 7.06 (2H, di, J=8.9Hz), 7.66 (2H, di, J=8.7Hz), 7.78 (2H, di, J=8.4Hz), 7.98 (2H, di, J=8.4Hz), 7.98-8.16 (4H, mn), 10.58 (1H, 10.71 (1H, s) MASS (in/z) :488 (M 4 +1) Preparation 323 NMR (DMSO-ci 6 6) :0.89 (6H, 1.05-1.72 (8H, mn), 2. 09-2. 30 (1H, mn), 2. 54-2. 73 (4H, mn), 3. 14-3. 37 (4H, mn), 3.90 (3H, 6.99 (2H, di, J=8.9Hz), 7.81 (2H, di, J=8.8Hz), 8.03 (2H, di, J=8.6Hz), 8.09 (2H, di, J=8.7Hz), 10.26 (11, 10.58 s) MASS (in/z) :493 (M+1) Preparation 324 IR (KBr) :1714, 1687, 1653, 1605, 1560, 1522, 1460, 1439 cin 1 WO 99/40108 PCT/JP99/00538 186 NMR (DMSO-d 6 6) 1.45-1.70 (2H, 1.87-2.10 (2H, m), 2.98-3.20 (2H, 3.56-3.78 (3H, 3.90 (3H, s), 4.56 (2H, 7.01 (2H, d, J=9.0Hz), 7.21-7.46 7.80 (2H, d, J=8.8Hz), 8.04 (2H, d, J=8.7Hz), 8.09 (2H, d, J=8.7Hz), 10.26 (1H, 10.58 (1H, s) MASS 488 (M+1) Preparation 325 NMR (DMSO-d 6 6) 1.18-2.05 (10H, 3.90 (3H, s), 4.34-4.50 (1H, 7.05 (2H, d, J=8.8Hz), 7.69 (2H, 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, 10.72 (1H, s) MASS 473 Preparation 326 IR (KBr) 2945, 2852, 1720, 1693, 1645, 1601, 1524, 1485 cm- 1 NMR (DMSO-d 6 6) 1.61 (2H, 1.87 (2H, 2.78-3.14 (3H, 3.90 (3H, 4.61 (2H, 6.96 (1H, d, J=9.2Hz), 7.27 (5H, 7.98-8.10 (1H, 8.03 (2H, d, J=8.7Hz), 8.10 (2H, d, J=8.6Hz), 8.70 (1H, d, J=2.3Hz), 10.34 (1H, 10.62 (1H, s) MASS 459 Preparation 327 NMR (DMSO-d 6 6) 1.36 (3H, t, J=7.0Hz), 3.90 (3H, s), 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, 10.72 (1H, s) MASS 419 Preparation 328 IR (KBr) 2951, 2872, 1724, 1680, 1651, 1605, 1554, 1497, 1439 cm- 1 NMR (DMSO-d 6 6) 1.57-1.89 (4H, 3.25 (3H, 3.39 (2H, t, J=6.2Hz), 3.91 (3H, 4.05 (2H, t, J=6.1Hz), 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 477 Preparation 329 IR (KBr) 1720, 1678, 1643, 1608, 1564, 1525, 1502 cm- 1 NMR (DMSO-d 6 5) 0.96-1.36 (5H, m) 1.49-1.91 (5H, m), 2.16-2.35 (1H, 2.52-2.75 (4H, 3.10-3.35 (4H, 3.90 (3H, 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, 10.59 (1H, s) MASS 465 Preparation 330 IR (KBr) 1722, 1676, 1641, 1608, 1500, 1446 cm 1 NMR (DMSO-d 6 5) 0.90 (3H, d, J=6.8Hz), 1.30-1.85 (9H, 2.11-2.30 (1H, 2.63-2.69 (4H, 3.18-3.38 (4H, 3.90 (3H, 6.99 (2H, d, J=9.0Hz), 7.81 (2H, d, J=8.8Hz), 8.04 (2H, d, J=9.1Hz), 8.09 (2H, d, J=8.7Hz), 10.27 (1H, 10.58 (1H, s) MASS 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, 1.08-1.51 (3H, 1.60-1.90 (4H, 2.14-2.35 (1H, 2.54-2.66 (4H, 3.13-3.36 (4H, 3.90 (3H, 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, 10.58 (1H, s) MASS 479 Preparation 332 NMR (DMSO-d 6 5) 1.18 (3H, t, J=7.0Hz), 3.52 (2H, q, 3.90 (3H, 4.52 (2H, 7.45 (2H, d, J=8.2Hz), 7.75 (2H, d, J=8.2Hz), 7.84 (2H, d, 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, 10.74 (1H, s) MASS 433 Preparation 333 NMR (DMSO-d 6 5) 3.28 (3H, 3.47-3.66 (4H, 3.91 (3H, 4.56 (2H, 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, 10.65 (1H, 10.74 (1H, s) MASS 463 Preparation 334 NMR (DMSO-d 6 5) 3.26 (3H, 3.39-3.55 (2H, m), 3.55-3.66 (2H, 3.77 (2H, t, J=4.5Hz), 3.90 (3H, 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=8.5Hz), 8.06 (2H, d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.61 (1H, 10.73 (1H, s) MASS 493 Preparation 335 NMR (DMSO-d 6 6) 1.12 (3H, t, J=7.0Hz), 1.88-2.12 (2H, 3.44 (2H, q, J=7.0Hz), 3.53 (2H, t, J=6.4Hz), 3.91 (3H, 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, 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) MASS 477 Preparation 336 NMR (DMSO-d 6 6) 1.14 (3H, t, J=7.0Hz), 3.52 (2H, q, 3.68-3.78 (2H, 3.90 (3H, 4.14- 4.22 (2H, 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=8.4Hz), 8.06 (2H, d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.61 (1H, 10.73 (1H, s) MASS 463 (M+1) Preparation 337 IR (KBr) 1724, 1680, 1655, 1605, 1495, 1437 cm- 1 WO 99/40108 PCT/JP99/00538 189 NMR (DMSO-d 6 6) 1.98 (2H, 3.26 (3H, 3.49 (2H, t, J=6.3Hz), 3.90 (3H, 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, d, J=8.7Hz), 8.10 (2H, d, J=8.7Hz), 10.60 (1H, s), 10.72 (1H, s) MASS 463 Preparation 338 IR (KBr) 1724, 1682, 1645, 1605, 1495, 1439, 1404 cm- 1 NMR (DMSO-d 6 6) 3.33 (3H, 3.69 (2H, 3.90 (3H, 4.16 (2H, 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) MASS 287 Preparation 339 IR (Nujol) 3259, 1724, 1672, 1626, 1605 cm- 1 NMR (DMSO-d 6 5) 1.9-2.2 (4H, 2.93 (3H, 3.0-3.4 (2H, 3.7-3.8 (2H, 3.90 (3H, 7.06 (2H, d, J=8.9Hz), 7.45 (4H, 7.82 (2H, d, J=8.9Hz), 8.0-8.2 (4H, 10.27 (1H, 10.59 (1H, s) (+)APCI MASS 522 (M+H) Preparation 340 IR (KBr) 3247.5, 1727.9, 1687.4, 1255.4 cm- 1 NMR (DMSO-d 6 5) 1.23-1.99 (16H, 2.15-2.45 (2H, m), 3.21 (3H, 3.27-3.35 (2H, 3.60 (3H, 4.02 (2H, t, J=6.4Hz), 7.00 (2H, d, J=8.6Hz), 7.83 (2H, d, J=8.6Hz), 9.74 (1H, 10.12 (1H, s) MASS 435 (M+1) Preparation 341 IR (KBr) 3236.0, 1724.0, 1677.8, 1255.4 cm- 1 NMR (DMSO-d 6 6) 0.91 (3H, t, J=7.0Hz), 1.30-1.50 (4H, 1.70-1.80 (2H, 3.87 (3H, 4.03 (2H, t, J=6.4Hz), 7.03-7.07 (2H, 7.68-8.00 (8H,m), 10.50-11.00 (2H, m) WO 99/40108 PCT/JP99/00538 190 MASS :467 (M+1) Preparation 342 IR :3201.3, 1714.4, 1594.8, 1253.5 cm- 1 NMR (DMSO-d 6 6) :1.30-1. 80 (8H, in), 2.42 (3H, s) 3.21 (3H, s) 3.28-3. 34 (2H, mn), 3. 34 (3H, s) 3.85 (3H, 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, 10.39 (1H, s) MASS :457 (M+1) Preparation 343 IR (KBr) :3199.3, 1716.3, 1608.3, 1253.5 cm- 1 NMR (DMSO-d 6 6) :1.37-1.80 (8H, mn), 3.21 (3H, s), 3.28-3.33 (2H, mn), 3.71 (3H, 4.03 (2H, t, J=6.4Hz), 6.39-6.59 (2H, in), 7.00-7.04 (2H, in), 7.24-7.47 (2H, in), 7.83-7.88 in), 10.35 (2H, d, J=6. 9Hz) MASS (in/z) :405 (M+1) Preparation 344 IR (KBr) :3193.5, 1718.3, 1606.4, 1249.6 crrC 1 NMR (DMSO-d 6 6) :1.00 (3H, t, J=7.4Hz), 1.75-1.85 (2H, m) 97-4. 03 (5H,im) ,7.06-8. 78 (12H, m) ,10. 64 (1H, 10.72 (1H, s) MASS (in/z) :483 (M+1) Preparation 345 IR (KBr) :3220.5, 1720.2, 1685.5, 1290.1, 1251.6 citC 1 NMR (DM50-cl 6 6) :1.30-1.80 (8H, in), 3.22 (3H, s), 3.28-3.34 (2H, in), 3.94 (3H, 4.05 (2H, t, J=6.3Hz), 7.04-7.08 (2H, mn), 7.91-8.71 (8H, in), 10.47 (1H, bs), 10.70 (iH, bs) MASS (in/z) :479 (M+1) The following compounds [Preparations 346 to 355 were obtained in a manner similar to that of Preparation 41.
Preparation 346 IR (KBr) :1726, 1284 cm- 1 WO 99/40108 PCT/JP99/00538 191 NMR (CDC1 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, 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, 8.55 (1H, s) MASS 491 (M +1) Preparation 347 NMR (CDC1 3
-CD
3 0D, 6) 1.15-1.40 (6H, 1.40-2.30 (12H, 2.80-3.55 (4H, 3.65-3.80 (4H, 3.97 (3H, 4.00-4.25 (1H, 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+l1) Preparation 348 NMR (CDC1 3
+CD
3 0D, 6) 1.20-1.60 (5H, 1.65-2.05 2.50-2.70 (1H, 3.97 (3H, 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 NMR (CDC1 3 6) 1.20-2.15 (10H, 3.97 (3H, s), 4.30-4.50 (1H, 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 IR (KBr) 1722, 1651, 1574, 1522, 1279 cm 1 NMR (CDC1 3 6) 0.92 (3H, t, J=6.7Hz), 1.2-1.9 (8H, m), 3.97 (3H, 4.01 (2H, t, J=6.5Hz), 7.01 (2H, d, 7.64 (2H, d, J=9.0Hz), 8.07 (2H, d, J=8.6Hz), 8.15 (1H, 8.17 (2H, d, J=8.6Hz), 8.46 (1H, s) MASS 465 Preparation 351 IR (KBr). 1727.9, 1249.6, 1180.2 cm 1 NMR (DMSO-d 6 5) 1.30-2.30 (18H, 3.21 (3H, s), 3.28-3.35 (2H, 3.62 (3H, 4.04 (2H, t, WO 99/40108 PCT/JP99/00538 192 J=6.4Hz), 7.07 (2H, d, J=8.7Hz), 7.85 (211, di, J=8. .7Hz) MASS (in/z) :433 (M+1) Preparation 352 IR (KBr) :1724.0, 1604.5, 1261.2, 1182.2 cm- 1 NMR (DMSO-d 6 6) :1.23-1. 80 mn), 2. 48 (3H, s) 3.22 (3H1, s) 3.22-3. 33 (2H, mn), 3. 33 (3H, s) 3. 87 (311, 4.07 (2H, t, J=6.4Hz), 7.13 (2H, d, J=8.9Hz), 7.76-8.00 (4H, m) MASS (in/z) :455 (M+1) Preparation 353 IR :1718.3, 1629.6, 1257.4, 1226.5 cm-i NMYR (DMSO-d 6 6) :1.25-1.75 (8H, mn), 3.21 (3H, s), 3.28-3.34 (2H, mn), 3.72 (3H, 4.06 (2H1, t, J=6.4Hz), 6.33-6.41 (2H, mn), 7.09-7.13 (211, m), 7.27-7.60 (2H, in), 7.90-7.95 (2H, mn) MASS :403 (Ivl) Preiparation 354 IR (KBr) :1716.3, 1297.9, 1255.4 cmrJ 1 NMR (DMSO-d 6 6) :1.20-1.80 (811, mn), 3.22 (3H, s), 3.28-3.33 (2H, mn), 3.95 (311, 4.08 (2H, t, J=6.4Hz), 7.12-7.17 (2H1, in), 7.97-8.73 (8H, mn) MASS :47 (M+1) Preparation 355 IR (KBr) :2935.1, 2854.1, 1257.4, 827.3 cm-1 NMR CCDCl 3 6) :0.80-1.10 (3H, mn), 1.20-1.60 (811, in), 1.70-2.00 (2H, mn), 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 (211, d, J=8.BHz), 7.95 (1H, s) APCI MASS (in/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 crrJ 1 MR (CDC13, 6) 66 (411, brs) 3.23 (411, brs) 3. 64 (2H, WO 99/40108 PCT/JP99/00538 193 3.90 (3H, 6.92 (3H, 7.26 (2H, 7.52 (2H, d, J=8.0Hz), 7.73 (2H, d, J=8.0Hz), 8.0-8.3 8.56 (1H, s) MASS 537 Preparation 357 IR (KBr) 1718, 1520, 1275, 1242 cm- 1 NMR (CDC1 3 5) 1.5-1.8 (6H, 3.24 (4H, t, J=5.3Hz), 3.97 (3H, 7.02 (2H, d, J=9.1Hz), 7.59 (2H, d, J=9.1Hz), 8.07 (2H, d, J=8.7Hz), 8.14 (1H, 8.17 (2H, d, J=8.7Hz), 8.44 (1H, s) MASS 446 Preparation 358 NMR (DMSO-d 6 5) 1.50-1.95 (4H, 2.60-3.05 (3H, m), 3.90 (3H, 3.95-4.10 (2H, 6.90-7.35 (7H, m), 7.65-8.15 (6H, m) APCI MASS 456 Preparation 359 NMR (CDC1 3 5) 2.0-2.2 (4H, 3.2-3.4 (4H, 3.97 (3H, 6.62 (2H, d, J=8.8Hz), 7.56 (2H, d, J=8.8Hz), 8.07 (2H, d, J=8.4Hz), 8.13 (1H, 8.17 (2H, d, J=8.4Hz), 8.40 (1H, s) MASS 432 (M 4 +1) Preparation 360 NMR (CDC1 3 5) 0.95 (3H, t, J=6.6Hz), 1.33-1.94 (6H, 3.99 (3H, 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 543 Preparation 361 IR (KBr) 1722, 1603, 1500, 1439, 1417 cm- 1 NMR (CDC1 3 5) 3.30-3.69 (8H, 3.93 (3H, 6.88-7.17 (3H, 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) MASS 457 WO 99/40108 PCT/JP99/00538 194 Preparation 362 NMR (CDC1 3 6) 0.95 (3H, t, J=7.4Hz), 1.40-2.16 (6H, 3.03-3.30 (2H, 3.45 (2H, t, J=6.7Hz), 3.44-3.95 (3H, 3.96 (3H, 6.85-7.12 (2H, m), 7.80-7.97 (2H, 8.07 (2H, d, J=8.6Hz), 8.15 (2H, d, J=8.6Hz) MASS 438 Preparation 363 IR (KBr) 1722, 1605, 1520, 1439, 1414 cm- 1 NMR (CDC1 3 6) 0.92 (6H, 1.12-1.90 (8H, 2.18-2.24 (1H, 2.68-2.86 (4H, 3.27-3.46 (4H, 3.96 (3H, 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 491 (M+1) Preparation 364 IR (KBr) 1716, 1606, 1520, 1441, 1417 cm- 1 NMR (CDC1 3 6) 1.70-2.26 (4H, 3.10-3.31 (2H, m), 3.60-3.84 (3H, 3.96 (3H, 4.60 (2H, s), 6.90-7.20 (2H, 7.26-7.46 (5H, 7.91 (2H, d, J=8.8Hz), 8.09 (2H, d, J=8.7Hz), 8.15 (2H, d, J=8.7Hz) MASS 486 Preparation 365 IR (KBr) 2941, 2845, 1713, 1601, 1549, 1504, 1431, 1404 cm 1 NMR (CDC1 3 6) 1.79 (2H, 2.01 (2H, 2.84 (1H, 3.08 (2H, 3.96 (3H, 4.64 (2H, 6.80 (1H, d, J=9.1Hz), 7.18-7.40 (5H, 8.03-8.23 8.73 (1H, d, J=2.3Hz) MASS 457 Preparation 366 IR (KBr) 2949, 2870, 1722, 1605, 1504, 1437 cm-i NMR (CDC1 3 5) 1.66-2.00 (4H, 3.27 (3H, 3.47 (2H t, J=6.0Hz), 3.97 (3H, 4.05 (2H, t, J=6.1Hz), 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, 8.17 (2H, d, MASS 475 Preparation 367 IR (KBr) 1720, 1605, 1522, 1439, 1416 cm- 1 NMR (CDC1 3 5) 1.00-1.41 (5H, 1.56-2.14 (5H, m), 2.24-2.41 (1H, 2.66-2.82 (4H, 3.27-3.43 (4H, 3.96 (3H, 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, J=8.6Hz) MASS 463 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, 2.24-2.47 (1H, 2.66-2.92 (4H, 3.28-3.53 (4H, 3.96 (3H, 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 477 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, 1.13-2.07 (7H, 2.24-2.50 (1H, 2.68-2.93 (4H, 3.30-3.52 (4H, 3.96 (3H, 6.97 (2H, 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 477 (M 4 +1) Preparation 370 IR (KBr) 2976, 1716, 1601, 1531, 1500, 1479, 1437 cm- 1 NMR (CDC1 3 6) 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) MASS 417 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, 1.51-2.05 (5H, m), 2.24-2.43 (1H, 2.69-2.84 (4H, 3.22-3.36 (4H, 3.97 (3H, 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, 8.09-8.15 (4H, m) MASS 539 (M +1) Preparation 372 IR (KBr) 1718, 1601, 1429 cm-
I
NMR (CDC1 3 6) 1.29 (6H, d, J=6.3Hz), 2.36-2.56 (2H, 3.44-3.63 (2H, 3.74-3.93 (2H, 3.96 (3H, 6.99 (2H, d, J=8.9Hz), 7.58 (2H, d, J=8.8Hz), 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 486 (M +1) Preparation 373 IR (KBr) 1707, 1603, 1529, 1498, 1433, 1414 cm-
I
NMR (CDC1 3 6) 1.23-2.12 (10H, 3.97 (3H, s), 4.18-4.38 (1H, 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, 8.06-8.25 (4H, m) MASS 471 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, 1.79 (2H, 3.97 (3H, 4.03 (2H, 7.00 (2H, m), 7.45-7.78 (4H, 7.96-8.29 (6H, m) MASS 445 (M +1) Preparation 375 IR (KBr) 1716, 1435 cm-
I
NMR (CDC1 3 6) 1.28 (3H, t, J=7.0Hz), 3.60 (2H, q, J=7.0Hz), 3.97 (3H, 4.58 (2H, 7.47 (2H, d, WO 99/40108 PCT/JP99/00538 197 J=8. 3Hz) 7. 56-7. 78 (4H, mn), 8. 04 29 (6H, m) MASS :431 Prep~aration 376 IR :1720, 1651, 1606, 1560, 1504, 1435 cm- 1 NMP. (CDC1 3 6) :3.42 (3H, in), 3.55-3.71 (4H, mn), 3.97 (3H, 4.64 (2H, 7.47 (2H, di, J=8.2Hz), 7.64 (2H, d, J=8.2Hz), 7.68-7.80 (2H, in), 8.04-8.26 (6H, Mn) MASS (in/z) :461 Preparation 377 IR (KBr) :2926, 2877, 1720, 1605, 1504, 1437 cnC- 1 MR (CDC1 3 6) 3. 41 (3H, s) 3. 54-3. 64 (2H,im) 3. 69-3. 78 (2H, mn), 3.86-3.96 (2H, mn), 3.97 (3H, 4.14-4.28 (2H, mn), 6.95-7.18 (2H, mn), 7.51-5.64 (2H, in), 5.64-6.77 (2H, mn), 8.00-8.26 (6H mi) MASS (in/z) 491 Prep~aration 378 MR (CDC1 3 6) 1.22 (3H, t, J=7. OHz) 2. 09 (2H, in), 3. 52 (2H, q, J=7.OHz), 3.63 (2H, t, J=6.2Hz), 3.97 (3H, 4.13 (2H, t, J=6.2Hz), 7.02 (2H, di, 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, mn) MASS (in/z) 475 Preparation 379 NMR (CDC1 3 6) 1.27 (3H, t, J=7.OHz), 3.63 (2H, q, J=7.OHz), 3.74-3.90 (2H, mn), 3.97 (3H, 4.14- 4.28 (2H, in), 7.04 (2H, d, J=8.7Hz), 7.59 (2K, di, J=8.7Hz), 7.69 (2H, di, J=8.3Hz), 8.06 (2H, di, J=8.2Hz), 8.10 (2H, d, 8.16 (2H, di, MASS (in/z) 461 Preparation 380 IR (KBr) 1722, 1605, 1531, 1500, 1435 cm- 1 MR (CDC13, 6) 2.09 (2H, in), 3.38 (3H, 3.59 (2K, t, J=6.lHz), 3.97 (3H, 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, mn), 7. 70 (2H, d, J=8. S~z) 8. 07 (2H, d, J=8. 4Kz) 8. 08-8.25 (4H, Mn) MASS (in/z) :461 Preparation 381 TR (KBr) :1720, 1643, 1603, 1531, 1500, 1435 cin 1 NM'R (CDC1 3 5) :3.48 (3H, 3.80 (2H, mn), 3.97 (3H, 4.18 (2H, mn), 7.04 (2H, di, J=8.8Hz), 7.51-7.,77 (4H, in), 8.03-8.23 (6H, in) MASS (in/z) 447 Prep~aration 382 IR (Nujol) 1714, 1601 cin' NMR (CDC1 3 5) :1.7-2.0 (4H, in), 2.75 (3K, 3.0-3.2 (211, in), 3.4-3. 6 (2H, mn), 3. 69 (3H, s) 6.77 (2H, d, J=8.8Hz), 7.08 (4H, 7.60 (2K, d, J=8.8Hz), 7.7-8.0 (4H, mn) (+)APCI MASS :520 The following compounds [Preparations 383 to 3881 were obtained in a manner similar to that of Preparation 33.
Preparation 383 IP. (KBr) :1699, 1684 cirC 1 NMR (DMSO-d 6 5) :0.86 (3K, t, J=6.6Hz), 1.2-1.7 in), 3.46 (2H, t, J=6.6Hz), 4.51 (2H, 7.50 (2K, d, J=8.6Hz), 7.95 (2K, d, J=8.6Hz), 8.13 (4H, s), 8.42 (1K, 9.36 (1H, s) MASS (in/z) :477 Prep~aration 384 IR (KBr) :1583, 1543, 1516, 1396 cm- 1 MR (DMSO-d 6 5) :2.4-2.6 (4K, in), 3.1-3.3 (4K, mn), 3.60 (2K, s) 6.77 (1K, t, 4Kz), 6.93 (2K, d, J=7.4Kz) 7.20 (2K, t, J=7.4Kz), 7.9-8.1 (6K, in), 8.39 (1K, 9.32 (1K, s) MASS :523 Preparation 385 IR (KBr) :1716, 1520, 1277, 1109 cm- 1 WO 99/40108 PCT/JP99/00538 199 MASS :432 Preparation 386 IR (KBr) :1684, 1518, 1252 cm-1 Preparation 387 NMR (DMSO-d 6 :1.60-2.10 (4H, in), 2.70-3.10 (3H, mn), 4.08 (2H, in), 7.10-7.40 (7H, in), 7.95 (2H, di, 8.18 (4H, AB-q, J=8.3Hz, J=16.lHz) APCI MASS :426 Prep~aration 388 IR (KBr) :1687, 1610, 1568, 1527 cm- 1 MASS :418 The following compounds [Preiparations 389 to 393 were obtained in a manner similar to that of Preparation 57.
Prep~aration 389 NIMR (CDC1 3
-CD
3 OD, 5) :2.10-2.25 (2H, in), 2.65-3.15 (3H, in), 3.45-3.70 (2H, in), 3.99 (3H, 7.30-7.40 mn), 7.90-8.40 (8H, in) APCI MASS :440 Preparation 390 NMR (DMSO-d 6 6) :1.10-2.10 (10H, in), 3.91 (3H, s), 4.40-4.60 (1H, in), 7.17 (2H, d, J=8.9Hz), 8.00-8.30 (6H, in) APCI MASS (positive) :379.2 Preparation 391 NIAR (DMSO-d 6 5) :1.20-1.60 (5H, mn), 1.60-1.95 (5H, mn), 2.50-2.75 (1H, in), 3.92 (3H 7.50 (2H, d, J=8.3Hz), 8.07 (2H, di, J=8.3Hz), 8.18 (2H, di, J=8.7Hz), 8.28 (2H, di, J=8.7Hz) APCI MASS (positive) :363.3 Preparation 392 IR (KBr) :1724.0, 1253.5, 1199.5 cm- 1 MR (ODC1 3 6) :0.95 (3H, t, J=7.OHz), 1.35-1.60 (4H, in), 1.70-1.95 (2H, mn), 3.88-4.05 (5K, in), 6.98-7.03 (2H, in), 7.57-8.17 (8H, in) MASS (in/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 6) 1.01 (3H, t, J=7.4Hz), 1.50-1.80 (2H, 3.97-4.05 (5H, 7.06-7.10 (2H, 7.70-9.35 (12H, m) MASS 465 (M+l) The following compounds [Preparations 394 to 457] were obtained in a manner similar to that of Preparation 49.
Preparation 394 NMR (DMSO-d 6 5) 1.10-1.95 (12H, 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 Preparation 395 NMR (DMSO-d 6 6) 1.10-1.60 (5H, 1.60-1.95 (5H, m), 2.50-2.70 (1H, 7.45 (2H, d, J=8.3Hz), 7.96 (2H, d, J=8.3Hz), 8.14 (4H, s) Preparation 396 NMR (DMSO-d 6 6) 1.20-2.10 (10H, 4.35-4.60 (1H, m), 7.13 (2H, d, J=8.9Hz), 7.95 (2H, d, J=8.9Hz), 8.12 (4H, s) APCI MASS (negative) 379.2 (M 4 -1) Preparation 397 NMR (DMSO-d 6 6) 1.50-2.00 (4H, 2.65-3.10 (3H, m), 3.95-4.15 (2H, 6.90-7.35 (7H, 7.70-8.30 (6H ,m) APCI MASS 442 Preparation 398 NMR (DMSO-d 6 6) 1.20-2.10 (10H, 4.40-4.60 (1H, m), 7.17 (2H, d, J=8.9Hz), 7.95-8.30 (6H, 13.0-13.5 (1H, m) APCI MASS (positive) 365.2 Preparation 399 NMR (CDC13, 6) 1.15-1.60 (5H, 1.65-2.05 (5H, m), 2.50-2.70 (1H, 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 Preparation 400 lIP (KBr) :2935, 2858, 1705, 1649, 1601, 1531, 1500, 1441, 1400 cm 1 i MASS 523 Prep~aration 401 MASS 527 Preparation 402 NNR (DMSO-d 6 6) :3.30-3.64 mn), 6.75-7.33 (7H, mn), 7.70-8.29 (6H, mn) MASS :443 (M+-2HC1+1) Preparation 403 NIAR (DMSO-d 6 6) :0.88 (3H, t, J=7.4Hz), 1.35-1.63 (4H 1.82-2.03 (2H, mn), 2.99-3.20 (2H mi), 3.40 t, J=6.6Hz), 3.40-3.80 (3H, mn), 7.09 (2H, d, J=9.OHz), 7.84 (2H, d, J=8.9Hz), 8.11 (4H, 13.22 (1H, brs) MASS :424 (M+-HC1+1) Preparation 404 IR (KBr) :1686, 1601, 1531, 1500, 1421 cm- 1 NMR (DMSO-d 6 5) :1.18 (6H, d, J=6.lHz), 2.24-2.45 (2H, mn), 3.63-3.82 (4H, in), 7.08 (2H, di, J=8.6Hz), 7.68 (2H, di, J=8.8Hz), 7.90 (2H, di, J=8.5Hz), 8.08 (2H, di, J=8.3Hz), 8.13 (2H, d, J=8.7Hz), 8.16 (2H, di, J=8 .7Hz) MASS (in/z) :472 (M 4 +1) Preparation 405 JR (KBr) :1705, 1606, 1524, 1441, 1412 cm 1 i MASS (in/z) :477 Preparation 406 JR (KBr) :1686, 1603, 1568, 1520, 1416 cirC 1 NMR (DMSO-d 6 6) :1.49-1.71 (2H, mn), 1.90-2.10 (2H, mn), 3.06-3.24 (2H, mn), 3.58-3.80 (3H, in), 4.56 (2H, s), 7.10 (2H, di, J=9.OHz), 7.23-7.46 (5H, in), 7.85 (2H, WO 99/40108 PCT/JP99/00538 202 d, J=8.9Hz), 8.10 (4H, m) MASS 472 Preparation 407 IR (KBr) 1682, 1606, 1572, 1524, 1498, 1427 cm- 1 NMR (DMSO-d 6 6) 1.25-2.05 (10H, 4.35-4.50 (1H, m), 7.07 (2H, d, J=8.8Hz), 7.64-7.94 (4H, 7.99-8.26 (6H, m) MASS 457 (M+1) Preparation 408 IR (KBr) 2933, 2846, 1686, 1599, 1552, 1500, 1429 cm-
I
NMR (DMSO-d 6 6) 1.56-2.00 (4H, 2.74-3.18 (3H, m), 4.62 (2H, 7.00-7.40 (6H, 7.99-8.26 (5H, m), 8.74 (1H, 13.20 (1H, brs) MASS 443 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, 7.65-8.25 (10H, m) MASS 403 (M +1) Preparation 410 IR (KBr) 1693, 1603, 1572, 1527, 1500, 1471, 1425 cm- 1 NMR (DMSO-d 6 6) 1.60-1.84 (4H, 3.25 (3H, s), 3.30-3.50 (2H, 4.00-4.16 (2H, 7.07 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.6Hz), 7.87 (2H, d, 8.04-8.20 (6H, m) MASS 461 Preparation 411 IR (KBr) 1705, 1606, 1524, 1441, 1412 cm- 1 NMR (DMSO-d 6 6) 1.00-2.20 (10H, 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 447 (M -1) WO 99/40108 PCT/JP99/00538 203 Preparation 412 IR (KBr) 1703, 1605, 1524, 1441, 1412 cm- 1 NMR (DMSO-d 6 6) 0.95 (3H, d, J=6.8Hz), 1.43-2.00 (9H, 3.16-3.48 (9H, 7.17 (2H, d, J=8.4Hz), 7.92 (2H, d, J=8.3Hz), 8.12 (4H, s) Preparation 413 IR (KBr) 1705, 1605, 1524, 1443, 1414 cm- 1 NMR (DMSO-d 6 6) 0.88 (3H, d, J=6.4Hz), 0.86-1.60 1.74-1.92 (2H, 2.00-2.20 (2H, 2.97-3.35 (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 NMR (DMSO-d 6 5) 0.95 (3H, t, J=7.2Hz), 1.44 (2H, m), 1.74 (2H, 4.05 (2H, 7.02-7.14 (2H, m), 7.66-8.30 (10H, m) MASS 431 Preparation 415 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, 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) MASS 417 (M +1) Preparation 416 IR (KBr) 1682, 1605, 1566, 1425 cm- NMR (DMSO-d 6 6) 3.28 (3H, 3.46-3.64 (4H, 4.56 (2H, 7.47 (2H, d, J=8.2Hz), 7.78 (2H, d, J=8.2Hz), 7.92 (2H, d, J=8.4Hz), 8.07-8.25 (6H, m) MASS 447 (M+1) Preparation 417 IR (KBr) 1684, 1603, 1500, 1423 cm 1 NMR (DMSO-d 6 6) 3.26 (3H, 3.35-3.54 (2H, m), 3.54-3.68 (2H, 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 477 Preparation 418 NMR (DMSO-d 6 6) 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, 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, 3.68-3.80 (2H, 4.13-4.24 (2H, 7.08 (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 447 Preparation 420 IR (KBr) 1686, 1603, 1529, 1498, 1470, 1427 cm- 1 NMR (DMSO-d 6 6) 1.98 (2H, 3.27 (3H, s), 3.50 (2H, t, J=6.2Hz), 4.09 (2H, 7.07 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, 8.10 (2H, d, J=8.5Hz), 8.10-8.21 (4H, m) MASS 447 (M +1) Preparation 421 IR (KBr) 1684, 1603, 1525, 1500, 1421 cm- 1 NMR (DMSO-d 6 6) 3.32 (3H, 3.69 (2H, 4.17 (2H, 7.09 (2H, d, J=8.9Hz), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.6Hz), 8.03-8.20 (6H, m) MASS 433 (M +1) Preparation 422 IR (Nujol) 1684, 1601 cm- 1 NMR (DMSO-d 6 6) 1.8-2.2 (4H, 2.94 (3H, 3.1-3.3 (2H, 3.7-3.9 (2H, 7.14 (2H, d, J=8.9Hz), 7.45 WO 99/40108 PCT/JP99/00538 205 (4H, 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 Preparation 424 IR (KBr) 1685.5, 1608.3, 1238.1 cm- 1 NMR (DMSO-d 6 5) 2.79-4.42 (13H, 6.92-7.14 (2H, m), 7.21-7.30 (4H, m) 7.81-7.96 (2H, 11.60 (1H, bs), 12.55 (1H, bs) MASS 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, 3.21 (3H, s), 3.28-3.35 (2H, 4.04 (2H, t, J=6.4Hz), 7.07 (2H, d, J=8.8Hz), 7.86 (2H, d, J=8.8Hz), 12.14 (1H, s) MASS 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, 1.60-1.90 (2H, 4.00-4.10 (2H, 7.02-7.08 (2H, 7.63-8.36 (8H, m) MASS 435 (M+1) Preparation 427 IR (KBr) 1693.2, 1305.6, 1259.3, 1178.3 cm- 1 NMR (DMSO-d 6 6) 1.38-1.80 (8H, 2.56 (3H, 3.22 (3H, 3.28-3.34 (5H, 4.06 (2H, t, J=6.4Hz), 7.12 (2H, d, J=8.9Hz), 7.72 (1H, 7.86 (1H, s), 7.97 (2H, d, J=8.8Hz), 13.12 (1H, bs) MASS 441 (M+1) Preparation 428 IR (KBr) 1675.8, 1606.4, 1259.3 cm- 1 NMR (DMSO-d 6 5) 1.40-2.00 (8H, 3.35 (3H, 3.40 (2H, t, J=6.3Hz), 4.03 (2H, t, J=6.3Hz), 6.13-6.20 (2H, 6.96-7.94 (6H, m) MASS 389 (M+1) WO 99/40108 PCT/JP99/00538 206 Preparation 429 IR (KBr) :1699.0, 1604.5, 1249.6, 1193.7 cmn 1 NMR (DMSO-d 6 6) :1.00 (3H, t, J=7.4Hz), 1.67-1.85 (28, in), 3.99 (2H, t, J=6.5Hz), 7.04-7.09 (2H, in), 7.65-9.32 (12H, mn) MASS (in/z) :451 (M+1) Preparation 430 IR (KBr) :1685.5, 1253.5, 1174.4 cm-1 NNR (DMSO-c1 6 6) :1.20-1.80 (8H, mn), 3.2 2 (3H, s), 3.29-3.35 (2H, mn), 4. 00-4 .15 (2H, mn), 7. 12-7. 17 (2H, mn), 7.97-8.68 (8H, mn) MASS :463 (M+1) Preparation 431 IK (KBr) :2950.6, 1708.6, 1608.3, 1473.3, 1419.4, 1367.3, 1259.3, 1211.1, 1174.4 crrC' MASS :477 Preiparation 432 IR (KBr) :2946, 1710, 1608, 1469, 1413, 1369, 1307, 1263, 1218, 1176 cm- 1 MASS (in/z) :491 Preiparation 433 IR (KBr) :2944, 1706, 1606, 1469, 1417, 1375, 1259, 1176 cm-i MASS :505 Prepjaration 434 IR (KBr) :3396, 2948, 2871, 1608, 1542, 1471, 1382, 1263, 1180, 1110 crrC 1 MASS :493 Preparation 435 1K (KBr) :2942, 1687, 1608, 1471, 1309, 1261, 1176 crrC 1 MASS (in/z) :521 Preparation 436 1K (KBr) :2937, 1706, 1683, 1606, 1469, 1417, 1307, 1255, 1174, 1110 ci WO 99/40108 PCT/JP99/00538 207 MASS 535 Preparation 437 IR (KBr) 2946, 2570, 1706, 1608, 1469, 1415, 1371, 1309, 1259, 1216, 1174, 1108 cm- 1 MASS 509 (M+H Preparation 438 IR (KBr) 2940, 2867, 2665, 2547, 1681, 1606, 1469, 1421, 1311, 1290, 1255, 1176, 1116 cm- 1 MASS 438 (M+H Preparation 439 IR (KBr) 2939, 2861, 1681, 1606, 1469, 1421, 1311, 1253, 1174, 1114, 1016, 833 cm- 1 MASS 452 Preparation 440 IR (KBr) 2935, 2858, 1681, 1606, 1571, 1467, 1419, 1311, 1253, 1174, 1112 cm- 1 MASS 466 (M+H Preparation 441 IR (KBr) 2931, 2854, 2663, 1679, 1606, 1467, 1421, 1311, 1290, 1253, 1174, 1116 cm-i MASS 480 Preparation 442 IR (KBr) 2935, 2850, 2819, 1608, 1589, 1537, 1473, 1417, 1240 cm-
I
MASS 405 (M+H Preparation 443 IR (KBr) 3361, 2969, 2848, 1606, 1585, 1535, 1475, 1402, 1238, 1180, 1114, 927 cm- 1 Preparation 444 IR (KBr) 2975, 2873, 2829, 2665, 1681, 1606, 1469, 1423, 1315, 1288, 1240, 1176 cm- 1 MASS 435 (M+H Preparation 445 IR (KBr) 2969, 2530, 1672, 1604, 1467, 1423, 1288, 1267, 1228, 1191 cm- 1 WO 99/40108 PCT/JP99/00538 208 MASS (in/z) :423 Preparation 446 IR (KBr) :2937, 1702, 1606, 1473, 1405, 1369, 1268, 1241, 1176 cmi MASS (in/z) :434 Preparation 447 MASS :488 Preparation 448 IR (KBr) :2956, 2869, 2665, 2543, 1681, 1608, 1544, 1492, 1469, 1423, 1332, 1292, 1245, 1172 cm- 1 MASS :394 Preparation 449 IR (KBr) :2954, 2865, 2665, 2545, 1681, 1608, 1544, 1492, 1423, 1332, 1292, 1247, 1172 cm- 1 NMR (DMSO-d 6 6) :0.91 (3H, t, J=6.8Hz), 1.3-1.5 (4H, mn), 1. 6-1. 8 (2H,im) 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 (in/z) :408 Preparation 450 IR (KBr) :2933, 2865, 2667, 2545, 1681, 1608, 1544, 1492, 1469, 1423, 1332 cm-i MASS (in/z) :422 Preparation 451 IR (KBr) :2933, 2863, 1677, 1606, 1469, 1421, 1313, 1292, 1255, 1174 cm- 1 MASS (in/z) :422 Preparation 452 IR (KBr) :2935, 2871, 2667, 2545, 1683, 1608, 1542, 1525, 1461, 1421, 1319, 1294, 1257, 1176 cm- 1 NMR (DMSO-d 6 6) :0..91 t, J=7.OHz), 1.2-1.5 (4H, mn), 1. 6-1. 9 (2H, m) 4.05S (2H, t, J=6. 5Hz) 7. 09 (2H, di, J=8.8Hz), 7.91 (2H, d, J=8.8Hz), 8.09 (2H, di, 8.22 (2H, d, J=8.5Hz), 13.3 (1H, s) MASS (in/z) :412 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, 1.85-1.96 (4H, m), 2.10-2.40 (2H, 3.58 (3H, 12.08 (1H, s) MASS 187 (M+1) Preparation 454 IR (KBr) 1724.0, 1702.8, 1309.4, 1265.1 cm- 1 NMR (DMSO-d 6 5) 2.49 (6H, 3.84 (3H, 7.70-7.72 (2H, 13.14 (1H, bs) Preparation 455 IR (KBr) 1727.9, 1675.8, 1232.3 cm- 1 NMR (DMSO-d 6 5) 3.70 (3H, 6.24-6.51 (2H, m), 7.24-7.46 (2H, 12.66 (1H, bs) MASS 157 (M+1) Preparation 456 IR (KBr) 1726.0, 1685.5, 1286.3, 1251.6 cm- 1 NMR (DMSO-d 6 5) 3.98 (3H, 7.68-7.77 (2H, 8.11 (2H, 8.64-8.82 (2H, 13.58 (1H, bs) MASS 231 (M+1) Preparation 457 IR (KBr) 1724.0, 1697.1, 1290.1 cm- 1 NMR (DMSO-d 6 5) 3.95 (3H, 8.04-8.08 (2H, m), 8.20-8.27 (2H, 8.68-8.71 (2H, m) MASS 231 (M+1) 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-HC1) (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 pentyloxyphenyl)isooxazol-3-yl]benzoic acid benzotriazol- WO 99/40108 PCT/JP99/00538 210 1-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, 1.6-1.9 (2H, 4.03 (2H, t, J=6.5Hz), 6.81 (1H, 7.01 (2H, d, J=8.3Hz), 7.3-7.6 (3H, 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, The Starting Compounds (459) to (461) used and the Object 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 WO 9940108PCTIJP99/00538 211 Preparation No. Formula HO OHO
H
2 N N~ HO NH 0 H I
HO//
OH 0 NaO 3 SO
HO
459
OHO
H3CI HON NH 0 NaO 3 SO 16 H 0
"'OH
WO 99/40108 WO 99/01 08PCT/JP99/00538 212 Preparation No. Formula
?'/OH
460
H
2
TN
WO 99/40108 PCT/JP99/00538 213 Preparation No. Formula
H,
OHO
H
3
H
2 N N HO NH 0
HOZ
ObH NaO 3
SO
HO
461
OHO
H
3
CI,.
$NHN
0HBN HO NH 0
H
HO/
N
N/H 0 Na03SO
HO
WO 99/40108 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 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 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 10% aqueous methanol (2 20% aqueous methanol (2 30% aqueous methanol (2 50% aqueous methanol (2 L), 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 6) 0.85 (3H, t, J=7.0Hz), 0.96 (3H, d, J=6.7Hz), 1.02 (3H, d, J=6.1Hz), 1.24 (26H, m), 1.35-1.50 (2H, 1.55-2.50 (11H, 2.80-3.30 (2H, 3.60-5.40 (20H, 6.60-6.80 (3H, 6.85- 7.75 (5H, 8.00-8.15 (2H, 8.71 (1H, broad S) APCI MASS 1141.1 (M'-Na) Preparation 460 A solution 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 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 by Dow Chemical) (1 L) and washed with water (3 L) The eluate was chromatographed on reversed WO 99/40108 PCT/JP99/00538 215 phase silica gel (ODS SP-120, prepared by Daiso Co., Ltd.) L) withwater (12 10% aqueous methanol (12 L) and 20% aqueous methanol (12 L) successively. The fractions containing the object compound were collected, concentrated by evaporation in vacuo and lyophilized to give Object Compound (460) (76 g, yield NMR (DMSO-d 6 5) 0.96 (3H, d, J=6.7Hz), 1.05 (3H, d, J=5.7Hz), 1.60-2.50 (7H, 3.10-5.20 (29H, m), 6.73 (1H, d, J=8.2Hz), 6.75-6.90 (2H, 6.90-7.10 (2H, 7.20-7.40 (7H, 7.63 (1H, d, J=7.8Hz), 8.00-8.15 (2H, m) ESI MASS (Negative) 1069.3 (M -Na) Preparation 461 To a solution of Starting Compound (461) (30 g) and sodium 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 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., Ltd.) (700 ml) eluting with water (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 6) 0.95 (3H, d, J=6.7Hz), 1.07 (3H, d, J=5.7Hz), 1.40-2.45 (7H, 2.85-3.30 (2H, m), 3.60-4.50 (13H, 4.60-5.35 (10H, 6.65-7.10 7.20-7.75 (8H, 7.92 (1H, broad d, J=8.4Hz), 8.84 (1H, s) ESI MASS (Negative) 1053.3 (Me-Na) WO 99/40108 PCT/JP99/00538 216 The Starting Compounds to (169) used and the Object Compounds 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 formulas of the object compounds are in the lower column, respectively.
WO 99/40108 WO 9940108PCT/JP99/00538 217 Example Formula No.
HO OH 0
(CH
9 C0H 0 2) 6
CH
3
H
2
N
WO 99/40108 WO 9940108PCT/JP99/00538 218 Example No.
Formula 4 NaO 3 s NaO 3 WO 99/40108 WO 9940108PCT/.JP99/00538 219 Example No.
Formula HO OH
H
3 ~A1
OH
H
3
C.-
.OH
WO 99/40108 WO 9940108PCT/JP99/00538 220 Example I Formula No.
H
3 C
H
2N NaO WO 99/40108 WO 9940108PCT/JP99/00538 221 Formula
H
3
H
2 1N
H
2
N
WO 99/40108 WO 9940108PCT/JP99/00538 222 ExampleFoml No.
'CH H 3
"OH
OH
OH
HQ
WO 99/40108 WO 9940108PCT/,JP99/00538 223 ExampleFoml No.
OH
HQ_ 0
NC
H G 0 H2 NH 0H
OH
3 0
OH
NaO 3 S 0_
HO
7 NaO 3
S
WO 99/40108 WO 9940108PCT/JP99/00538 224 Example Formula No.
HQ.
H H 2 N N 0 HO NF- 0 H0 NaO 3 S
HO
8
OH
H
3
C
WO 99/40108 WO 9940108PCT/JP99/00538 225 Example Formula No.
OH
HQ
H-N
H
2
OH
.1 WO 99/40108 PCT/JP99/00538 226 WO 99/40108 WO 9940108PCT/JP99/00538 227 Example 1Formula No.
OH
(CH
2 7 0CH 3 WO 99/40108 WO 99/01 08PCT/JP99/00538 228 E xampl1e Formula No.
NaO 3 Si HO0
(GB
2 6 0CH 3 Na0 3 s' WO 99/40108 WO 9940108PCT/JP99/00538 229 Example Formula No.
NaO 3
S
HO
H
3
C.
(CH
2 6 0CH 3
OH
Na0 3
I
WO 99/40108 PCT/JP99/00538 230 WO 99/40108 WO 9940108PCT/JP99/00538 231 Example Formula No.1
H
NaO 3
S(
N
(CH
2 6 0CH 3
.OH
.1 WO 99/40108 WO 9940108PCT/JP99/00538 232 Exmpe Formula No.
OH
H
3 C
H
2 0 Hb OH 0 HO NH 0 CH 3 y
OH
NaO 3S C
HO
16
H
3 H N Na0 3
I
WO 99/40108 WO 9940108PCT/JP99/00538 233 Example No.
Formula i
H
3 H N
(CH
2 3
CH
3
L
WO 99/40108 WO 99/0 108PCT/JP99/00538 234 ExampleFoml HO OH
(CH
9 6
GH
3
(CH
2 6
CH
3 WO 99/40108 WO 9940108PCT/JP99/00538 235 Example Formula No.
HO OH
(CH
2 3
CH
3 H 3 C Na0 3 H3 H2' O-o (CH 2 3
CH
3
~OH
Na0 3 .1 WO 99/40108 WO 9940108PCT/JP99/00538 236 Example Foml No.
HO,
PH
00
HO.
HOC
HO0
H
2 1N
(CH
2 4
CH
3 Nao 3
I
WO 99/40108 WO 9940108PCT/JP99/00538 237 Example No.
Formula
I
HO- OH H -O(CH 2 7
CH
3 Na0 3 0 -C11(CH2 7
CH
3 Na0 3 WO 99/40108 PCT/JP99/00538 238 WO 99/40108 WO 9940108PCT/JP99/00538 239 Example No.
Formula i 0 1H1,,, C2 4
CH
3 CH2) 4
CH
3 .7 WO 99/40108 PCT/JP99/00538 240 WO 99/40108 WO 9940108PCT/JP99/00538 241 Example Formula No.
HO OH HQ 0 o
H
2 N y0 o H -OH 0 4IHc H 0 CH 3 0
H
HO N H 0 NaO 3
HO
HO 0 f O ,H ,NH-CNK)-o(CH 2 5
CH
3 .1.
WO 99/40108 WO 9940108PCT/JP99/00538 242 Example Formula No.
HO 0 HO0O
H
3 FNH-C
H
2 N N 0 -I 0 RN OH (CH 2 6
CH
3 0 NH 0= CR 3 0
N
H
RQ N
OH
NaO 3 SO
HO
26 HO 0 0 N NH
H
3 C H z~ N C
-I
H
2 N Y0 =O H OH (CH 2 6
CH
3 Na0 3
I
WO 99/40108 WO 9940108PCT/JP99/00538 243 Example I Formula No.
H2N
CH
2 5
CH
3
CH
2 5
CH
3 NaO 3 WO 99/40108 WO 9940108PCT/JP99/00538 244 Example No.
Formula
OH
(CH
2 8 0CH 3
H
2
N
CCH
2 8 0CH 3 Na0 3
S(
WO 99/40108 WO 9940108PCT/JP99/00538 245 Example Formula No.
HO O HO 0 0
H
3 C- H
H
2 N y 0H 0
O
0 HO H 0
CH
3 0
N
HO H HQ N OH OH 0 NaO 3
SO_~
HO
29
~OH
HO0 H I NH O (CH 2 7 0CH 3 I WO 99/40108 WO 9940108PCT/JP99/00538 246 Exml Formula No.
NaO 3
S'
(CH
2 5
CH-
3
I
WO 99/40108 WO 9940108PCT/JP99/00538 247 Example No.
31 Formula
OH
Na0 3
S'
(CH
2 5
CH
3 Na0 3
I
WO 99/40108 WO 9940108PCT/JP99/00538 248 Example No.
Formula NaO
(CH
2 7
CH
3 r- WO 99/40108 WO 99/0 108PCT/JP99/00538 249 Example Fo rmul1a No.
H
3
H
2
N
CH
2 5
CH
3 Na0 3 WO 99/40108 WO 9940108PCT/JP99/00538 250 ExampleFoml No.
H
3
C,.
OH
(CH
2 8 0CH 3 .1 WO 99/40108 WO 9940108PCT/JP99/00538 Example No.
Formula NaO 3
S(
H2N WO 99/40108 WO 99/01 08PCT/JP99/00538 252 Example No.
Formula NaO 3
S(
36
I
WO 99/40108 WO 9940108PCT/JP99/00538 253 ExampleFoml No.
~OH
HOQ
N
H
2
NY
HN OH H01 CH 3 0
N
H J HQ- N O
OH
NaO 3
SO--
HO
37
OH
HO H (C2 2H Na0 3 WO 99/40108 WO 9940108PCT/JP99/00538 254 ExampleFoml No.
HQ
H 3
H
2 N N 0 HO NH
HQ-
H
NaO 3 SO
HO
38 3
CH
3 WO 99/40108 WO 99/01 08PCT/JP99/00538 255 Example No.
Formula i NaO 3
S(
4
CH
3 NaO WO 99/40108 WO 9940108PCT/JP99/00538 256 Example Formula NaO 3 H3
H
2
'N
5
CH
3 NaO WO 99/40108 WO 9940108PCT/JP99/00538 257 Example Formula No.
NaO 3
S(
6CH3
-I
WO 99/40108 WO 9940108PCT/JP99/00538 258 Example Formula No.
~OH
HO' 0
N
NH
2
H
2 N Y0 0 HN OH 0HO H 0 H 3 0
N
H
HQ-
OH
NaO 3SO
HO
42 0Oi HO 0 I (CH 2 3
-ND
WO 99/40108 WO 9940108PCT/JP99/00538 259 Examp-le Formula No.
~OH
HQ 0
HH
H
2 N
N
I--0 HN
OH
0 HO NH 0- CH 3 0
N
H
OH0 NaO 3 SO-
C
HO
43
HOOH
H3H H
H
2 9
CH
3 WO 99/40108 PCT/JP99/00538 260 WO 99/40108 WO 99/0 108PCT/JP99/00538 261 Example.1 Formula No.
NaO 3
(CH
2 -T H 3 WO 99/40108 WO 9940108PCT/JP99/00538 262 Example Formula No.
~OH
HQ 0
H
2 NY0 0 HN OH 0
N
H
HQON
OH
NaO 3SO
HO
46
OH
HO 0 1 HC H 0 (j(o-
H
2 N
OH
HO N5 H 0= CH 3
HO
H 0 NaO 3 SO HO0 WO 99/40108 WO 9940108PCT/JP99/00538 263 Example Formula No.
NaO 3
S'
H
3
C.
(CH
2 4 _0- Na0 3
I
WO 99/40108 WO 9940108PCT/JP99/00538 264 Example No.
48 Formula HN H Na0 3
S'
HO0
(CH
2 8 0CH 3 WO 99/40108 WO 99/01 08PCT/JP99/00538 265 Example No.
Formula
OH
CH
3 H 3
C.
(CH
2 Na0 3
S
WO 99/40108 WO 9940108PCT/JP99/00538 266 Exml Formula No.
NaO 3
S(
)4-0-0 WO 99/40108 WO 9940108PCT/JP99/00538 267 Example No.
Formula 4 NaO 3 sl NaO 3 WO 99/40108 PCT/JP99/00538 268 WO 99/40108 WO 9940108PCT/JP99/00538 269 Example 1Formula No.
NaO3S( 0CH 3 WO 99/40108 WO 9940108PCT/JP99/00538 270 ExampleFoml No.
NaO 3 .1 WO 99/40108 WO 9940108PCT/JP99/00538 271 Example No.
Formula
I
CCH
2 4
GH
3
H
2
N,
Na0 3 WO 99/40108 WO 9940108PCT/JP99/00538 272 Example Formula .1
H
3
~OH
H
NH
2 0 HN OH NaO 3
S
H2N WO 99/40108 WO 9940108PCT/JP99/00538 273 Example No.
F'ormul1a 4 H 3 H 2N'
(OH
2 7
CH
3
(CH
2 7
CH
3 NaO 3
S'
WO 99/40108 WO 99/01 08PCT/JP99/00538 274 Example No.
Formula
OH
H
3
H
2
N
6
CH
3 NaO 3
S'
HO0 6
CH
3 H 2
N\
Na0 3 WO 99/40108 WO 99/01 08PCT/JP99/00538 275 Example Formula No.
H "(CH 2 4
CH
3 0
OH
2 4
CH
3 Na0 3 .1 WO 99/40108 WO 9940108PCT/JP99/00538 276 Example No.
Formula
.I
(CH
2 5
CH
3 H21 HO 0
(CH
2 5
CH
3
H
2
N
OH
Na0 3
S(
I
WO 99/40108 WO 9940108PCT/JP99/00538 277 Example Foml No.
'OH
NaO 3
S
OH
2 9
CH
3
.OH
Na0 3
S
WO 99/40108 WO 9940108PCT/JP99/00538 278 Example No.
Formula .1.
NaO 3
S(
HO
H
3
H
2
N
9CH
OH
WO 99/40108 WO 9940108PCT/JP99/00538 279 Example Formula No.
OH
HO 0 HHH2 HN OH 0 H :CH 3 0
H
OH
NaO 3 S C
HO
63
OH
HO 0j 4-
H
2 \1 (C
I
WO 99/40108 WO 9940108PCT/JP99/00538 280 Example No.
Formula NaO 3 s
OH
H
2
N
'OH
L
WO 99/40108 PCT/JP99/00538 281 WO 99/40108 WO 9940108PCT/JP99/00538 28 2 Example No. Formula
H
2
N
S'I& OCH 2M- 0 WO 99/40108 WO 9940108PCT/JP99/00538 283 Example No.
67 Formula NaO 3 HO0
H
3
C
H
2 N N
(CH
2 5-0J0
OH
WO 99/40108 WO 9940108PCT/JP99/00538 284 Exml Formula No.1 NaO 3
.OH
CCH
9 300 .1 WO 99/40108 WO 99/01 08PCT/JP99/00538 285 Example Fo rmul1a No.
NaO 3
S(
69
(CH
2 5 0CH 3
H
3 WO 99/40108 WO 9940108PCT/JP99/00538 286 Example No.
Fo rmul1a NaO 3
S
HO 0
H
3 C H-
).~D(CH
2 8
OCH
3
I
WO 99/40108 WO 9940108PCT/JP99/00538 287 ExampleFoml No.
H2
N
(CH
2 2
CH
3 H 3
C..
OH
L
WO 99/40108 WO 99/01 08PCT/JP99/00538 288 Example Formula No.
NaO 3
S(
H3C
H
3 C. (CH 2 4
CH
3 WO 99/40108 PCT/JP99/00538 289 WO 99/40108 WO 9940108PCT/JP99/00538 290 ExampleFoml No.
H
3
H
2
N
H N NaO 3
S(
WO 99/40108 WO 99/0 108PCT/JP99/00538 29 1 Example No.
Formula Na 3 Nc 7 'Ja0 3
SO
WO 99/40108 PCT/JP99/00538 29 2 WO 99/40108 WO 9940108PCT/JP99/00538 2 93 Example No. Formula 0 S&ND- 0 N-N WO 99/40 108 PCT/.JP99/00538 2 94 Example No.
Formula WO 99/40108 PCT/JP99/00538 2 WO 99/40108 WO 9940108PCT/JP99/00538 29 6 Example No. Formula OHO0
H
2 N N 0 800
I
WO 99/40108 WO 9940108PCT/JP99/00538 2 97 Example No.
Formula 4 NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 2 98 Example No Formula NaO 3
HO
0 .2 WO 99/401 08 PCT/JP99/00538 299 WO 99/40108 WO 9940108PCT/JP99/00538 300 Example No.
Formula ~OEt WO 99/40108 WO 9940108PCT/JP99/00538 1 Example No. Formula NaO 3
SO
m
H
0 WO 99/40108 PCT/JP99/00538 302 Example No. Formula
HO
3
SO
I
WO 99/40108 WO 99/01 08PCT/JP99/00538 303 Example No. Formula
OH
OHO0
H
3
N
H2 N2 0 HN O 0
C
0 0
OH
HO
H
3 C/I H
N
H
2
NH
0N -H IVS(CH 2 7 0CH 3 NaO 3
SO
WO 99/40108 PCT/JP99/00538 304 Example No. Formula
I
WO 99/40108 WO 9940108PCT/JP99/00538 Example No. Formula OHO0
H
3Ci,,,.6
H
2 N N 0 0 WO 99/40108 PCT/JP99/00538 6 Example No. Formula
OH
OHO0
N/
H
3
C,
11 H NH H2N N O0 N O
H
N
H
IN 1 )1O 0 WO 99/40108 WO 9940108PCT/JP99/00538 7 Example No. Formula H0 3
SO
H
IN
O,/H
0 WO 99/40108 WO 99/01 08PCT/JP99/00538 8 Example No. Formula *1~
""OH
NaO 3
SO'
WO 99/40108 WO 9940108PCT/JP99/00538 9 Example No. Formula OHO0
H
3
H
2 N N 0 930 a- WO 99/40108 WO 9940108PCT/JP99/00538 3 Example No.
Formula I1 NaO 3
S'
94 WO 99/40108 WO 9940108PCT/JP99/00538 31 1 Example No. JFormula OH 0
O(CH
2 6 0CH 3 WO 99/40108 WO 9940108PCT/J'99/00538 3 12 Example No. Formula OHO0
(CH
2 2
CH
3 NaO 3 SO WO 99/40108 WO 99/0 108PCT/3P99/00538 3 13 Example No. Formula NaO 3 S1 .1 WO 99/40108 WO 9940108PCT/JP99/00538 3 14 Example No.
Formula
"",OH
I
WO 99/40108 WO 99/01 08PCT/JP99/00538 31 Ex ampl1e No.
Formula 4-
OH
)SCH 3 WO 99/40108 WO 9940108PCT/JP99/00538 31 6 ExampleFoua 100
I
WO 99/40108 WO 9940108PCT/JP99/00538 3 17 Example No. Formula
H
3 101 1
"I/OH
1 2 2 CH 3 Na0 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 31 8 Example No. Formula .a.
OH
102 NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 31 9 Example No. Fo rmul1a
H
3 CI/i,.q 103 WO 99/40108 WO 9940108PCT/JP99/00538 320 Example No. IFormula 104 NaO 3
SO
WO 99/40108 WO 99/0 108PCT/JP99/00538 3 21 Example No. Formula 4 H0 3
SO
105 1 1 0/H WO 99/40108 WO 9940108PCT/JP99/00538 3 22 Example No. Formula H0 3
SO
106 WO 99/40108 WO 99/01 08PCT/JP99/00538 32 3 Example No. Fo rmul1a
I
NaO 3
S'
107
'/OH
WO 99/40108 WO 9940108PCT/JP99/00538 3 24 Ex ampl1e No. Formula .4-
H
2
N
0 108
II/OH
j WO 99/40108 WO 9940108PCT/JP99/00538 32 Example No. Formula OHO0
H
3
H-
2 N N 0 109
N-N
M/OH
NaO 3 WO 99/40108 WO 9940108PCT/JP99/00538 32 6 Example1 No. Formula H0 3
SO
110 WO 99/40108 WO 9940108PCT/JP99/00538 32 7 Example No. Formula H0 3
SO
ill NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 32 8 Example No. Formula OHO0
H
3 0i, 11 0 z HO NBl 0
OH
H0 3 SO
HO
112 Na0 3 WO 99/40108 WO 9940108PCT/JP99/00538 3 29 Ex ampl1e1 No. JFormula H0 3
SO
113 WO 99/40108 PCT/JP99/00538 330 Example No. Formula
OH
OHO0
H
2 N N O HN O 0 0 N 114 NaO 3
SO
WO 99/40108 PCT/JP99/00538 33 1 WO 99/40108 PCT/JP99/00538 3 32 WO 99/40108 WO 9940108PCT/JP99/00538 3 33 Example No. Formula OHO0
H
3
<N
1
H,,NN
0 0 NH 0 H0 3 SO
HO
117
N-N
WO 99/40108 WO 9940108PCT/JP99/00538 33 4 Example No. Formula 1* H0 3
SO
118 N- N WO 99/40108 PCT/JP99/00538 3 WO 99/40108 WO 9940108PCT/JP99/00538 33 6 Example No. Formula H0 3
SO
120 WO 99/40108 WO 9940108PCT/J P99/00538 3 37 Example No. Formula OHO0
H
3 H2N N 0 0 H N
HO
3
S
121 OHO _OH
H-,N
HO ONH 0 OH 0
HO
3
SO/
HO
WO 99/40108 WO 9940108PCT/JP99/00538 3 38 Example No. JFormula H0 3
SO
122
I
WO 99/40108 WO 99/01 08PCT/JP99/00538 33 9 Example No. Formula H0 3 123 NaO 3
SO
WO 99/40108 WO 99/0 108PCT/JP99/00538 340 Example No. Formula OHO0
H
2
NN
H N
HOO
H NO HO124~CH
HH
HON N 01u, N H 0=4H NaO 3
SO
J
WO 99/40108 WO 99/01 08PCTIJP99/00538 34 1 Example No. JFormula 125 N
O(J
WO 99/40108 WO 9940108PCT/JP99/00538 34 2 Example No.
Formula .1.
H0 3 126 WO 99/40108 WO 9940108PCT/JP99/00538 34 3 Example1 No. jFormula H0 3
SO
127 IbN/1 WO 99/40108 WO 9940108PCT/JP99/00538 344 Example No. Formula
"IOH
128 s)/oYcG CH O(CH 2 2 Me
N-N
WO 99/40108 WO 9940108PCT/JP99/00538 34 Formula Example No.
Formula H0 3
SO
129 O(CH 2 3 0EL WO 99/40108 WO 9940108PCT/JP99/00538 34 6 Example No.
Formula
HAN
130 O(CH 2 3 OMe
N-N
I
WO 99/40 108 PCT/JP99/00538 34 7 Example No. Formula
OH
OHO0 T \NI H2,N N O HN O 0 N N
HO
OHO 0 0 0 N-N 0 N 0 NaO3SO rl OH WO 99/40108 WO 9940108PCT/JP99/00538 34 8 Example No. I Formula
OH
H I
H
,;H
132 NaO 3
SO
I WO 99/40108 PCT/JP99/00538 34 9 Example No. Formula
OH
OHO0
H
2 N N 0 0 H-N OH 0 01-~ 1 0
ND
NaOSO WO 99/40108 PCT/JP99/00538 350 Example No. Formula
OH
OHO0
N/
H3011, H
H
2 N N O HN O 0 0 N '34 NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 1 Example No. Formula 4- 135 NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 3 52 Example No. Formula
H
2
N
136 0 0(CH 2 5 N 0 H S 0 WO 99/40108 WO 9940108PCT/JP99/00538 3 Example No. Formula 137 Na0 3
SO
-I
WO 99/40108 WO 9940108PCT/JP99/00538 3 54 Example No. Formula
I
""/OH
NaO 3
SO'
138 WO 99/40108 WO 99/0 108PCT/JP99/00538 E xampl1e No.
Formula 139 NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 6 Example No.
Formula 4 140 O(CH,2) 5 N
S
HN OH 0
H
N 1/1)/O
H
0 NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 3 57 Example No. IFormula OHO0
H
3 1
H
2 1N
HO
141 O(CH 2 5 OMe H 'LfN~ S WO 99/40108 WO 9940108PCT/JP99/00538 8 Example No.
Formula 4
H
2
N,
142 N j OCH 2)SOMe H
N
0 WO 99/40108 WO 9940108PCTIJP99/00538 3 59 Example No. Formula NaO 3
SO
143
"'OH
WO 99/40108 WO 9940108PCT/JP99/00538 36 0 Example No. Formula ""OH/0 Na 3 144 WO 99/40108 WO 9940108PCT/JP99/00538 36 1 Example No. jFormula NaO 3
SO'
145
I
WO 99/40108 WO 9940108PCT/JP99/00538 3 62 ExampleT No. Formula Na0 3
SO
HO
146
H
3 ,N No- J
J
WO 99/40108 PCT/JP99/00538 3 63 Example No. Formula OHO0
H
2
NN
0 N
OHO
0 HN OH H HO0~H 140
HOH
H3/1
N/N~'O
\0H
HOH
WO 99/40108 PCT/JP99/00538 Example No. Formula
OH
OHO 0
H
2 N N O1 HN
OH
06 NH 0 H HO
N
WO 99/40108 WO 9940108PCT/JP99/00538 36 Example No.
Formula NaO 3 149 WO 99/40108 WO 9940108PCT/JP99/00538 3 66 Example No.
Formula
-I
NaO 3
SO
150 NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 3 67
I
Example No. Formula NaO 3
SO
151 WO 99/40108 WO 9940108PCT/JP99/00538 3 68 Example No. Formula OHO0
HAN
152
N
H N SK =0 i WO 99/40108 WO 9940108PCT/JP99/00538 36 9 Example No. Formula OHO0
H
3 Ci,,.
0 HO NH 0
'KTH
NaO 3 SO
HO
153
H
3 CI,1 WO 99/40108 WO 9940108PCT/JP99/00538 3
I
Example No.
Formula NaO 3
SO
154 WO 99/40108 PCT/JP99/00538 371 Example No. Formula
OH
OHO
H-N/
H
2 N N :0 0 HN OH 00
H
HO
NaO 3
SO
OHO
OH i 0CH 2 0
NN
iH s
HO
WO 99/40108 WO 9940108PCTIJP99/00538 3 72 Example No. Formula NaO 3
SO
156 H3c//d WO 99/40108 WO 99/0 108PCT/JP99/00538 Ex ampl1e No. Formula O0 HO NI 0
HO
0 OH NaO 3 SO
HO
157 WO 99/40108 WO 9940108PCT/JP99/00538 3 74 Example No. Formula 0OH10
H
2 N Y HO N 0
HO
0 OH NaO 3 SO
HO
158 WO 99/40108 WO 9940108PCT/JP99/00538 37 Example No. Formula
OH
HAN
NaO 3 159
HIN
N
0 NaOISO WO 99/40108 WO 99/0 108PCT/JP99/00538 3 76 Example No.
Formula 4.
160 NO-O WO 99/40108 WO 9940108PCT/JP99/00538 3 77 Example1 No. jFormula
OH
H
3
H
2
N
0 kSN o\ N N-=
-L
WO 99/40108 WO 9940108PCT/JP99/00538 3 78 Example No. Formula
OH
OH 02 H2N N 00O 0 N 162 OHO 0
:QH
H
2 1N N
W
11
H
NaO3 WO 99/40108 WO 9940108PCT/JP99/00538 3 79 Example No. Formula
OHI
OHO 0 l* H3CbJ) H N O(CH 2 7
OMC
H
2 N UN: 0 HO 0- 0-IN H 3 00 NaO 3 SO
HO
163
H
3
C,
WO 99/40108 WO 9940108PCT/JP99/00538 3 Example No. JFormula 0 N 0(CH 2 7 OMe NaO 3
SO
164 N -Q--O(CH 27 OMe =0
OH
(164-1)
O(F
2 7 OMe :0
OQH
N (164-H1)
"I/OH
WO 99/40108 WO 9940108PCT/JP99/00538 3 81 Example No.
Formula 1* 165
H
3 Ci,,.
NaO 3
SO
.I
WO 99/40108 WO 9940108PCT/JP99/00538 3 82 Example No. Formula
H
2
N
NaO 3
SO
166
I""OH
NaO 3
SO
WO 99/40108 WO 9940108PCT/JP99/00538 3 83 Exampl.e No.
Formula H0 3
SO
167
NK"
I
WO 99/40108 WO 9940108PCT/JP99/00538 384 Example No. Formula H0 3
SO
168
O(CH
2 4
CH
3 H0 3 S0-
K
WO 99/40108 PCT/JP99/00538 38 WO 99/40108 PCT/JP99/00538 386 Example 1 To a suspension of Starting Compound (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 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 Sand eluted with 30% 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 (0.417 g).
IR (KBr) 3350, 1668.1, 1629.6, 1241.9 cm 1 NMR (DMSO-d 6 5) 0.87 (3H, t, J=6.7Hz), 0.96 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.2-1.55 (8H, m), 1.55-2.1 (5H, 2.1-2.5 (4H, 3.01 (1H, 3.19 (1H, 3.46 (1H, 3.6-3.87 (3H, m), 3.87-4.55 (13H, 4.6-5.5 (8H, 6.52 (1H, d, J=8.1Hz), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.85 (1H, 7.0-7.15 (3H, 7.19 (1H, 7.27-7.55 (3H, 7.55-7.78 (3H, 7.8-8.0 (2H, 8.76 (1H, 8.85 (1H, s) MASS 1248 (M+Na Elemental Analysis Calcd. for C 53
H
7 2
N
9 NaO 21 S7H 2 0 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 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, 2.0-2.6 (4H, 2.6-2.8 (1H, m) 3.1-3.3 (1H, 3.3-3.5 (1H, 3.5-4.5 (16H, 4.6-4.9 (2H, 5.1-5.5 (5H, 6.72 (1H, d, 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, 7.05 (1H, d, J=1.9Hz), 7.4-7.9 (3H, m) 8.84 (1H, s) MASS :965 (M+Na Elemental Analysis Calcd. for C 35
H
51
N
8 0 19 SNa*5.5H 2 0 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 :1266 (M-Na Example 4 To a suspension of Starting Compound (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.
The lower layer (trifluoroacetic acid layer) of the reaction mixture was poured into a large volume of an ice cooled aqueous NaHCO 3 solution 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 was purified by column chromatography on ODS to afford Object Compound NMR (DMSO-d 6 5) 0.95 (3H, d, J=6.7Hz), 1.04-1.12 (3H, 1.48-2.00 (3H, 2.07-2.50 (4H, m), 2.90-3.34 (2H, 3.60-4.48 (18H, 4.60-5.40 (9H, 6.72 (1H, d, J=8.2Hz), 6.81 (1H, dd, J=8.2 and 1.6Hz), 6.84 (1H, 6.98 (1H, 7.04 (1H, d, J=1.6Hz), 7.28-7.50 (6H, 7.58 (2H, 7.73 (2H, d, J=7.4Hz), 7.84 (1H, 7.88 (2H, d, J=7.6Hz), 8.84 (1H, s) MASS :1141 (M Example To a solution of Starting Compound (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 temperature. Ethyl acetate (2.5 L) was added to the reaction WO 99/40108 PCT/JP99/00538 388 mixture and the mixture was stirred for 30 minutes. The powder was collected by filtration to give Object Compound (34.6 g).
Example 6 To a solution of Starting Compound (0.3 g) and triethylsilane (0.44 ml) in methylene chloride (7 ml) at 10 0
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 10 0 C. The aqueous 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 (0.13 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, 1.60-2.50 (9H, 2.90-2.97 (1H, m), 3.16-3.50 (2H, 3.69-4.50 (13H, 4.74-5.31 6.72-7.65 (14H, 7.93-7.97 (1H, 8.71 (1H, s) Example 7 To a solution of Starting Compound (110 mg) in water ml) was added 10% palladium on carbon (11 mg), and hydrogen gas at atmosphere pressure for 7 hours. The reaction mixture was filtered through celite and lyophilized to give Object Compound (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, J=6.0Hz), 1.88-5.83 (35H, 6.68-8.71 (10H, m) MASS 903.17 (M-Na Example 8 To a solution of Starting Compound (350 mg) in N,Ndimethylformamide (6 ml) was added 4-[4-(4-cyclohexylphenyl)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 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- (Trademark: prepared by Yamamura Chemical Lab.)) eluting 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 (160 mg).
IR (KBr) 1666.2, 1633.4, 1608.3, 1511.9, 1230.4 cm 1 NMR (DMSO-d 6 5) 0.95 (3H, d, J=6.7Hz), 1.09 (3H, d, J=5.4Hz), 1.2-1.5 (6H, 1.6-2.1 (7H, 2.1-2.6 3.02 (1H, 3.1-3.5 (10H, 3.6-4.5 (14H, 4.6-5.3 (9H, 6.73 (1H, d, J=8.2Hz), 6.77 (1H, d, J=8.2Hz), 6.80 (1H, 6.91 (2H, d, J=8.7Hz), 6.9-7.1 (5H, 7.26 (1H, 7.3-7.5 (2H, 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 1311 (M+Na Elemental Analysis Calcd. for C 58
H
77
N
1 00 20 S-6H 2 O 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 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, 1.7-2.6 (7H, 2.94 (1H, 3.1-3.5 (6H, 3.6-4.6 (14H, 4.7-5.3 (9H, 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.84 (1H, 7.04 (1H, 7.06 (2H, d, J=8.7Hz), 7.18 (1H, WO 99/40108 PCT/JP99/00538 390 7.3-7.5 (2H, 7.66 (1H, br 7.83 (2H, d, J=8.7Hz), 8.0-8.2 (5H, 8.75 (1H, d, J=7.1Hz), 8.84 (1H, s) MASS :1266 (M-Na Example 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, 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (4H, m), 1.6-2.6 (9H, 2.95 (1H, 3.1-3.5 (2H, 3.6-4.6 (16H, 4.7-5.4 (9H, 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.90 (1H, 7.06 (1H, 7.14 (2H, d, J=8.9Hz), 7.23 (1H, 7.3-7.5 (2H, 7.68 (1H, br 7.90 (2H, d, J=8.9Hz), 7.8-8.2 (5H, 8.60 (1H, d, J=6.7Hz), 8.85 (2H, s) MASS 1308 (M-Na Elemental Analysis Calcd. for C 5 7
H
7 0
N
11
O
2 1
S
2 Na-10H 2 C 45.26, H 6.00, N 10.19 Found C 45.05, H 5.83, N 10.19 Example 11 NMR (DMSO-d 6 5) :0.95 (3H, d, J=6.7Hz), 1.12 (3H, d, 1.2-1.6 (8H, 1.6-2.6 (9H, 2.9-3.1 (1H, 3.1-3.5 (7H, 3.6-4.6 (16H, 4.6-5.4 (9H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.13 (2H, d, J=8.8Hz), 7.16 (1H, 7.3-7.6 (2H, 7.67 (1H, br), 7.97 (2H, d, J=8.8Hz), 7.9-8.2 (5H, 8.7-9.0 (2H, m) MASS 1327.07 (M-Na Elemental Analysis Calcd. for C 5 8
H
7 5
N
10 NaO 22
S
2 .5H 2 0 C 48.33, H 5.94, N 9.72 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 powder was collected by filtration and washed with ethyl acetate L) to give crude N-acylated Starting Compound (12) (93.0 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 trifluoroacetic acid (450 ml) at 0°C 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<ll, Temperature<7 0 The separated organic layer was extracted with water twice. The combined aqueous solution was subjected to column chromatography on (7 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 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, 1.65-2.60 (9H, m), 2.80-3.50 (5H, 3.22 (3H, 3.60-4.60 (14H, m), 4.07 (2H, t, J=6.7Hz), 4.60-5.30 (9H, 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.13 (2H, d, J=8.9Hz), 7.16 (1H, 7.42-7.46 (2H, 7.66 (1H, br), 7.97 (2H, d, J=8.8Hz), 8.07-8.13 (5H, 8.77 (1H, d, J=6.8Hz), 8.84 (1H, s) MASS :1313.25 (M-Na Elemental Analysis Calcd. for C 57
H
73 N100 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 13 A solution of Starting Compound (13) (400 mg) in N,N- WO 99/40108 PCT/JP99/00538 392 dimethylformamide (4 ml) was treated with 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 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.
Product-containing fractions were pooled, evaporated to remove acetonitrile, and lyophilized to give Object 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 NMR (DMSO-d 6 5) 0.97 (3H, d, J=6.6Hz), 1.09 (3H, d, J=5.4Hz), 1.30-1.60 (6H, 1.65-2.60 (10H, m), 2.80-4.60 (17H, 3.22 (3H, 3.32 (2H, t, J=6.3Hz), 4.07 (2H, t, J=6.5Hz), 4.68-5.80 (8H, 6.68 (1H, d, J=8Hz), 6.76 (1H, d, J=8Hz), 6.86 (1H, 6.98 (1H, 7.13 (2H, d, J=8.8Hz), 7.16 (1H, 7.30-7.50 (3H, 7.97 (2H, d, J=8.8Hz), 8.03-8.13 (4H, 8.76-8.79 (2H, m) MASS 1343.13 (M+Na Elemental Analysis Calcd. for C 5 7
H
7 3
N
10 0 2 1
S
2 Na.8H 2 O 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 IR (KBr) 1675.8, 1650.8, 1631.5, 1540.8, 1513.8, -i 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, 1.80-2.60 (10H, m), 2.90-3.05 (1H, 3.21 (3H, 3.27 (2H, t, J=6.3Hz), 3.30-3.50 (2H, 3.68-4.60 (14H, 4.07 (2H, t, WO 99/40108 PCT/JP99/00538 393 J=6Hz), 4.70-5.45 (8H, 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.87 (1H, 6.97 (1H, 7.13 (2H, d, J=8.9Hz), 7.15 (1H, 7.42-7.71 (3H, 7.97 (2H, d, J=8.7Hz), 8.03-8.12 (4H, 8.73-8.81 (3H, m) MASS 1311.32 (M-Na Elemental Analysis Calcd. for C 58
H
75
N
10
O
21
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 A solution of Starting Compound (15) (508 mg) in N,N-dimethylformamide (10 ml) was treated with 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 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 16-17% aqueous acetonitrile. Fractions containing the object compound were combined, evaporated to remove acetonitrile, and lyophilized to give Object Compound (15) (400mg) as an amorphous white powder.
IR (KBr) 1668.1, 1650.8, 1631.5, 1538.9, 1513.8, 1450.2, 1259.3 cm- 1 NMR (DMSO-d 6 5) 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.9Hz), 1.30-1.60 (6H, 1.65-2.60 (9H, m), 2.80-3.50 (5H, 3.22 (3H, 3.60-4.60 (14H, m), 4.07 (2H, t, J=6.7Hz), 4.60-5.30 (9H, 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.13 (2H, d, J=8.9Hz), 7.16 (1H, 7.42-7.46 (2H, 7.66 (1H, br), 7.97 (2H, d, J=8.8Hz), 8.07-8.13 (SH, 8.77 (1H, d, J=6.8Hz), 8.84 (1H, s) MASS :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-7H2O C 46.78, H 5.99, N 9.57 Found C 46.56, H 5.94, N 9.45 Example 16 To a solution of Starting Compound (16) (200 mg) and 4-[5-(4-piperidin-l-yl-phenyl)-1,3,4-thiadiazol-2-yl]benzoic acid benzotriazol-l-yl ester in N, N-dimethylformamide (3ml) was added dimethylaminopyridine (0.034 and the mixture was stirred for 6.5 hours at ambient temperature. The reaction 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 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 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 5) 0.95-5.30 (49H, 6.63-8.72 (19H, m) MASS 1250.22 (M-Na Elemental Analysis Calcd. for C 55
H
68
N
11 NaO 19
S
2 -12H20 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 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 l-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 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 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).
NMR (DMSO-d 6 6) 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, 2.95 (1H, 3.1-3.5 (2H, 3.6-4.6 (16H, 4.7-5.5 (9H, 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.14 (2H, d, J=8.9Hz), 7.24 (1H, 7.3-7.5 (2H, 7.68 (1H, br 7.90 (2H, d, J=8.9Hz), 7.8-8.1 (5H, 8.56 (1H, d, J=6.7Hz), 8.85 (2H, s) MASS :1341 (M+Na Example 18 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 dissolved in pH 6.86 phosphate-buffer, and adjusted to pH with 1N sodium hydroxide aqueous solution. The solution was subjected to column-chromatography on ODS (YMC-gel ODS-AM Sand eluted with 30% 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 (18) (136 mg) IR (KBr) 3350, 2933, 1668, 1635, 1540, 1471, 1249, 1045 cm 1 NMR (DMSO-d 6 6) 0.88 (3H, t, J=6.7Hz), 0.96 (3H, d, 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, 2.8-4.1 (16H, 4.1-5.3 (11H, m), 6.6-7.2 (9H, 7.3-7.7 (3H, 7.9-8.3 (4H, m), 8.7-8.9 (1H, d, J=6.0Hz), 9.04 (1H, s) MASS 1244.5 (M+Na Elemental Analysis Calcd. for C 54
H
72
N
9 0 2 0 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.
Example 19 NMR (DMSO-d 6 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, 2.95 (1H, 3.1-3.5 (2H, m), 3.6-4.6 (16H, 4.7-5.4 (8H, 6.71 (1H, d, J=8.1Hz), 6.78 (1H, d, J=8.1Hz), 6.87 (1H, 6.97 (1H, 7.14 (2H, d, J=8.9Hz), 7.24 (1H, 7.44 (1H, d, J=7.9Hz), 7.5-7.8 (2H, 7.89 (2H, d, J=8.9Hz), 7.9-8.0 (6H, 8.12 (1H, d, J=7.7Hz), 8.60 (1H, d, J=7.2Hz), 8.72 (1H, 8.85 (1H, s) MASS :1278 (M-Na Example NMR (DMSO-d 6 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, 2.95 (1H, 3.1-3.5 (2H, m), 3.6-4.6 (16H, 4.7-5.4 (8H, 6.71 (1H, d, J=8.1Hz), 6.78 (1H, d, J=8.1Hz), 6.87 (1H, 6.97 (1H, 7.14 (2H, d, J=8.9Hz), 7.24 (1H, 7.44 (1H, d, J=7.9Hz), 7.5-7.8 (2H, 7.89 (2H, d, J=8.9Hz), 7.9-8.0 (6H, 8.12 (1H, d, J=7.7Hz), 8.60 (1H, d, J=7.2Hz), 8.72 (1H, 8.85 (1H, s) MASS :1338 (M+Na The following compounds [Examples 21 to 22] were obtained according to similar manner to that of Example 1.
Example 21 IR (KBr) 3353, 1666.2, 1631.5, 1510, 1236 cmn 1 WO 99/40108 WO 9940108PCT/JP99/00538 397 NMR (DMSO-c1 6 5) 0.86 (3H, t, J=6.8Hz), 0.95 (3H, d, J=6.7Hz), 1.09 (3H, d, J=z5.8Hz), 1.2-1.5 (10H, I), 1.55-2.6 (9H, in), 2.95 (1H, in), 3.0-3.5 (10H, mn), 3.6-4.5 (15H, mn), 4.6-5.4 (10H, in), 6.6-7.1 (10H, mn), 7. 27 (1H, s) 7. 35-7.5S (2H, mn), 7. 65 (1H, br s) 7. 78 (2H, di, J=8.8Hz), 8.03 (1H, di, J=8.7Hz), 8.30 (1H, ci, J=8.7Hz), 8.83 (1H, s) MASS :1357 (M+Na)+ Elemental Analysis Calcd. for C 60
H
83
N,
0 21 SNa5-S 2
O
C 50.55, H 6.58, N 9.83 Found C 50.56, H 6.59, N 9.76 Exanle 22 IR (KBr) 3350, 1658.5, 1633, 1278 cmJ 1 NMR (DMSO-d 6 5) 0.86 (3H, t, J=6.7Hz), 0.96 (3H, ci, J=6.7Hz), 1.11 (3H, di, J=5.7Hz), 1.2-1.4 (8H, mn), 1.45-2.45 (9H, mn), 2.62 (2H, t, J=7.4Hz), 2.98 (1H, mn), 3.2 (1H, mn), 3.25-3.5 (1H, in), 3.6-5.4 (23H, mn), 6.73 (1H, d, J=8.2H-z), 6.83 (1H, dcl, J=1.Sand8.2Hz), 6.88 (1H, 7.05 (1H, d, J=l.SHz), 7.31 (2H, di, J=8.2Hz) 7. 1-7. 5 (4H, in), 7. 64 (2H, d, J=8.2Hz) 7.74 (2H, ci, J=8.4Hz), 7.6-7.8 (1H, mn), 7.95 (2H, di, J=8. 4Hz) 8. 0-8.2 (1H, mn), 8.61 (1H, di, J=6.7Hz) 8. 84 s) MASS (in/z) :1243 (M+Na)+ Elemental Analysis Calcd. for C 55
H
7 3
N
8 NaO 20 S-6H 2
O
C 49.69, H 6.44, N 8.43 Found C 49.99, H 6.53, N 8.40 Examrle 23 IR (Nujol) 1668.1, 1629.6, 1540.8, 1515.8 c- MR (DMSO-d 6 5) :0.87 (3H, t, J=6.7Hz), 0.95 (3H, di, J=6.7Hz), 1.07 (3H, di, J=5.9Hz), 1.25-1.48 (4H, in), 1.49-2.05 (5H, i),.2.05-2.70 (8H, mn), 2.70-3.05 (3H, in), 3.08-3.45 (2H, in), 3.55-3.86 (2H, in), 3.88-4.50 (11H, in), 4.65-5.36 (10H, mn), 6.67-6.90 (3H, in), 7.04 (1H, ci, J=l.OHz), 7.10-7.80 (12H, mn), 8.00 (1H, di, WO 99/40108 WO 99/0 108PCT/JP99/00538 398 J=8 .4Hz) 8 .13 (1H, d, J=7. 7Hz) 8. 84 (1H, s) MASS (in/z) :1227.5 (M+Na)+ Elemental Analysis Calcd. for C 55
H
73
N
8 NaO 20 S'5H 2 0 C 50.38, H 6.38, N 8.54 Found C 50.07, H 6.60, N 8.58 Example 24 IR (KBr) 3350, 2929, 1664, 1635, 1515, 1440, 1278, 1245, 1085, 1047 cmJ 1 MR (DMSO-d 6 5) 0.86 (3H, mn), 0.96 (3H, d, J=7.7Hz), 1.11 (3H, d, J=5.7Hz), 1.30 (6H, mn), 1.5-2.4 (9H, mn), 2. 6-2.8 (2H, t, J=7.2Hz) 2. 9-3. 1 (1H, in), 3. 1-3. 3 (1H, mn), 3.4-3.6 (1H, in), 3.7-4.6 (14H, mn), 4.6-5.3 (9H, in), 6.7-7.0 (3H, in), 7.04 (1H, 7.21 (1H, 7.30 (2H, d, J=8.2Hz), 7.4-7.5 (1H, in), 7.6-7.8 (SH, mn), 7. 95 (2H, d, J=8.4Hz) 8. 10 (1H, di, J=8. 4Hz) 8. 60 (1H, di, J=8.4Hz), 8.84 (1H, s) MASS (in/z) :1230 (M+Na) Elemental Analysis Calcd. for C 54
H
71
N
8 NaO 20 S-4.5H 2
O
C 50.34, H 6.26, N 8.70 Found C 50.43, H 6.19, N 8.59 IR (KBr) 3350, 1666.2, 1631.5, 1510.0, 1236.1 cm- 1 MR (DMSO-d 6 6) 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, mn), 1.6-2.1 (5H, in), 2.1-2.5 (4H, mn), 2.8-3.0 (1H, mn), 3.1-3.3 (5H, mn), 3.3-3.4 (4H, in), 3.6-5.4 (23H, mn), 6.73 (1H, d, J=8.lHz), 6.8-6.9 (4H, mn), 6.94 (2H, d, J=9.3Hz), 7.01 (2H, d, J=8.7Hz), 7.04 (1H, 7.2-7.5 (3H, mn), 7.6-7.7 (1H, mn), 7.78 (2H, di, J=8.7Hz), 8.05 (1H, d, J=8Hz), 8.30 (1H, d, J=6.7Hz), 8.85 (1H, s) MASS (in/z) :1329 (M+Na)+ Elemental Analysis Caici. for C 58
H
7 9
N
1 0 0 21 SNa-6H 2
O
C 49.22, H 6.48, N 9.90 Found C 49.46, H 6.44, N 9.96 EzAxnja_2& WO 99/40108 WO 9940108PCT/JP99/00538 399 IR (KBr) 3347.8, 1670.1, 1652.7, 1635.3 cm- 1 NNR (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, mn), 1.50-2.10 (5H, mn), 2.10-2.60 (4H, in), 2.76 (2H, t, J=7.6Hz), 2.85-3.50 (3H, mn), 3.60-4.60 (14H, in), 4.60-5.33 (9H, in), 6.67-7.00 (3H, in), 7.05 (1H, di, J=0.4Hz), 7.20-7.50 (4H, in), 7.60-7.80 (2H, mn), 7.85-8.00 (3H, in), 8.10 (1H, d, J=8.5Hz), 8.45 (1H, 8.68 (iH, d, J=8.4Hz), 8.48 (1H, s) MASS (in/z) :1217.4 (M+Na-1) Elemental Analysis Calcd. for C 53
H
71
N
8
O
2 lSNa-4H 2
O
C 49.61, H 6.20, N 8.73 Found C 49.62, H 6.38, N 8.68 Example 27 IR (KBr) 3361.3, 1668.1, 1635.3 cin 1 NMR (DMSO-d 6 65) :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, in), 1.55-2.13 (5H, in), 2.13-2.60 (4H, in), 2.76 (2H, t, J=7.6Hz), 2.89-3.08 (1H, in), 3.10-3.50 (3H, in), 3.60-3.85 (2H, in), 3.85-4.65 (12H, mn), 4.65-5.50 (8H, mn), 6. 62-7. 05 (3H, in), 7. 06 (1H, di, J=0. 4Hz) 7. 15-7. (4H, in), 7.55-7.80 (2H, in), 7.80-8.03 (3H, mn), 8.03-8.20 (1H, mn), 8.45 (1H, 8.60-9.05 (2H, in) MASS (in/z) :1203.4 (M+Na-1) Elemental Analysis Calcd. for C 52
H
69
N
8 NaO 20 S-6H 2
O
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, 1045.2 cin-' NMR (DMSO-d 6 6) :0.95 (3H, d, J=6.5Hz), 1.08 (3H, di, J=5.6Hz), 1.2-1.6 (10H, in), 1.6-2.1 (5H, in), 2.1-2.5 (4H, mn), 2.95 (1H, mn), 3.0-3.2 (5H, in), 3.20 (3H, s), 3.29 (3H, t, J=6.4Hz), 3.2-3.5 (SH, in), 3.6-4.5 (16H, in), 4.6-5.4 (9H, mn), 6.73 (1H, di, J=8.2Hz), 6.8-7.1 WO 99/40108 WO 9940108PCT/JP99/00S38 400 (1lOH, in), 7 .2 5 (2H, in), 7. 70 (1H, br s) 7. 78 (2H, d, J=8.6Hz), 8.10 (1H, br 8.32 (1H, d, J=7.2Hz), 8.90 (1H, br s) MASS :1387 (M+Na) Elemental Analysis Calcd. for C 61
H
84
N,
0
O
22 SNa-8H 2
O
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, 1045.2 cm- 1 MR (DMSO-d 6 5) :0.93 (3H, d, J=6.6Hz), 1.07 (3H, d, J==5.7Hz), 1.2-1.6 (8H, mn), 1.6-2.1 (5H, mn), 2.1-2.6 (4H, mn), 2.96 (1H, mn), 3.1-3.3 (5H, mn), 3.19 (3H, s), 3.28 (3H, t, J=6.5Hz), 3.3-3.5 (5H, in), 3.7-4.5 (16H, in), 4. 65-5. 3 (9H, in), 6.71 (1Hi, d, J=8.lHz), 6.8-7.1 (9H, in), 7.26 (1H, 7.3-7.5 (2H, in), 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 :1373 (M+Na)+ The following compounds [Examples 30 to 54A] were obtained in a manner similar to that of Ex~le8 IR (KBr) :3369, 2935, 1664, 1631, 1444, 1257, 1047 c- MR (DMSO-d 6 5) :0.89 (3H, d, J=6.9Hz), 0.95 (3H, d, J=6.8Hz), 1.11 (3H, d, J=5.8Hz), 1.2-1.5 (6H, mn), 1.6-2.4 (9H, in), 2.9-3.4 (2H, mn), 3.6-4.5 (16H, in), 4.7-5.4 (9H, in), 6.73 (1H, d, J=8.2Hz), 6.8-7.0 (2H, in), 7.0-7.2 (4H, in), 7.3-7.7 (3H, mn), 7.97 (2H, d, J=8.7Hz) 8. 1-8.3 (5H, in), 8. 81 (1H, d, J=7. OHz) 8. (iH, s) MASS :1329.8 (M+Na)+ Elemental Analysis Calcd. for C 56
H
7 jN 10
O
21
S
2 Na C 46.93, H 5.98, N 9.77 Found C 46.72, H 6.11, N 9.72 ExMple 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), 1.6-2.4 (9H, 2.9-3.2 (2H, 3.3-3.4 (1H, m), 3.8-4.6 (16H, 4.6-5.4 (9H, 6.7-7.0 (3H, m), 7.0-7.2 (4H, 7.3-7.7 (3H, 7.9-8.3 (7H, m), 8.7-8.9 (2H, m) MASS 1313.0 (M+Na) Elemental Analysis Calcd. for C 56
H
7 1
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 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, 2.9-3.2 (2H, 3.4-4.6 (16H, m), 4.6-5.3 (9H, 6.5-7.5 (8H, 7.6-8.2 (4H, 8.31 (1H, 8.43 (1H, dd, J=8.7 and 2.5Hz), 8.6-8.8 (1H, d, J=6.3Hz), 8.85 (1H, 8.99 (1H, d, MASS 1315.3 (M+Na) Elemental Analysis Calcd. for C 56
H
7 3
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 Example 33 IR (KBr) 3350, 2925, 1670, 1625, 1259, 1047 cm-1 NMR (DMSO-d 6 5) 0.7-1.0 (6H, 1.1-1.2 (3H, d, J=5.7Hz), 1.2-2.5 (15H, 3.0-3.3 (2H, 3.4-3.6 (1H, 3.6-3.8 (2H, 3.9-4.6 (16H, 4.7-5.4 (9H, 6.6-7.3 (6H, 7.3-8.0 (5H, 8.0-8.3 8.6-9.0 (2H, m) MASS 1286.8 (M+Na) Elemental Analysis Calcd. for C 55
H
70
N
9 0 22 NaS.5.5H 2 0 C 48.46, H 5.99, N 9.25 Found C 48.47, H 6.01, N 9.26 WO 99/40108 PCT/JP99/00538 402 Example 34 MASS :1387 (M+Na) Example IR (KBr) 3363, 1662.3, 1631.5, 1240 cm- 1 NMR (DMSO-d 6 5) 0.95 (3H, d, J=6.8Hz), 0.8-1.5 1.5-2.6 (16H, 2.8-3.5 (11H, 3.6-4.6 (14H, 4.6-5.3 (9H, 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.84 (1H, 7.00 (2H, d, J=8.8Hz), 7.04 (1H, 7.13 (1H, 7.3-7.5 (2H, 7.63 (1H, br 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 1215 (M-S0 3 +Na) Elemental Analysis Calcd. for C 58
H
84
N
1 00 20 S-7H 2 C 49.78, H 7.06, N 10.01 Found C 49.93, H 6.92, N 9.98 Example 36
-I
IR (KBr) 1648, 1631 cm 1 NMR (DMSO-d 6 0.95 (3H, d, J=6.8Hz), 1.12 (3H, d, J=5.7Hz), 1.65-2.50 (7H, 2.84-3.13 (3H, m), 3.74-5.41 (23H, m) 3.83 (3H, 6.74 (1H, d, J=8.2Hz), 6.77 (1H, d, J=10.6Hz), 6.83 (1H, 7.08 (3H, m), 7.17 (1H, 7.43 (2H, 7.65 (1H, 7.77 (2H, d, J=8.7Hz), 7.92 (2H, d, J=8.5Hz), 8.08 (1H, 8.11 (2H, d, J=8.4Hz), 8.22 (2H, d, J=7.6Hz), 8.25 (2H, d, J=7.6Hz), 8.85 (2H, m) MASS 1273 Elemental Analysis Calcd. for C 57
H
65
N
10 0 2 2 SNa-11H 2 0 C 45.78, H 5.86, N 9.37 Found C 45.75, H 5.95, N 9.27 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, 2.75-3.10 (3H, 3.60-5.35 (23H, 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, 7.07 (3H, 7.16 (1H, 7.43 (2H, 7.64 (1H, 7.74 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.5Hz), 8.00 (1H, 8.10 (2H, d, 8.21 (2H, d, J=7.4Hz), 8.25 (2H, d, J=8.3Hz), 8.83 (2H, m) MASS :1301 Elemental Analysis Calcd. for C 59
H
69
N
10 0 2 2 SNa*10H 2 0 C 47.07, H 5.96, N 9.30 Found C 46.88, H 5.70, N 9.14 Example 38 IR (KBr) 2935, 2873, 1668, 1651, 1632 cm 1 NMR (DMSO-d 6 5) 0.92-0.99 (6H, 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, 4.05 (2H, t, J=5.5Hz), 3.74-5.25 (23H, 6.74 (1H, d, J=8.2Hz), 6.78 (1H, d, J=9.5Hz), 6.87 (1H, m), 7.07 (3H, 7.17 (1H, 7.43 (2H, 7.65 (1H, 7.70 (1H, 7.74 (2H, d, J=8.7Hz), 7.91 (2H, d, 8.00 (1H, 8.10 (2H, d, J=8.6Hz), 8.21 (2H, d, J=7.6Hz), 8.25 (2H, d, J=8.1Hz), 8.88 (2H, m) MASS 1315 Elemental Analysis Calcd. for C 60
H
7 1
N
1 00 22 SNa9H20 C 48.00, H 5.97, N 9.33 Found C 48.05, H 5.95, N 9.34 Example 39 IR (KBr) 2943, 2870, 1668, 1651, 1632 cm-1 NMR (DMSO-d 6 6) 0.95 (6H, 1.13 (3H, d, J=5.7Hz), 1.39 (4H, 1.60-2.50 (9H, 2.80-3.20 (3H, m), 3.74-5.25 (23H, 4.04 (2H, t, J=6.3Hz), 6.74 (1H, d, J=8.2Hz), 6.78 (1H, d, J=11.2Hz), 6.88 (1H, 7.07 (3H, 7.17 (1H, 7.45 (2H, 7.67 (1H, 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, 8.85 (1H, s) WO 99/40108 PCT/JP99/00538 404 MASS :1330, 1329 Elemental Analysis Calcd. for C 61
H
7 3
N
10 0 22 SNa-10H 2 O C 47.78, H 6.11, N 9.18 Found C 47.90, H 6.05, N 9.18 Example 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, 3.02 (3H, 4.04 (2H, t, J=6.4Hz), 3.74-5.25 (23H, 6.74 (1H, d, J=8.2Hz), 6.78 (1H, d, J=11.lHz), 6.88 (1H, 7.07 (3H, 7.17 (1H, 7.43 (2H, 7.67 (1H, 7.75 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.5Hz), 8.00 (1H, 8.11 (2H, d, 8.20 (2H, d, J=7.9Hz), 8.25 (2H, d, J=8.1Hz), 8.84 (2H, m) MASS 1343, 1327 Elemental Analysis Calcd. for C 62
H
7 5
N
10 0 22 SNa-7H2 C 49.86, H 6.01, N 9.38 Found C 49.87, H 6.01, N 9.30 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, 2.80-3.20 (3H, 4.03 (2H, t, J=6.3Hz), 3.74-5.25 (23H, 6.72 (1H, d, J=8.2Hz), 6.78 (1H, d, J=9.7Hz), 6.87 (1H, 7.06 (3H, 7.16 (1H, 7.44 (2H, 7.70 (1H, 7.74 (2H, d, J=8.8Hz), 7.90 (2H, d, J=8.5Hz), 8.00 (1H, 8.10 (2H, d, J=8.6Hz), 8.20 (2H, d, J=7.8Hz), 8.25 (2H, d, J=8.2Hz), 8.84 (2H, m) MASS 1361, 1357, 1341 Elemental Analysis Calcd. for C 63
H
77
N
10 0 22 SNa-6H 2 0 C 50.80, H 6.02, N 9.40 Found C 50.79, H 6.28, N 9.48 Example 42 WO 99/40108 WO 9940108PCT/JP99/00538 405 IR (KBr) 2939, 1668, 1651, 1632 cm- 1 MR (DMSO-d 6 5) 0.96 (3H, di, J=5.3Hz), 1.13 (3H, cd, J=6.OHz), 1.35-2.50 (15H, mn), 2.60-3.20 mn), 3.65-5.40 (25H, mn), 6.73 (1H, d, J=8.5Hz), 6.78 (1H, d, J=11.2Hz), 6.88 mn), 7.09 (3H, in), 7.17 (1H, mn), 7. 44 (2H, mn), 7. 70 (1H, in), 7. 76 (2H, di, J=7.lHz), 7.91 (2H, d, J=6. 6Hz) 8. 08 (1H, in), 8. 11 (2H, d, J=7. 4Hz) 8. 22 (2H, d, J= 6.1lHz) 8. 25 (2H, d, J=6.3Hz), 8.84 (2H, m) MASS (in/z) :1388, 1384, 1368 Elemental Analysis Calcd. for C 64
H
7 8
N,
1 22 SNa-7H 2
O
C 50.09, H 6.04, N 10.04 Foundi C 50.18, H 6.03, N 9.65 Exam~ieA43 IR CKBr) 1650.8, 1629.6 cmJ 1 MR (DMSO-d 6 :0.80-0.86 (3H, in), 0.96 (3H, di, J=6.6Hz), 1.12 (3H, d, J=5.6Hz), 1.23 (14H, br s), 1.74-2.50 (9H, mn), 2.98 (1H, di, J=13.4Hz), 3.10-3.46 (2H, in), 3.70-4.60 (16H, mn), 4.64-5.32 (9H, in), 6.73 (1H, di, J=8.2Hz), 6.83 (1H; di, J=8.4Hz), 6.89 (1H, br 7.05 (1H, di, J=1.7Hz), 7.16 (1H, br 7.42-7.47 (2H, in), 7. 66 (1H, br s) 8. 06-8. 17 (6H, mn), 8. 65 (1H, 8.80 (1H, di, J=7.5Hz), 8.84 (1H, s) MASS (in/z) :1297.03 (M-Na)+ Elemental Analysis Calci. for C 57
H
77 Nl 2
O
2 lSNa-7H 2
O
C 47.30, H 6.34, N 11.61 Founci C 47.33, H 6.16, N 11.54 Example 44 IR (KBr) 3361.3, 1650.8, 1631.5 cin 1 NNR (DMSO-ci 6 5) :0.80-0.90 (3H, mn), 0.96 (3H, di, J=6.7Hz), 1.15 (3H, di, J=6Hz), 1.23 (14H, br s), 1.70-2.65 (9H, in), 2.90-3.10 (1H, in), 3.20-3.42 (2H, in), 3.65-4.60 (16H, in), 4.66-5.40 (9H, in), 6.73 (1H, di, J=8.3Hz), 6.83 (1H, di, J=8.8Hz), 6.89 (1H, 7.05 (1H, 7.18 (1H, 7.42-7.46 (2H, in), 7.66 (1H, WO 99/40108 PCT/JP99/00538 406 br 8.05 (4H, 8.08 (1H, 8.57 (1H, s), 8.57-8.84 (3H, m) MASS 1313.01 (M-Na) Elemental Analysis Calcd. for C 57
H
77
N
1 2020S 2 Na7H 2 0 C 46.78, H 6.27, N 11.48 Found C 46.89, H 6.34, N 11.41 Example IR (KBr) 1650.8, 1631.5 cm 1 NMR (DMSO-d 6 6) 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=6Hz), 1.70-2.60 (9H, 2.80-3.60 (3H, m), 3.60-4.60 (19H, 4.65-5.40 (8H, 6.73 (1H, d, J=8.2Hz), 6.81-6.99 (6H, 7.05 (1H, 7.11 (2H, d, J=8.8Hz), 7.34-7.26 (2H, 7.34-7.73 (3H, 7.76 (2H, d, J=8.8Hz), 7.91 (2H, d, J=8.4Hz), 8.11 (2H, d, J=8.4Hz), 8.19-8.30 (4H, 8.70-9.00 (3H, m) MASS 1393.13 (M-Na) Elemental Analysis Calcd. for C 65
H
7 3
N
1 00 23 SNa9H 2 0 C 49.43, H 5.81, N 8.87 Found C 49.24, H 5.61, N 8.77 Example 46 IR (KBr) 3361.3, 1668.1, 1650.8, 1631.5 cm 1 NMR (DMSO-d 6 6) 0.96 (3H, d, J=6.6Hz), 1.12 (3H, d, J=5.6Hz), 1.70-2.60 (7H, 2.80-5.27 (26H, 4.65 (2H, d, J=5.2Hz), 5.27-5.48 (2H, 5.99-6.18 (1H, 6.72 (1H, d, J=8.1Hz), 6.82 (1H, d, J=8.1Hz), 6.89 (1H, 7.07 (1H, 7.10 (2H, d, J=8.8Hz), 7.12 (1H, 7.46 (2H, br 7.68 (1H, br 7.75 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.4Hz), 8.11 (2H, d, 8.19-8.31 (4H, 8.80-8.83 (2H, m) MASS 1298.97 (M-Na) Elemental Analysis Calcd. for C 5 9
H
67
N
1 00 2 SNa-9H20 C 47.71, H 5.77, N 9.43 Found C 47.90, H 5.61, N 9.41 Example 47 IR (KBr) 1650.8, 1631.5, 1540.8, 1513.8 cm 1 WO 99/40108 WO 9940108PCT/JP99/00538 407 MR (DMSO-d 6 0.96 (3H, di, J=6.7Hz), 1.12 (3H, d, J=5.7Hz), 1.70-2.60 (11H, mn), 2.80-3.60 (3H, i) 3.60-4.60 (18H, mn), 4.65-5.40 (9H, mn), 6.73 (1H, d, J=8.lHz), 6.82 (1H, di, J=9.5Hz), 6.87-6.97 (5H, mn), 7.06 (1H, 7.09 (2H, d, J=8.8Hz), 7.25-7.33 (2H, in), 7. 33-7. 73 (3H, in), 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, mn), 8.70-8.90 (3H. mn) MASS (in/z) :1407.15 (M-Na)+ Elemental Analysis Calcd. for C 66
H
7 5
N
10 0 23 SNa*7H 2 0 C 50.90, H 5.76, N 8.99 Found C 50.80, H 5.90, N 8.90 IR (KBr) 1675.8, 1650.8, 1540.8, 1513.8 cm- 1 NMR (DMSO-ci 6 6) :0.96 (3H, di, J=6.9Hz), 1.13 (3H, d, J=5.9Hz), 1.20-1.60 (12H, mn), 1.64-2.68 (7H, mn), 2.80-3.60 (3H, mn), 3.21 (3H. 3.60-5.40 (27H, in), 6.73 (1H, d, J=8. 4Hz) 6.83 d, J=9.3Hz) 6. 89 (1H,, 7.05 (1H, 7.07 (2H, d, J=8.7Hz), 7.17 (1H, s), 7.30-7.70 (3H. mn), 7.74 (2H, d, J=8.7Hz), 7.91 (2H, d, J=8.4Hz), 8.11 (2H, di, J=8.5Hz), 8.19-8.27 (4H, in), 8.74-8.90 (3H. in) MASS (in/z) 1401.12 (M-Na)+ Examr~le 4 IR (KBr) 1675.8, 1650.8, 1540.8 cmn 1 NMR (DMSO-d 6 5) :0.96 di, J=6.4Hz), 1.03-1.10 (9H, mn), 1.5.0-2.50 (11H, in), 2.70-5.50 (34H, in), 6.71 d, J=7.3Hz), 6.79-6.90 (2H, in), 7.00-7.10 (4H, in), 7. 30-7. 80 (3H, mn), 7.75 (2H, di, J=8. 6Hz) 7. 91 (2H, di, J=8.4Hz), 8.11 (2HN, di, J=7.4Hz), 8.19-8.27 (4H, mn), 8.60-8.90 (3H, in) MASS (in/z) 1414.08 (M-Na)+ Elemental Analysis Calcl. for C 65
H
80
N,
1 2 3 SNa-11.6H 2 0 C 47.39, H 6.31, N 9.35 Found C 47.40, H 6.07, N 9.22 WO 99/40108 PCT/JP99/00538 408 Example IR (KBr) 3353.6, 1650.8, 1631.5, 1538.9, 1515.8, 1442.5, 1114.7 cm- 1 NMR (DMSO-d 6 6) 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.7Hz), 1.7-2.6 (11H, 2.9-3.1 (1H, 3.1-3.5 (2H, 3.7-4.6 (18H, 4.7-5.3 (9H, 6.74 (1H, d, J=8.0Hz), 6.83 (1H, d, J=8.0Hz), 6.87-7.02 (4H, m), 7.05 (1H, 7.15 (2H, d, J=8.7Hz), 7.17 (1H, m), 7.2-7.4 (2H, 7.4-7.6 (2H, 7.67 (1H, br), 7.98 (2H, d, J=8.7Hz), 7.9-8.2 (5H, 8.77 (1H, d, 8.84 (1H, s) MASS 1346.72 (M-Na)+ Elemental Analysis Calcd. for C 60
H
71
N
10 NaO 22 S*1IH 2 0 C 45.92, H 5.97, N 8.92 Found C 46.13, H 5.75, N 8.92 Example 51 IR (KBr) 3363.2, 1650.8, 1538.9, 1515.8, 14425, 1247.7 cm-1 NMR (DMSO-d 6 6) 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.9Hz), 1.5-2.5 (13H, 2.9-3.1 (1H, 3.1-3.5 (2H, 3.6-5.4 (27H, 6.73 (1H, d, J=8.2Hz), 6.82 (1H, d, J=8.2Hz), 6.87-7.00 (4H, 7.05 (1H, 7.14 (2H, d, J=8.7Hz), 7.16 (1H, 7.27 (2H, 7.42 (2H, 7.66 (1H, br), 7.97 (2H, d, J=8.7Hz), 7.9-8.2 8.7-8.9 (2H, m) MASS 1360.75 (M-Na) Elemental Analysis Calcd. for C 61
H
7 3
N
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 Example 52 IR (KBr) 3365.2, 1650.8, 1631.5, 1538.9, 1515.8, 1442.5, 1245.8 cm 1 NMR (DMSO-d 6 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.6Hz), 1.7-2.7 (9H, 2.9-3.1 (1H, 3.1-3.5 (2H, 3.6-4.6 (18H, 4.6-5.5 (9H, 6.73 (1H, WO 99/40108 WO 9940108PCT/JP99/00538 409 di, J=8. 3Hz) 6. 83 (1H, di, J=8. 3Hz) 6. 84-7. 00 (4H, in), 7. 05 (1H, s) 7. 17 (2H, d, J=8. 7Hz) 7. 19 (1H, m), 7.2-7. 6 (4H, in), 7. 67 (1H, br) 7. 98 (2H, d, J=8. 7Hz) 7.8-8.2 (5H, mn), 8.6-9.0 (2H, m) MASS :1332.97 (M-Na)+ Elemental Analysis Calcd. for C 59
H
69
N
10 NaO 2 2 S'8H 2
O
C 47.20, H 5.71, N 9.33 Found C 47.10, H 5.59, N 9.24 Example IR (KBr) 3353.6, 1650.8, 1631.5, 1538.9, 1513.8, 1450.2, 1442.5, 1257.4 cmJ 1 NMR (DMSO-d 6 5) :0.96 (3H, d, J=6.6Hz), 1.12 (3H, d, J=5.7Hz), 1.3-2.6 (13H, mn), 2.9-3.1 (1H, in), 3.1-3.6 (7H, in), 3.6-4.6 (16H, mn), 4.6-5.5 (9H, mn), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.13 (2H, di, J=8.8Hz), 7.15 (1H, in), 7.3- 7.8 (3H, mn), 7.97 (2H, d, J=8.8Hz), 7.8-8.2 (5H, in), 8.6-9.0 (2H, br) MASS (in/z) :1298.85 (M-Na)+ Elemental Analysis Calcd. for C 56
H
71
N
1 0 NaO 2 2 S'10H 2
O
C 44.74, H 6.10, N 9.32 Found C 44.78, H 5.96, N 9.27 Examnie 54 IR (KBr) :3365, 1647, 1541, 1516, 1437, 1248, 1047 cmrC 1 NMR (DMSO-d 6 5) :0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.6Hz), 1.49-1.74 (6H, mn), 1.74-2.55 (7H, mn), 2. 90-3.50 (3H, in), 3. 60-3. 85 (6H, in), 3. 85-4.59 (13H, in), 4.70-5.40 (8H, mn), 6.74 (1H, di, J=8.2Hz) 6. 81 (1H, s) 6.87 (1H, di, J=8.2Hz) 6.99 (1H, d, J=9. lHz) 7. 06 (1H, 7.19 (1H, 7.35-7.50 (2H, mn), 7.68 (1H, in), 8.05 (1H, in), 8.06 (4H, 8.08 (1H, dd, J=9.1 and 2.5Hz), 8.71 (1H, di, J=2.5Hz), 8.77 (1H, di, J=7.4Hz), 8.82 (1H, br s) MASS (in/z) :1266.93 (M-Na)+ Elemental Analysis Calcd. for C 54
H
67 Nl 2 NaO 20
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.
Example IR (KBr) 3359, 1651, 1539, 1522 cm-1 NMR (DMSO-d 6 6) 0.8-1.0 (6H, 1.11 (3H, d, 1.3-1.6 (4H, 1.6-2.15 (5H, 2.2-2.5 (4H, 2.97 (1H, 3.20 (1H, 3.74 (2H, m), 3.8-4.6 (14H, 4.6-5.4 (10H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.22 (1H, 7.45 (3H, 7.52 (2H, d, J=4.9Hz), 7.66 (1H, 7.96 (5H, 8.08 (1H, d, J=8.2Hz), 8.59 (1H, d, J=6.4Hz), 8.85 (1H, 8.89 (1H, s) MASS 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 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, 1.2-1.6 (6H, 1.6-2.1 (7H, 2.1-2.4 (4H, m) 2.96 (1H, 3.19 (1H, 3.42 (1H, 3.74 (2H, 3.8-4.6 (12H, 4.73 (1H, 4.8-5.0 (3H, 5.06 (1H, d, J=5.8Hz), 5.1-5.3 (5H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.15 (2H, d, J=8.8Hz), 7.23 (1H, 7.3- (2H, m) 7.66 (1H, 7.88 (2H, d, J=8.8Hz), 7.95 (4H, 8.07 (1H, d, J=7.8Hz), 8.58 (1H, d, J=7.8Hz), 8.85 (2H, s) MASS 1319.74 (M-Na) Elemental Analysis Calcd. for C 58
H
70
N
11
O
21
S
2 Na-10H 2 0 C 45.70, H 5.95, N 10.11 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, 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, 2.9-3.5 (4H, 3.7-4.5 (16H, m), 4.7-4.8 (1H, 4.87 (1H, d, J=5.9Hz), 5.0-5.4 6.7-6.9 (4H, 6.96 (1H, 7.17 (1H, 7.40 (1H, d, J=8.4Hz), 7.5-7.8 (2H, 8.0-8.2 (2H, m), 8.61 (1H, d, J=7.7Hz), 8.68 (1H, d, J=8.9Hz) MASS 1182.4 (M+Na) Elemental Analysis Calcd. for C 49
H
7 0
N
9 NaO 20 S-4H 2 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 NMR (DMSO-d 6 6) 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, 2.58 (2H, t, J=7.6Hz), 2.9-3.1 (1H, 3.2-3.6 (3H, 3.7-4.2 (5H, 4.1-4.6 (8H, m), 4.7-5.2 (7H, 5.3-5.4 (1H, 6.7-7.8 (14H, m), 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 1227.5 (M+Na) Elemental Analysis Calcd. for C 55
H
7 3
N
8 NaO 9 S-5H20 C 51.00, H 6.46, N 8.65 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), 1.48-2.06 (5H, 2.06-2.70 (8H, 2.70-3.08 (3H, WO 99/40108 PCT/JP99/00538 412 3.09-3.50 (2H, 3.60-4.65 (14H, 4.65-5.50 (9H, 6.65-6.90 (3H, 6.90-7.90 (13H, 8.02 (1H, d, J=8.4Hz), 8.15 (1H, d, J=7.7Hz), 8.71 (1H, s) MASS :1227.5 (M+Na) Elemental Analysis Calcd. for C 5 5
H
7 3
N
8 NaOl 9 S*5H20 C 50.99, H 6.46, N 8.65 Found C 50.84, H 6.62, N 8.81 Example IR (KBr) 3353.6, 1635.3, 1257.4 cm-1 NMR (DMSO-d 6 6) 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, 2.97 (1H, 3.1-3.5 (2H, m), 3.6-4.6 (16H, 4.7-5.4 (8H, 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.87 (1H, 6.97 (1H, 7.13 (2H, d, J=8.9Hz), 7.16 (1H, 7.4- 7.8 (3H, 7.97 (2H, d, J=8.9Hz), 7.9-8.2 (5H, m), 8.72 (1H, 8.78 (1H, d, J=7.1Hz) MASS 1267 (M-Na) The following compounds [Examples 61 to 721 were obtained in a manner similar to that of Example 13.
Example 61 IR (KBr) 1650.8, 1631.5 cm-i NMR (DMSO-d 6 6) 0.80-0.87 (3H, 0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.9Hz), 1.23 (14H, br s), 1.73-2.65 (10H, 2.92-3.50 (3H, 3.60-4.60 (16H, 4.70-5.50 (8H, 6.71 (1H, d, J=8.2Hz), 6.77-6.81 (1H, 6.86 (1H, 6.97 (1H, 7.07-7.86 (4H, 8.11 (1H, 8.06-8.17 (4H, 8.66 (1H, s), 8.66-8.88 (3H, m) MASS 1326.62 (M+Na) Elemental Analysis Calcd. for C 57
H
7 7
N
1 20 2 0 SNa7H 2 O C 47.83, H 6.41, N 11.74 Found C 47.77, H 6.45, N 11.62 Example 62 IR (KBr) 1668.1, 1650.8, 1631.5 cm- 1 WO 99/40108 WO 9940108PCT/JP99/00538 413 NMR (DMSO-c1 6 6) 0.81-0.90 (3H, mn), 0.97 (3H, d, J=6.7Hz), 1.10 (3H, di, J=6Hz),1.23 (14H, br s), 1. 75-2. 70 (10H, mn), 2. 95-3. 02 (1H, mn), 3. 17-3. 30 (2H, mn), 3.60-4.60 (16H, mn), 4.70-5.46 (8H, in), 6.71 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.5Hz), 6.87 (1H, br s), 6.98 (1H, 7.18 (1H, br 7.40-7.80 (3H, mn), 8.05-8.10 (4H, in), 8.08 (1H, 8.57 (1H, s), 8.71-8.80 O3H, in) MASS (in/z) :1297.14 (M-Na)+ Elemental Analysis Calcd. for C 57
H
77 Nl 2
O
1 9
S
2 Na-7H 2
O
C 47.30, H 6.34, N 11.61 Found C 47.07, H 6.23, N 11.42 IR (KBr) 1675.8, 1650.8 cm- 1 NNR (DMSO-d 6 6) 97 (3H, di, J=6. 6Hz) 1. 11 (3H, di, J=6.4Hz), 1.70-2.60 (10H, mn), 2.90-3.60 (3H, in), 3.60-4.60 (18H, mn), 4.68-5.60 (8H, in), 6.70 (1H, d, J=8.3Hz), 6.78 (1H, di, J=9.7Hz), 6.87 (1H, s), 6.93-6.99 (4H, in), 7.11 (2H, di, J=8.8Hz), 7.26-7.34 (2H, in), 7. 09-7.78 (4H, in), 7.7 6 (2H, d, J=8.7Hz) 7. 91 (2H, d, J=8. 5Hz) 8.12 (2H, d, J=8. 6Hz) 8. 19-8.27 (4H, mn), 8.60-9.00 (3H, m) MASS (in/z) :1377.26 (M-Na)+ Elemental Analysis Calcd. for C 65
H
7 3
N
10
O
22 SNa-6H 2
O
C 51.72, H 5.68, N 9.28 Found C 51.54, H 5.73, N 9.25 ExamnIe 64 IR (KBr) 1675.8, 1650.8, 1631.5 cin 1 NNR (DMSO-d 6 6) :0.97 (3H, di, J=6.7Hz) 1.11 (3H, d, J=5.6Hz), 1.70-2.60 (8H, mn), 2.80-3.60 (3H, in), 3.60-5.26 (22H, in), 4.65 (2H, di, J=5.2Hz), 5.26-5.48 (2H, in), 5.99-6.18 (1H, in), 6.70 (1H, di, J=8Hz), 6.78 (1H, d, J=9.9Hz), 6.87 (1H, 6.97 (1N, 7.00-7.20 (iN, in), 7.10 (2H, di, J=8.9Hz) 7.30-7. 80 (3H, in), 7.75 (2H, di, J=8.9Nz), 7.92 (2H, di, J=8.5Hz), 8.12 (2H, di, WO 99/40108 PCT/JP99/00538 414 J=8.6Hz), 8.19-8.27 (5H, 8.50-9.00 (2H, m) MASS :1282.84 (M-Na) Elemental Analysis Calcd. for C 59
H
67
N
1 00 2 1 SNa'7H 2 0 C 49.44, H 5.70, N 9.77 Found C 49.33, H 5.64, N 9.74 Example IR (KBr) 1650.8, 1631.5, 1540.8, 1513.8, 1245.8 cm- 1 NMR (DMSO-d 6 5) 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.9Hz), 1.80-2.60 (11H, 2.80-3.60 (3H, m), 3.65-4.60 (19H, 4.63-5.50 (8H, 6.70 (1H, d, J=8Hz), 6.77 (1H, d, J=7.9Hz), 6.87-6.97 (5H, m), 7.02-7.22 (1H, 7.09 (2H, d, J=8Hz), 7.25-7.33 (2H, 7.40-7.80 (3H, 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), 8.50-9.00 (3H, m) MASS 1391.07 (M-Na) Elemental Analysis Calcd. for C 66
H
7 5
N
1 00 22 SNa-7H20 C 51.42, H 5.82, N 9.09 Found C 51.37, H 5.78, N 9.05 Example 66 IR (KBr) 3353.6, 2939.0, 1650.8, 1631.5, 1538.9, 1513.8, 1442.5 cm-1 NMR (DMSO-d 6 5) 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=5.7Hz), 1.7-2.6 (12H, 2.9-3.1 (1H, 3.1-3.7 (2H, 3.7-4.7 (18H, 4.7-5.5 (8H, 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, 7.2-7.35 (2H, m), 7.35-7.9 (3H, 7.98 (2H, d, J=8.7Hz), 7.9-8.2 8.75 (1H, br), 8.80 (1H, d, MASS 1331.28 (M-Na) Elemental Analysis Calcd. for C 60
H
71
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 IR (KBr) 3353.6, 1666.2, 1650.8, 1631.5, 1538.9, WO 99/40108 WO 9940108PCT/JP99/00538 415 1513.8, 1442.5, 1247.7 cm- 1 NMR (DMSO-d 6 5) :0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.4-2.7 (14H, mn), 2.9-3.1 (1H, in), 3.1-3.5 (2H, mn), 3.6-4.6 (18H, mn), 4.7-5.5 (8H, in), 6.71 (1H, di, J=8. lHz) 6.79 (1H, d, J=8. lHz) 6. 84-7. 00 (5H, n) 7.14 (2H, di, J=8.7Hz) 7.16 (1H, mn), 7.27 (2H, mn), 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, in), 8. 75 (1H, br) 8.7 9 (1H, di, J=7.2Hz) MASS :1345.3 (M-Na)+ Elemental Analysis Calcd. for C 61
H
73
N
10 Na0 2 lS 2 *8H 2 0 C 48.41, H 5.93, N 9.25 Found C 48.30, H 5.91, N 9.17 IR (KBr) 3353.6, 2937.1, 1650.8, 1540.8, 1513.8, 1452.1, 1243.9 cirJ 1 NMR (DMSO-d 6 5) :0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.7-2.7 (10H, in), 2.9-3.1 (1H, in), 3.1-3.6 (2H, mn), 3.6-4.7 (18H, mn), 4.7-5.5 (8H, in), 6.71 (1H, di, J=8. lHz) 6.79 (1H, di, J=8. lHz) 6.84-7. 10 (5H, mn), 7.17 (2H, di, J=8.7Hz), 7.19 (1H, in), 7.2-7.4 (2H, in), 7.44 (1H, di, J=9.2Hz), 7.5-7.9 (2H, mn), 7.98 (2H, d, J=8.7Hz), 7.9-8.2 (5H, in), 8.6-9.0 (2H, in) MASS :1316.8 (M-Na)+ Elemental Analysis Calcd. for C 59
H
69
N
10 NaO 2 lS 2 '9H 2 0 C 47.13, H 5.83, N 9.32 Found C 47.40, H 5.67, N 9.30 IR (KBr) 3361.3, 2937.1, 1650.8, 1631.5, 1538.9, 1513.8, 1450.2, 1440.6, 1257.4 cmf 1 NMR (DM50-cl 6 6) :0.99 (3H, mn), 1.11 (3H, mn), 1.3-2.7 (14H, mn), 2.9-3.1 (1H, in), 3.1-3.6 (7H, in), 3.6-4.7 (16H, in), 4.7-5.6 (8H, mn), 6.69 (1H, di, J=8.2Hz) 6.77 (1H, d, J=8.2Hz), 6.86 (1H, 6.98 (1H, 7.13 (2H, d, j=8.7Hz), 7.15 (1H, in), 7.3-7.9 (3H, mn), 7.97 (2H, WO 99/40108 PCT/JP99/00538 416 d, J=8.7Hz), 7.9-8.2 (5H, 8.6-8.9 (2H, m) MASS 1283.2 (M-Na) Elemental Analysis Calcd. for C 56
H
71
N
10 NaO 21
S
2 *10H 2 0 C 45.22, H 6.17, N 9.42 Found C 45.30, H 5.90, N 9.38 Example IR (KBr) 3400, 1651, 1541, 1261 cm- 1 NMR (DMSO-d 6 0.95-5.40 (58H, 6.67-8.77 (19H, m) MASS 1325.29 (M-Na) Elemental Analysis Calcd. for C 59
H
7 7
N
10 NaO 2 1
S
2 -37/4H 2 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 NMR (DMSO-d 6 6) 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 1254 (M-Na) Elemental Analysis Calcd. for C 59
H
69
N
10 NaO 21 S-41/5H 2 0 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 0.87-5.30 (50H, 6.66-8.73 (20H, m) MASS 1236.29 (M-Na) Elemental Analysis Calcd. for C 56
H
70
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 in a manner similar to that of Example 17.
Example 73 IR (KBr) 3359, 1676, 1651, 1632, 1514 cm 1 NMR (DMSO-d 6 6) 0.87-1.0 (6H, 1.09 (3H, d, J=5.4Hz), 1.2-1.6 (4H, 1.6-2.1 (5H, 2.1-2.6 (5H, 3.00 (1H, 3.2 (1H, 3.5 (1H, 3.6-4.6 WO 99/40108 PCT/JP99/00538 417 (16H, 4.6-5.6 (8H, 6.70 (1H, d, J=8.2Hz), 6.77 (1H, d, J=8.2Hz), 6.87 (1H, 6.97 (1H, 7.20 (1H, 7.3-7.8 (6H, 7.8-8.4 (6H, 8.4-8.8 (2H, m), 8.89 (1H, s) MASS 1292.51 (M-Na) Elemental Analysis Calcd. for C 57
H
7 0
N
11
O
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 IR (KBr) 3359, 1668, 1650, 1631 cm-i NMR (DMSO-d 6 5) 0.97 (3H, d, J=6.4Hz), 1.08 (3H, d, J=5.4Hz), 1.2-1.6 (6H, 1.6-2.0 (7H, 2.1-2.4 (4H, 3.01 (1H, 3.20 (1H, 3.67 (1H, m), 3.7-4.6 (16H, 4.6-5.6 (8H, 6.68 (1H, d, J=8.2Hz), 6.76 (1H, d, J=8.2Hz), 6.85 (1H, 7.15 (2H, d, J=8.9Hz), 7.16 (1H, 7.2-7.8 (4H, m) 7.88 (2H, d, J=8.9Hz), 7.96 (4H, 8.56 (1H, 8.84 (2H, s) MASS 1304.08 (M-Na) Elemental Analysis Calcd. for C 58
H
70
N
11
O
20
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.
Example IR (KBr) 1668, 1649, 1632, 1541, 1516 cm 1 NMR (DMSO-d 6 6) 0.86 (3H, m) 0.97 (3H, d, J=6.7Hz), 1.0-1.2 (3H, 1.2-1.4 (8H, 1.45-1.65 (2H, m), 1.7-2.6 (8H, 2.8-3.5 (3H, 3.46 (2H, t, J=6.4Hz), 3.6-4.6 (14H, 4.51 (2H, 4.7-5.4 (8H, m), 6.65-6.85 (2H, 6.88 (1H, 6.97 (1H, 7.18 (1H, 7.4-7.8 (3H, 7.50 (2H, d, J=8.6Hz), 8.02 (2H, d, J=8.6Hz), 8.0-8.2 (5H, 8.41 (1H, 8.72 (1H, 8.7-8.9 (1H, 9.35 (1H, s) MASS 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 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, 2.9-3.1 (1H, 3.1-3.5 (2H, m), 3.6-4.6 (14H, 4.03 (2H, t, J=6.4Hz), 4.7-5.1 (4H, 5.15-5.25 (3H, 5.3-5.45 (1H, 6.7-6.85 (2H, 6.87 (1H, 6.97 (1H, 7.10 (2H, d, J=8.9Hz), 7.18 (1H, 7.4-7.8 (3H, 7.85 (2H, d, J=8.9Hz), 8.0-8.2 (5H, 8.06 (1H, 8.72 (1H, 8.75- 8.9 (1H, 9.23 (1H, s) MASS 1333 (M -23) Elemental Analysis Calcd. for C 59
H
7 3
N
12 NaO 20
S
2 -8H 2 O C 47.20, H 5.97, N 11.19 Found C 47.27, H 6.04, N 11.26 Examrple 77 IR (KBr) 1633, 1608, 1531, 1444, 1419 cm- 1 NMR (DMSO-d 6 5) 0.88-1.25 (6H, m) 1.49-2.50 (11H, m), 2.84-5.48 (33H, 6.62-6.98 (3H, 7.00-7.16 (2H, 7.10 (2H, d, J=8.5Hz), 7.25-7.80 (7H, 7.85 (2H, d, J=8.5Hz), 7.91-8.14 (6H, 8.65-8.89 (2H, m) MASS 1371.69(M-Na') Elemental Analysis Calcd. for C 62
H
7 4
N
11 NaO 2 1
S
2 *8H 20 C 48.34, H 5.89, N 10.00 Found C 48.39, H 5.65, N 9.95 Example 78 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, 2.78-3.50 (7H, m), 3.64-5.34 (23H, 6.47 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, 7.00-7.50 (10H, 7.67 (1H, brs), 7.98-8.20 (6H, 8.74(1H, d, WO 99/40108 PCT/JP99/00538 419 8.65-8.92 (2H, m) MASS :1343.11 (M-Na') Elemental Analysis Calcd. for C 60
H
71
N
12 NaO 20
S
2 *7H 2 0 C 48.25, H 5.74, N 11.25 Found C 48.32, H 5.62, N 11.24 IR (KBr) :1637, 1539, 1512, 1443 cm- 1 NNR (DMSO-d 6 6) :0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=7. lHz) 1. 36 (3H, t, J=6.9Hz) 1. 73-2. 52 (8H, in), 2. 79-3. 34 (3H, mn), 4. 10 (2H, q, J=7. OHz) 3. 66-4. (14H, mn), 4.70-5. 54 (8H, in), 6.71 (1H, d, J=8.l1Hz) 6.79 (1H, dd, J=8.4 and 1.7Hz), 6.87 (1H, 6.98 (1H, d, J=1.7Hz), 7.06(2H, d, J=8.9Hz), 7.19 (1H, 7.45(1H, d, JTh8.8Hz), 7.60 (1H, mn), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 7.96-8.24 (8H, mn), 8.73 (1H, brs), 8.80(1H, d, J=7.3Hz) MASS :1287.49 (M-Na") Elemental Analysis Calcd. for CS8H 67
N
10 NaO 20
S
2 -7H 2
O
C 48.46, H 5.68, N 9.74 Found C 48.19, H 5.69, N 9.56 ExaMpile 0 IR (KBr) :1649, 1635, 1510, 1443 cm-1 NMR (DMSO-d 6 65) :0.96 (3H, d, J=6.8Hz), 1.12 (3H, d, J=S.8Hz), 1.55-2.51 (11H, mn), 2.76-3.64 (3H, mn), 3.25 (3H, s) 3. 64-4. 60 (18H, mn), 4.60-5. 54 (9H, in), 6.73 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.6Hz), 6.89 (1H, 7.02-7.15 (3H, mn), 7.36-7.79 (3H, in), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.4Hz), 8.00-8.26 (8H, in), 8.70-8.92 (2H, in) MASS :1361.12 (M-Na 4 Elemental Analysis Calcd. for C 6 lH 73 Nl 0 NaO 22
S
2 -7H 2
O
C 48.47, H 5.80, N 9.27 Found C 48.63, H 5.71, N 9.19 Exale 81 IR (KBr) :1633, 1533, 1512, 1443 cin-1 WO 99/40108 PCT/JP99/00538 420 NIAR (DMSO-d 6 5) 97 O3H, d, J=6.7Hz) 1. 10-1. 20 (3H, mn), 1. 56-2. 50 (12H, mn), 2. 88 28 (3H, 3. 25 (3H, s) 3. 63-4. 56 (18H, mn), 4. 70-5.50 (8H, 6. 69 (1Hi, d, J=8.lHz), 6.77 (1H, d, J=8.lHz), 6.87 (1H, s), 6.98 (1H, 7.07 (2H, d, J=8.8Hz), 7.28-7.72 (3H, mn), 7.73 (2H, d, J=8.7Hz), 7.87 (2H, d, J=8.4Hz), 7.94-8.20 (8H, mn), 8.64-8.92 (2H, in) MASS (in/z) :1345.44 (M-Na+) Elemental Analysis Calcd. ffor C 6 lH 7 3
N
10 NaO 21
S
2 -6H 2
O
C 49.59, H 5.80, N 9.48 Found C 49.52, H 5.68, N 9.39 IR (KBr) :1635, 1608, 1531, 1444, 1419 cm- 1 NMR (DMSO-d 6 97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.7Hz), 1.03-1.20 (5H, in), 1.50-2.55 (14H,in), 2.55S-2.77 (4H, m) 89-3. 55 (7H, m) 67-4. 63 (14H, mn), 4.68-5.50(8H, in), 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, 7.44 (1H, d, 7.58 (1H, mn), 7.71 (1H, mn), 7. 85 (2H, d, J=8. 8Hz) 7.94-8.20 (5H, in), 8.72 8.78 (1H, d, J=7.OHz), MASS (in/z) :1332.99 (M-Na') Elemental Analysis Calcd. for C 60
H
7 7 Nl 2 NaOl 9
S
2 -7H 2
O
C 48.58, H 6.18, N 11.33 Found C 48.58, H 6.02, N 11.22 IR (KBr) :1633, 1535, 1512, 1443 cm- 1 NNR (DMSO-d 6 5) :0.95 (3H, J=7.4Hz), 0.97 (3H, d, J=7.l1Hz) 1. 11 O3H, d, J=5. 6Hz) 1. 35-1.56 (2H, in), 1.66-2.55(10H, in), 2.90-3.38 (3H, in), 3.68-4.62 (16H, in), 4.75-5. 52 (8H, mn), 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, in), 7.73 (2H, d, J=8.7Hz), 7.86 (2H, di, J=8.4Hz), 8.05-8.25 (8H, WO 99/40108 PCT/JP99/00538 421 in), 8.50-8.92 (2H, m) MASS :1315.58 (M-Na') Elemental Analysis Calcd. for C 60
H
71
N
1 0 NaO 2 0
S
2 dlOH 2
O
C 47.43, H 6.04, N 9.22 Found C 47.60, H 5.66, N 9.24 Example 84 IR (KBr) :1647, 1539, 1512, 1448 cm- 1 NMR (DMS0- d 6 6) 97 (3 H, d, J= 6. 7Hz) 1. 16 20 (3 H, mn), 1.15 (3H, t, J=7.OHz), 1.73-2.58 (8H, mn), 2. 84-3 .35 (3H, mn), 3. 49 (2H, q, J=7. OHz) 3. 66-4 .62 (18H, in), 4.74-5.50 (8H, mn), 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 7.74 (2H, d, J=8.8Hz), 7. 87 (2H, d, J=8. 5Hz) 8. 02-8.24 (8H, in), 8. 63-8. (2H, mn) MASS :1331.2 (M-Na+) Elemental Analysis Calcd. for C 6 0
H
7 1
N
10 NaO 2 1
S
2 -8H 2
O
C 48.06, H 5.85, N 9.34 Found C 47.93, H 5.82, N 9.23 IR (KBr) :1633, 1537, 1513, 1443 cm- 1 NMR (DMSO-d 6 6) :0.97 (3H, d, J=6.8Hz), 1. 11 (3H, d, J=5.8Hz) 1.74-2.52 (8H, mn), 2.90-3.40(3H, mn), 3.35 (3H, s) 3. 62-4.57 (18H, in), 4. 70-5.49 (8H, mn), 6.70 (1H, d, J=8.lHz), 6.78 (1 H, d, J=8.lHz), 6.87 (1H, 6.97 (1H, 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, in), 8.56-8.92 (2H, in) MASS (in/z) :1317.28 (M-Na+) Elemental Analysis Calcd. for C 5 9
H
69
N
10 NaO 21
S
2 '9H 2
O
I C 47.13, H 5.83, N 9.32 Found C 47.24, H 5.55, N 9.35 Exam~le 8 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-lyl]benzoic acid benzotriazol-l-yl-ester (0.12 g) in N,Ndimethylformamide (3 ml) was added diaminopyridine (0.024g), and the mixture was stirred for 15 hours at ambient temperature.
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.) 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 NMR (DMSO-d 6 5) 0.96 (3H, d, J=6.4Hz), 1.08 (3H, d, J=5.4Hz), 1.44-5.17 (55H, 6.69-8.72(22H, m) MASS 1405.4 (M+Na) Elemental Analysis Calcd. for C 64
H
83
N
10 NaO 21 S*7.5H 2 0 C 50.62, H 6.50, N 9.32 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 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 1327.5 (M-Na) Elemental Analysis Calcd. for C 60
H
83
N
10 NaO 20 S'6.5H 2 0 C 49.07, H 6.59, N 9.54 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 6) 0.96 (3H, d, J=6.7Hz), 1.07 (3H, d, J=5.9Hz), 1.40-5.40 (52H, 6.69-8.71 (19H, m) MASS 1249.3 (M-Na) WO 99/40108 PCT/JP99/00538 423 Elemental Analysis Calcd. for C 58
H
77
N
10 NaOj 9 S-8H 2
O
C 49.15, H 6.61, N 9.88 Found C 48.96, H 6.49, N 9.79 IR (KBr) :1668.1, 1631.5, 1238.1 cm- 1 NNR (DMSO-d 6 6) :0.82-5.38 (69H, in), 6.69-8.40 (14H, Mn) MASS :1265.6, 1243.5 (N-Na) Elemental Analysis Calcd. for C 57
H
83 Nl 0 NaO 19 S-7H 2
O
C 49.13, H 7.02, N 10.05 Found C 49.19, H 7.02, N 10.00 Example IR (KBr) :1664.3, 1629.6, 1232.3 crrC 1 NMR (DMSO-d 6 5) :0.96 (3H, d, J=6.7Hz), 1.07 (3H, d, J=5.6Hz), 1.16-5.20 (53H,m), 6.70-8.30(18H,m) MASS :1265.4 (M-Na) Elemental Analysis Calcd. for C 58
H-
77
N
1 Na 2 S8.5H 2 0 C 48.29, H 6.57, N 9.71 Found C 48.04, H 6.21, N 9.60 ExamplIe91 IR (KBr) :1666.2, 1631.5, 1232.3, 1045.2cm-i NMR (DMSO-d 6 6) :0.96 O3H, d, J=6.7Hz), 1.07 (3H, d, J=5.8Hz), 1.30-5.40 (53H, mn), 6.69-8.71 (18H,m) MASS :1296.3 (M+Na) Elemental Analysis Calcd. for C 5 8H 77
N
10 NaO 19 S-8H 2
O
C 49.15, H 6.61, N 9.88 Found C 49.14, H 6.53, N 9.90 Exampe 2 IR (KBr) :3330.5, 1666.2, 1631.5, 1255.4cm 1 l NNR (DMSO-d 6 6) :0.94-5.26 (68H, in), 6.66-8.26 (11H, Mn) MASS (in/z) :1319.35 (N-Na) Elemental Analysis Calcd. for C 5 7
H
7 9
N
1 0 NaO 2 2
S
2 -4.5H 2 0 C 48.06, H 6.23, N 9.83 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 6) 0.88-1.45 (11H, 1.60-3.40 (18H, 3.75-5.30 (22H, 6.72-9.00 (20H, m) MASS 1334.69 (M-Na) Elemental Analysis Calcd. for C 59
H
71
N
1 0 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 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 1341.55 (M-Na) Elemental Analysis Calcd. for C 59
H
77
N
10 NaO 22
S
2 *6H 2 0 C 48.09, H 6.09, N 9.51 Found C 47.98, H 6.01, N 9.49 Example 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) MASS 1289.3 (M-Na) Elemental Analysis Calcd. for C 55
H
73
N
10 NaO 2 2
S
2 .7H20 C 45.89, H 6.09, N 9.73 Found C 45.67, H 5.91, N 9.74 Example 96 IR (KBr) 1666.2, 1633.4, 1249.6 cm- 1 NMR (DMSO-d 6 6) 0.96-5.20 (47H, m) ,6.72-9.29 (24H,m) MASS 1351.41 (M-Na) Elemental Analysis Calcd. for C 63
H
7 1
N
10 NaO 22 S*8.5H 2 0 C 49.51, H 5.80, N 9.16 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 6) 0.94-5.24 (55H, m) ,6.72-8.84 m) WO 99/40108 PCT/JP99/00538 425 MASS :1363.41 CM-Na) Elemental Analysis Calcd. for C 6 jH 75
N
10 Na0 22
S
2 -7H 2
O
C 48.41, H 5.93, N 9.25 Found C 48.45, H 5.80, N 9.14 Exam]le 98 (KBr) :3355.5, 2935.1, 2873.4, 1633.4, 1521.6, 1438.6, 1255.4 cm- 1 NNR (DMSO-d 6 6) :0.85-1.05 Cm, 6H), 1.10 Cd, 3H, J=5.8Hz), 1.25-1.60 Cm, 4H), 1.60-2.60 (in, 9H), 2.80-3.10(m, 1H), 3.10-3.60 2H), 3.60-4.60 (in, 16H), 4.60-5.60 9H), 6.71 1H, J=8.2Hz), 6.81 Cd, 1H, J=8.2Hz), 6.89 Cs, 1H), 7.05 Cs, 1H), 7.08 Cd, 2H, J=8.9Hz), 7.15-7.30 (in, 1H), 7.30-7.55 Cm, 2H), 7.55-7.70 Cm, 1H), 7.80 Cd, 2H, J=8.3Hz), 7.91 Cd, 2H, J=8.9Hz), 7.96 Cd, 2H, J=8.3Hz), 8.00-8.20 Cm, 1H), 8.38 1H), 8.65 Cd, 1H, J=6.8Hz), 8.75-9.00 Cm, 1H) MASS Cm/z) :1268.40 CM-Na) Elemental Analysis Calcd. for C 56
H
70
N
9 Na0 21
S
2 -8H 2
O
C 46.82, H 6.03, N 8.78 Found C 47.11, H 5.84, N 8.82 IR CKBr) :3396.0, 2933.2, 2871.5, 1648.8, 1631.5, 1538.9, 1515.8, 1456.0, 1438.6, 1253.5cm- 1 MR CDMSO-d 6 5) :0.75-0.90Cm, 3H), 0.96Cd, 3H, J=6.7Hz), 1.11 Cd, 3H, J=5.8Hz), 1.10-1,60 Cm, 6H), 1.60-2.60(m, 9H), 2.80-3.10(m, 1H), 3.10-3.60(m, 2H), 3.60-4.65 Cm, 16H), 4.65-5.60 9H), 6.73 Cd, 1H, J=8.2Hz), 6-82(d, 1H, J=8.2Hz), 6.89 Cs, 1H), 7.05 Cs, 1H), 7.07 Cd, 2H, J=8.9Hz), 7.15-7.30 Cm, 1H), 7.30-7.55 Cm*, 2H), 7.55-7.75 Cm, 1H), 7.80 Cd, 2H, J=8.3Hz), 7.91(d, 2H, J=8.9Hz), 7.96 Cd, 2H, J=8.3Hz), 8.00-8.20 Cm, iN), 8.38 Cs, 1H), 8.65 Cd, iH, J=6.8Hz) 8.75-9.00 Cm, 1H) MASS Cm/z) :1282.09 CM-Na) WO 99/40108 PCT/JP99/00538 426 Elemental Analysis Calcd. for C57H 7 2N9NaO 2 1
S
2 -7H20 C 47.79, H 6.05, N 8.80 Found C 47.89, H 5.96, N 8.77 Example 100 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 6) 0.75-0.90 3H), 0.96 3H, J=6.7Hz), l.ll(d, 3H, J=5.6Hz), 1.10-1.55 8H), 1.60-2.60 9H), 2.80-3.10 1H), 3.10-3.60 (m, 2H), 3.60-4.65 16H), 4.65-5.40 9H), 6.74 (d, 1H, J=8.2Hz), 6.83 1H, J=8.2Hz), 6.89 1H), 7.05 1H), 7.08 2H, J=8.8Hz), 7.20(s, 1H), 7.30-7.55 2H), 7.60-7.75 1H), 7.80 2H, J=8.2Hz), 7.92 2H, J=8.8Hz), 7.96 2H, J=8.2Hz), 8.07 1H, J=7.0Hz), 8.38 1H), 8.66 1H, J=6.8Hz), 8.85 1H) MASS 1296.16 (M-Na) Elemental Analysis Calcd. for C 5 8
H
74
N
9 NaO 2 1
S
2 -6H 2 0 C 48.77, H 6.07, N 8.82 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 6) 0.80-1.10 6H), 1.10 3H, J=5.7Hz), 1.60-2.60 10H), 2.85-3.10 1H), 3.10-3.60 2H), 3.60-4.60 16H), 4.65-5.50 (m, 8H), 6.71 1H, J=8.1Hz), 6.79 1H, J=8.1Hz), 6.88 1H), 6.98 1H), 7.06 2H, J=8.8Hz), 7.20 1H), 7.30-8.20 12H), 7.70 2H, J=8.8Hz), 8.48 1H), 8.60-8.85 2H) MASS 1300.35 (M-Na) Elemental Analysis Calcd. for C 60
H
70
N
9 NaO 2 0
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 5) 0.70-1.05 6H), 1.08 3H, J=5.9Hz), 1.20-1.55 4H), 1.60-2.60 2.80-3.10 1H), 3.10-3.60 2H), 3.60-4.60 (m, 16H), 4.60-5.50 8H), 6.70 1H, J=8.1Hz), 6.77 1H, J=8.1Hz), 6.86 1H), 6.96 1H), 7.07 2H, J=8.9Hz), 7.20 1H), 7.30-7.50 1H), 7.50-7.80 2H), 7.79 2H, J=8.4Hz), 7.90 (d, 2H, J=8.9Hz), 7.96 2H, J=8.4Hz), 8.00-8.20 (m, 1H), 8.37 1H), 8.50-8.80 2H) MASS 1252.57 (M-Na) Elemental Analysis Calcd. for C 5 6
H
7 0
N
9 NaO 2 0
S
2 -7H 2 0 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 NMR (DMSO-d 6 5) 0.75-0.95 3H), 0.97 3H, J=6.8Hz), 1.10 3H, J=5.9Hz), 1.20-1.55 6H), 1.60-2.60 10H), 2.80-3.10 1H), 3.10-3.60 (m, 2H), 3.60-4.60(m, 16H), 4.65-5.50 8H), 6.71 (d, 1H, J=8.2Hz), 6.78 1H, J=8.2Hz), 6.87 1H), 6.97 1H), 7.04 2H, J=8.7Hz), 7.20 1H), 7.30-7.90 3H), 7.67 2H, J=8.7Hz), 8.01 (s, 4H), 8.05-8.20 1H), 8.26 1H), 8.60-8.90 (m, 2H) MASS 1266.27 (M-Na) Elemental Analysis Calcd. for C 57
H
72
N
9 NaO 20
S
2 6H 20 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, 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 3H, J=6. 8Hz) 1.-10 3H-, J=6. OHz) 1. 20-1. 60 (in, 6H) 1. 60-2. 60 (in, 10H) 2. 80-3. 10 (in, 1H) 3.10-3. 60 (mn, 2H) 3. 60-4. 65 (in, 16K) 4.70-5.50 (mn, 8H) 6.71 (d, 1K, J=8. lHz) 6.7 9 1H1, J=8. 1Hz) 6.88 1H), 6.98 1H), 7.08 2H, J=8.9Hz), 7.21 (mn, 1H), 7. 44 1K, J=7. 4Hz) 7. 50- 7. 80 (mn, 2H), 7.80 (d, 2H, J=8.4Hz), 7.91 (di, 2H, J=8.9Hz), 7.97 2K, J=8.4Kz), 8.12 1H, 8.37 1K), 8.60-8.80 (mn, 1H), 8.72 1K) MASS (in/z) :1266.27 (M-Na) Elemental Analysis Caici. for C 57
K
72
N
9 NaO 2 0
S
2 -6H 2
O
C 48.96, K 6.05, N 9.01 Found C 48.75, K 5.98, N 8.91 Examiple 105 IR (KBr) :1666.2, 1629.6, 1240.0, 1047.2 cm- 1 NIMR (DMSO-d 6 6) :0.96 (3H, d, J=6.6Hz), 1.07 d, J=5.8Kz), 1.60-5.40(47,in), 6.68-8.80(18K,m) MA-SS :1231.3 (M+1) Elemental Analysis Calcd. for C 55
H
71 Nj 0 NaO 19 S-8K 2
O
C 48.03, K 6.38, N 10.18 Found C 47.84, H 6.46, N 10.12 Examiple 106 A solution of Starting Compound (106) (200 ing) in N,N-diinethylformainide (4 ml) was treated with 4-[5-[4-14- (2-iethoxyethoxy) ethoxylphenyllphenyl]-1, 3,4thiadiazol-2-yllbenzoic acid benzotrizol-1-yl ester (144 mg) and diulsopropyl ethyl amine (58 111) and the mixture was stirred for 19 hours at room temperature. Ethyl acetate was added to the reaction mixture and the resulting precipitate was colle cted 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 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 ing) as an amorphous pale yellow powder.
IR (KBr) :1659, 1633, 1533, 1510, 1444 cm- 1 NIMR (DMSO-d 6 5) :0.97 (3H, d, J=6.7Hz), 1.10 (3H1, d J=5.6Hz) 1.76-2.47 (8H, mn), 2.83-3.32 (311, mn), 3.26 (3H, s) 3. 40-4. 60 (22H, mn), 4. 70-5. 54 (8H, in), 6. 69 (1H, d, J=8.2 Hz), 6.77 (lH, d, J=8.211z), 6.87 (111, brs), 6.98 (1H1, 7.09 (2H, d, J=8.8Hz), 7.34- 7.55 (3H, mn), 7.74 (2H, d, J=8.7Hz), 7.87 (2H, d, 8.00-8.20 (8H, in), 8.66-8.92 (2H, m) MASS (in/z) :1361.4 (M-Na+) Elemental Analysis Calcd. for C 6 lH 7 3 Nl 0 NaO 22
S
2 '10H 2
O
C 46.80, H1 5.99, N 8.95 Found C 46.93, H 5.80, N 8.89 The following compounds [Examples 107 to 122a] were obtained in a manner similar to that of Example 106.
Examie 107 IR (KBr) :3367, 2925, 1668, 1631, 1538, 1511, 1450, 1265, 1230, 1085, 1047 cm- 1 NNR (DMSO-d 6 6) :0.95 (311, d, J=6.7Hz), 1.07 (3H, d J=5.9Hz) 1. 2-1. 6 (5H, in), 1. 6-2.1 (1011, mn), 2. 1-2. (811, in), 2.63 (4H, in), 2.79 (211, in), 2.98 (2H1, mn), 3.06 (4H, in), 3.20 (1H, in), 3.71 (211, in), 3.8-4.6 (1411, in), 4. 6-5. 6 (911, in), 6.70 (1H1, d, J=8.2 Hz) 6.78 (1H, 6.83 (3H, d, J=8.2Hz), 6.94 (2H, d, J=8.711z) 7.04 (3H, in), 7.2-7.7 (3H, in), 7.74 (211, d, J=8.7Hz) 8. 07 (1H, in), 8.23 (1H, in), 8.56 (1H, mn), 8.84 (1H, s) MASS (in/z) :1348.35 CM-Na 4 *Elemental Analysis Calcd. For C 63
H
8 6
N,
1 NaO 20
S
2 *11H 2
O
C 48.18, H 6.93, N 9.81 Found C 48.19, H 6.68, N 9.71 Examnie 108 IR (KBr) :1676, 1651, 1622, 1514 cmirC WO 99/40108 PCT/JP99/00538 430 NMR (DMSO-d 6 6) :0.97 (3H, d, J=6.6Hz), 1.05-1.1 (3H, mn), 1.7-2.65 (12H, 2.8-3.2 (7H, in), 3.60 (2H, s) 2. 65- 4.1 (5H, mn), 4. 1- 4.6 (9H, in), 4. 7 45 (8H, mn), 6. 65-7. 85 (3H, mn), 7. 85-7.05S (4H, mn), 7. 15-7.3 (3H, mn), 7.4-7. 8 (3H, mn), 7.52 (2H, d, J=8. 6Hz) 7. 94 (2H, d, J=8. 6Hz) 8. 0-8.2 (5H, in), 8. 41 (1H, s) 8.72 (1H, 8.75-8.9 (1H, mn), 9.34 (1H, s) MASS :1407 (M"-23) Elemental Analysis Calcd. For C 64
H
75
N
1 4 NaO 19
S
2 *9H 2 0 C 48.24, H 5.88, N 12.30 Found C 48.41, H 5.68, N 12.22 Eampe IR (KBr) :1649, 1632, 1541, 1514 crtC 1 NMR (DMSO-d 6 6) :0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=5.7Hz), 1.1-1.35 (5H, in), 1.35-2.5 (17H, mn), 2.85-3.55 (6H, mn), 3.55-4..1 (8H, in), 4.1-4.6 (9H, in), 4.7-5.45 (8H, mn), 6.71 (1H,d, J=8.3Hz), 6.78 (1H,d, J=8.3Hz), 6.85-6.9 (1H, in), 6.9-7.0 (1H, in), 7.08 (2H, d, J=8.9Hz), 7.1-7.25 (1H, in), 7.35-7.75 (3H, in), 7.84 (2H, d, J=8.9Hz), 7.9-8.2 (5H, mn), 8.6-8.85 (2H, in) MASS (in/z) :1348 (M+-23) Example110 IR (KBr) :1651, 1632, 1539, 1514 cin 1 NMR (DMSO-d 6 65) :0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.8Hz), 1.2-1.6 (SH, mn), 1.6-2.75 (14H, mn), 2.85-3.1 (1H, mn), 3.1-3.55 (2H, mn), 3.65-4.1 mn), 4.1-4.6 (9H, mn), 4.6-5.45 (8H, mn), 6.71 (1H, d, J=9.OHz), 6.78 (1H, d, J=9.OHz), 6.85-6.95 (1H, mn), 6.95-7.0 (1H, in), 7.1-7.25 (1H, in), 7.4-7.8 (3H, mn), 7.46 (2H, di, J=8.3Hz), 7.96 (2H, d, J=8.3Hz), 8.0-8.2 (1H, mn), 8.06 (2H, d, J=8.8Hz), 8.12 (2H, d, J=8.8Hz), 8.72 (1H, 8.75-8.85 (1H, in) MASS (in/z) :1249 (M+-23) Elemental Analysis Calcd. For C 5 6
H
6 9
N
1 0 NaO 1 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 NMR (DMSO-d 6 5) 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=6.1Hz), 1.1-1.65 (6H, 1.65-2.5 (12H, m), 2.85-3.6 (3H, 3.6-4.1 (5H, 4.1-4.6 (10H, m), 4.75-5.45 (8H, 6.71 (1H, d, J=8.9Hz), 6.78 (1H, d, J=8.9Hz), 6.85-6.9 (1H, 6.9-7.0 (1H, m), 7.14 (2H, d, J=8.9Hz), 7.15-7.25 (1H, 7.4-7.8 (3H, 7.95 (2H, d, J=8.9Hz), 8.05 (2H, d, J=8.9Hz), 8.1-8.2 (1H, 8.11 (2H, d, J=8.9Hz), 8.72 (1H, 8.75-8.85 (1H, m) MASS 1265 (M-23) Elemental Analysis Calcd. For C 5 6
H
69
N
1 0 NaO 2 0
S
2 *9H 2 0 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 NMR (DMSO-d 6 6) 0.97 (3H, d, J=6.5Hz), 1.05-1.2 (3H, 1.5-1.75 (6H, 1.75-2.5 (8H, 2.8-3.5 (7H, 3.6-4.1 (5H, 4.1-4.6 (9H, 4.7-5.5 (8H, 6.65-6.85 (2H, 6.87 (1H, 6.97 (1H, s), 7.07 (2H, d, J=9.2Hz), 7.1-7.25 (1H, 7.35-7.8 (3H, 7.75 (2H, d, J=9.2Hz), 8.0-8.2 (1H, 8.06 (4H, 8.32 (1H, 8.6-8.9 (2H, 9.17 (1H, s) MASS 1316 (M -23) Elemental Analysis Calcd. For C 58
H
70
NI
3 NaOl 9 S2-10H 2 0 C 45.82, H 5.97, N 11.98 Found C 45.80, H 5.74, N 11.91 Examiple 113 IR (KBr) 1633, 1518, 1250 cm- 1 NMR (DMSO-d 6 5) 0.8-1.05 (6H, 1.12 (3H, d, J=5.4Hz), 1.2-1.55 (6H, 1.65-2.5 (9H, 2.9-3.5 (3H, m), WO 99/40108 PCT/JP99/00538 432 3.6-4.6 (16H, 4.7-5.35 (9H, 6.73 (1H, d, J=8.3Hz), 6.83 (1H, d, J=8.3Hz), 6.85-6.95 (1H, m), 7.0-7.25 (2H, 7.10 (2H, d, J=9.1Hz), 7.3-7.55 (2H, 7.6-7.75 (1H, 7.85 (2H, d, J=9.1Hz), 8.0-8.2 (5H, 8.36 (1H, 8.7-8.9 (1H, 8.84 (1H, 9.24 (1H, s) MASS 1349(M+-23) Elemental Analysis Calcd. For C 5 9
H
7 3
N
12 NaO 2 1
S
2 -8H 2 0 C 46.70, H 5.91, N 11.08 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, 2.6-3.1 (4H, 3.1-3.5 (2H, 3.6-4.6 (16H, 4.6-5.45 (8H, 6.71 (1H, d, J=8.9Hz), 6.78 (1H, d, J=8.9Hz), 6.87 (1H, 6.98 (1H, d, J=1.8Hz), 7.18 (3H, d, J=8-.9Hz), 7.2-7.35 (5H, 7.4-7.8 (3H, 7.97 (2H, d, J=8.9Hz), 8.0-8.2 (1H, 8.09 (2H, d, J=8.4Hz), 8.20 (2H, d, J=8.4Hz), 8.72 (1H, 8.75-8.9 (1H, m) MASS 1310 (M+-23) Elemental Analysis Calcd. For C 6 1
H
72
N
11 NaO 20 S*9H 20 C 48.67, H 6.06, N 10.30 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, 2.6-3.1 (4H, 3.1-3.5 (2H, 3.6-4.6 (16H, 4.7-5.45 (8H, 6.71 (1H, d, J=8.1Hz), 6.78 (1H, d, J=8.1Hz), 6.8-6.9 (1H, 6.9-7.0 (1H, 7.18 (3H, d, J=9.2Hz), 7.2- 7.35 (5H, 7.35-7.8 (3H, 7.87 (2H, d, J=9.2Hz), 8.0-8.2 (5H, 8.72 (1H, 8.75-8.85 (1H, m) MASS 1326 (M -23) WO 99/40108 PCT/JP99/00538 433 Elemental Analysis Calcd. For C 61
H
72
N
11 NaOl9S 2 *9H 2 0 C 48.44, H 6.00, N 10.19 Found C 48.54, H 5.91, N 10.15 Example 116 IR (KBr) 1676, 1649, 1541, 1514, 1255 cm- 1 NMR (DMSO-d6, 6) 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.6Hz), 1.2-2.5 (18H, 2.9-3.1 (1H, 2.9-3.6 (2H, 3.65-4.1 (5H, 4.1-4.6 (10H, m), 4.7-5.45 (8H, 6.72 (1H, d, J=9.3Hz), 6.78 (1H, d, J=9.3Hz), 6.85-6.95 (1H, 6.95-7.0 (1H, m), 7.1-7.25 (1H, 7.18 (2H, d, J=8.9Hz), 7.4-7.8 (3H, 8.0-8.15 (5H, 8.21 (2H, d, J=8.6Hz), 8.72 (1H, 8.75-8.95 (1H, m) MASS 1249 (M-23) Elemental Analysis Calcd. For C 5 6
H
69 No 1 NaO 2 1 S-9H 20 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 NMR (DMSO-d 6 6) 0.95 (3H, d, J=6.8Hz), 1.09 (3H, d, 1.2-1.6 (5H, 1.6-2.7 (14H, 2.8-3.6 (3H, 3.6-4.1 (5H, 4.1-4.6 (9H, 4.6-5.4 (8H, 6.7-7.0 (4H, 7.1-7.2 (1H, 7.4-7.8 (3H, 7.49 (2H, d, J=7.2Hz), 8.05-8.2 (5H, m), 8.21 (2H, d, J=8.4Hz), 8.70 (1H, 8.8-8.9 (1H, m) MASS 1233 (M+-23) Elemental Analysis Calcd. For C 5 6
H
69 No 1 NaO 2 0 S'8H 20 C 48.00, H 6.11, N 9.99 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 6) 0.97 (3H, d, J=6.1Hz), 1.11 (3H, d, 1.07-1.37 (5H, 1.50-2.44 (14H, m), 2.56-3.50 (11H, 3.65-4.60 (14H, 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, 7.35-7.77 (2H, mn), 7.44 (1H, d, J=9.4Hz), 7.66 (2H, d, J=8.8Hz), 7.85 (2H, di, J=8. 5Hz) 7. 95-8. 21 (7H, in), 8.72 (1H, s) 8. 80 (1H, d, MASS :1409.4 (M-Na") Elemental Analysis Calcd. For C 66
H
81
N
12 NaO 19
S
2 -7H 2
O
C 50.83, H 6.14, N 10.78 Found C 51.17, H 6.03, N 10.42 Examipe 11 IR (KBr) :1659, 1633, 1531, 1508, 1443 cm- 1 I'ThR (DMSO-d 6 6) :0.97 (3H, d, J=6.6Hz), 1.00 (3H, t, J=7.4Hz) 1. 10 (3H, di, J=5. 6Hz) 1. 66-2. 56 (10H, m) 2. 91-3. 36 (3H, mn), 3. 65-4. 60 (14H, in), 4. 00 (2H, d, J=6.4Hz) 4. 72-5. 52 (8H, mn), 6.70 (1H, d, J=8.l1Hz) 6.77 (1H, d, J=8.lHz), 6.87 (1H, 6.98 (1H, s), 7.07 (2H, d, J=8.9Hz), 7.34-7.82 (3H, mn), 7.73 (2H, d, J=8.8Hz), 7.86 (2H, d, J=8.5Hz), 8.04-8.22 (8H, mn), 8.74-8.92 (2H, in) MASS :1301.2 (M-Na)+ Elemental Analysis Calcd. For C 5 9
H
6 9
N
1 0 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 ExamT.ie 1J20 IR (KBr) :1659, 1635, 1533, 1510, 1444 cm- 1 NMR (DMSO-d 6 6) :0.97 (3H, d, J=6.lHz), 1.11 (3H, d, 8Hz) 1. 18 (6H, d, J=6.1lHz) 1. 74-2. 69 (10H, mn), 2. 80-3. 52(OH,im) 59-4 .59 (18H,im) 72-5.4 9(8H, mn), 6.71 (1H, d, J=8.lHz), 6.79 (1H, cid, J=8.1 and 1.6Hz), 6.87 (1H, 6.98 (1H, d, J=1.6Hz) 7.07 (2H, di, J=9.OHz), 7.18 (1H, 7.33-7.72 (3H, mn), 7.68 (2H, d, J=8.8Hz), 7.85 (2H, di, J=8.5Hz), 7.96-8.25 (7H, mn), 8.72 (1H, s) 8.80 (1H, d, MASS :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 2 0 C 48.28, H 6.01, N 9.99 Found C 48.54, H 5.94, N 9.95 Example 121 IR (KBr) 1659, 1635, 1606, 1529, 1518, 1444, 1419 cm- 1 NMR (DMSO-d 6 6) 0.90 (6H, s) 0.97 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.8Hz), 1.03-2.66 (21H, 2.66- 3.54 (8H, 3.65-4.58 (14H, 4.68-5.43 (8H, m), 6.71 (1H, d, J=8.1Hz), 6.79 (1H, dd, J=8.1 andl.6Hz), 6.87 (1H, 6.98 (1H, d, J=1.6Hz) 7.11 (2H, d, J=8.6Hz), 7.18 (1H, 7.44 (1H, d, 7.48-7.77 (2H, 7.88 (2H, d, J=8.7Hz), 7.95-8.20 8.72 (1H, 8.78 (1H, d, J=7.7Hz) MASS 1361.4 Elemental Analysis Calcd. For C 62
H
82
N
12 01 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 NMR (DMSO-d 6 6) 0.97 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.8Hz), 1.10-2.68 (18H, 2.90-3.55 (3H, m), 3.66-4.62 (15H, 4.72-5.52 (8H, 6.71 (1H, d, J=8.1Hz), 6.79 (1H, d, J=8.1Hz), 6.87 (1H, 6.98 (1H, 7.07 (2H, d, J=8.9Hz), 7.19 (1H, 7.45 (1H, d, J=8.9Hz), 7.47-7.77 (1H, 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, 8.81 (1H, d, J=7.7Hz) MASS 1341.3 (M-Na Elemental Analysis Calcd. For C 6 2
H
73 No 1 NaO 2 0
S
2 8H 2 0 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-d6, 6) 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, 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, 4.70- 5.34 (9H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.90 (1H, 6.97-7.13 (3H, 7.19 (1H, 7.33 (1H, 7.44 (2H, 7.70 (1H, brs), 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 8.00-8.22 (6H, 8.80 (1H, d, J=6.9Hz), 8.84 (1H, s) MASS 1303.3 (M-Na Elemental Analysis Calcd. For C 58
H
67 No 1 NaO 2 1
S
2 10
OH
2 0 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 6) 0.96 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5.5Hz), 1.05-1.36 (5H, 1.47-2.50 (13H, m), 2.58-3.46 (11H, 3.64-4.60 (14H, 4.70-5.34 (9H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=-8.2Hz), 6.89 (1H, 7.08 (2H, d, J=8.7Hz), 7.01-7.25 (2H, 7.35-7.74 (3H, 7.86 (2H, d, J=8.8Hz), 7.98-8.26 (5H, 8.53-8.86 (1H, 8.85 (1H, s) MASS 1349.05 (M-Na') Elemental Analysis Calcd. For C 60
H
77
N
12 NaO 20
S
2 '6H 2 0 C 48.64, H 6.05, N 11.34 Found C 48.38, H 6.09, N 11.15 Example 125 IR (KBr) 1658, 1633, 1606, 1531, 1444, 1419 cm- 1 NMR (DMSO-d 6 6) 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, m), 2.51-2.70 (4H, 2.88-3.46 (7H, 3.55-4.59 (14H, 4.69-5.56 (8H, 6.70 (1H, d, J=8.1Hz), 6.77 (1H, d, J=8.1Hz), 6.86 (1H, 6.97 (1H, s) 7.08 (2H, d, J=8.7Hz), 7.09-7.78 (3H, 7.86 (2H, d, J=8.7Hz), 7.96-8.18 (6H, 8.63-8.92 (1H, 8.78 (1H, d, J=6.9Hz) MASS 1347.3 (M-Na') WO 99/40108 PCT/JP99/00538 437 Elemental Analysis Calcd. For C 61
H
79
N
12 NaOl 9
S
2 11H 2 0 C 46.68, H 6.49, N 10.71 Found C 46.67, H 6.19, N 10.64 Example 126 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, 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, 2.96-3.54 (7H, 3.65-4.60 (14H, 4.70-5.28 (8H, 6.71 (1H, d, J=8.3Hz), 6.79 (1H, dd, J=8.3 and 1.7Hz), 6.87 (1H, 6.98 (1H, d, J=1.7Hz), 7.07 (2H, d, 7.18 (1H, 7.44 (1H, d, J=8.4Hz), 7.50-7.78 (2H, 7.85 (2H, d, J=8.9Hz), 7.95-8.24 (5H, 8.72 (1H, 8.79 (1H, d, J=7.1Hz) MASS 1347.3 (M-Na') Elemental Analysis Calcd. For C 61
H
7 9
N
12 NaOl 9
S
2 *11H 2 0 C 46.68, H 6.49, N 10.71 Found C 46.77, H 6.20, N 10.65 Example 127 IR (KBr) 1633, 1533, 1516, 1443, cm- 1 NMR (DMSO-d 6 6) 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, 3.52 (2H, q, J=7.0Hz), 3.63-4.60 (16H, 4.53 (2H, 4.71-5.53 (6H, 6.68 (1H, d, J=8.0Hz), 6.76 (1H, d, J=7.8Hz), 6.87 (1H, s), 6.98 7.28-7.83 (3H, 7.47 (2H, d, 7.77 (2H, d, J=8.2Hz), 7.92 (2H, d, 8.00-8.25 (8H, 8.70-8.85 (2H, m) MASS 1301.3 (M-Na') Elemental Analysis Calcd. For C 5 9
H
69
N
1 0 NaO 2 0
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- NMR (DMSO-d 6 5) 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, 2.81-3.36 (3H, 3.28 (3H, 3.47-4.64 (20H, 4.56 (2H, 4.74- 5.60 (6H, 6.69 (1H, d, J=8.3Hz), 6.77 (1H, d, J=8.3Hz), 6.87 (1H, 6.98 7.26-7.84 (3H, 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, 8.74-8.90 (2H, m) MASS 1331.3 (M-Na Elemental Analysis Calcd. For C 60
H
7 1 NoNaO 2 1
S
2 '9H 2 0 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, m) 1.12 (3H, t, J=7.0Hz), 1.70-2.50 (10H, m), 2.80-3.30 (3H, 3.41 (2H, q, J=7.0Hz), 3.53 (2H, t, J=6.4Hz), 3.66-4.60 (14H, 4.10 (2H, t, J=6.4Hz), 4.70-5.52 (8H, 6.71 (1H, d, J=8.1Hz), 6.79 (1H, dd, J=8.1 and 1.6Hz), 6.87 (1H, 6.98 (1H, d, J=1.6Hz), 7.08 (2H, d, J=8.8Hz), 7.18 (1H, 7.32-7.68 (3H, 7.73 (2H, d, J=8.8Hz), 7.87 (2H, d, J=8.5Hz), 8.04-8.24 (7H, 8.56-8.91 (1H, 8.81 (1H, d, MASS 1345.3 (M-Na+) Elemental Analysis Calcd. For C 61
H
73 NoNaO 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 NMR (DMSO-d 6 5) 0.97 (3H, d, J=6.6Hz), 1.10 (3H, d, J=5.7Hz), 1.74-2.22 (10H, 2.80-3.30 (3H, m), 3.27 (3H, 3.50 (2H, t, J=6.3Hz), 3.65-4.60 (14H, 4.09 (2H, t, J=6.4Hz), 4.60-5.58 (8H, 6.70 (1H, d, J=8.1Hz), 6.77 (1H, d, J=8.1Hz), 6.87 (1H, 6.99 (1H, 7.07 (2H, d, J=8.9Hz), 7.10-7.72 WO 99/40108 PCT/JP99/00538 439 (3H, mn), 7.73 (2H, d, J=8. 8Hz) 7. 87 (2H, d, 8.00-8.35 (8H, in), 8.64-8.96 (2H, mn) MAS S (in/z) :1331.3 (M-Na+) Elemental Analysis Caici. For C 60
H
71
N
1 0 NaO 21
S
2 '9H 2 0 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 cxtC 1 NIVR (DMSO-d 6 5) :0.97 (3H, di, J=6.8Hz), 1.10 (3H, d, J=5.3Hz), 1.7-2.5 (12H, mn), 2.94 (3H, s), 2.94-4.6 (21H, mn), 4.7-S.4 (8H, in), 6.71 (1H, d, J=8Hz), 6.79 (1H, dd, J=8.4andl.7Hz), 6.88 (1H, brs), 6.97 (1H, brs), 7.15 (2H, d, J=9Hz), 7.17 (1H, brs), 7.45 (4H, 7.4-7.8 (3H, mn), 7.87 (2H, d, J=8.8Hz), 8.02 (4H, 8.02-8.07 (1H, mn), 8.72 (1H, 8.78 (1H, d, J=7.6Hz) MASS :1390.23 (lA-Na) Elemental Analysis Calcd. For C 62
H
73 ClNl 1
O
20
S
2 Na-7H 2
O
C 48.32, H 5.69, N 10.00 Found C 48.15, H 5.51, N 9.93 Examie 12 IR (KBr) :1633.4, 1535.1, 1523.5, 1442.5, 1419.4, 1276.6, 1243.9 cm- 1 NMR (DMSO-d 6 5) :0.96 (3H, d, J=6.8Hz), 1.12 (3H, di, J= 6Hz) 1. 7-2. 5 (1 OH, m) 2. 94 (3H, s) 2. 9-5. 4 (31H, mn), 6.73 (1H, d, J=8.3Hz) 6. 81-6. 85 (1H, in), 6. 89 (1H, brs) 7. 05 (1H, brs) 7.15 (2H, d, J=8.7Hz), 7.17 (1H, brs), 7.45 (4H, s), 7.3-7.7 (3H, in), 7.87 (2H, di, J=8.7Hz), 8.06 (4H, 8.-0-8.15 (1H, mn), 8.7-9.0 (2H, mn) MASS :1405.8 (M-Na') Elemental Analysis Calcd. For C 6 2
H
7 3 C1Nll0 2 lS 2 Na-6H 2
O
C 48.39, H 5.57, N 10.01 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-ylbutyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6yl]benzoic acid (147 mg), 1-ethyl-3-(3'dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HC1) (74 mg) and 1-hydroxybenzotriazole (66 mg) in N,Ndimethylformamide (4 ml) was added diisopropylethylamine ml). After stirring for 24 hours at ambient temperature, the Starting Compound (133) (200 mg) was added to the solution and 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 (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 (Trademark prepared by Yamamura Chemical Lab. )eluting with 20% 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 (133) mg).
IR (KBr) 3326, 2933, 1666, 1631, 1523, 1463, 1367, 1257 cm-1 NMR (DMSO-d 6 6) 0.95 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (8H, 1.6-2.15 (5H, 2.2-2.5 2.97 (2H, 3.20 (1H, 3.74 (2H, m), 3.8-4.6 (14H, 4.6-5.4 (9H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz),6.88 (1H, 7.04 (1H, 7.14 (2H, d, J=8.8Hz), 7.23 (1H, 7.3-7.5 (2H, 7.66 (1H, 7.88 (2H, d, J=8.8Hz), 7.95 (4H, 8.07 (1H, d, J=7.8Hz), 8.58 (1H, d, J=7.8Hz), 8.85 (1H, 8.95 (1H, s) MASS 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 NMR (DMSO-d 6 6) 0.95 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (10H, 1.6-2.15 (5H, m), 2.2-2.5 (10H, 2.97 (2H, 3.20 (1H, m) 3.74 (2H, 3.8-4.6 (14H, 4.6-5.4 (9H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, 7.67 (1H, 7.90 (2H, d, J=8.8Hz), 7.96 (4H, 8.07 (1H, d, J=7.8Hz), 8.57 (1H, d, J=7.8Hz), 8.85 (1H, 8.95 (1H, s) MASS 1391.13 (M-Na') 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, 1.6-2.15 (5H, m), 2.2-2.5 (10H, 2.97 (2H, 3.20 (1H, m) 3.74 (2H, 3.8-4.6 (14H, 4.6-5.4 (9H, 6.74 (1H, d, J=8.2Hz), 6.83 (1H, d, J=8.2Hz), 6.89 (1H, s), 7.05 (1H, 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m), 7.3-7.5 (2H, 7.67 (1H, 7.90 (2H, d, J=8.8Hz), 7.96 (4H, 8.07 (1H, d, J=7.8Hz), 8.60 (1H, d, J=7.8Hz), 8.85 (1H, 8.95 (1H, s) MASS 1405.31 (M-Na Elemental Analysis Calcd. For C 63
H
81
N
12 NaO 2 1
S
2 8H20 C 48.09, H 6.21, N 10.68 Found C 48.04, H 6.15, N 10.49 30 Example 136
'I
IR (KBr) 3351, 2939, 1658, 1633, 1527, 1465, 1444, 1257 cm- 1 NMR (DMSO-d 6 6) 0.95 (3H, d, J=6.7Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 (4H, 1.6-2.15 (5H, 2.2-2.5 (10H, 2.97 (2H, 3.20 (1H, m) 3.56 (4H, t, WO 99/40108 PCT/JP99/00538 442 J=4.6Hz), 3.71 (2H, mn), 3.8-4.6 (14H, in), 4.6-5.4 (9H,im) 6.74 (1H, d, J=8.2Hz) 6. 85 (1H1, d, J=8.2Hz) 6.93 (1H, 7.04 (1H, 7.14 (2H, d, J=8.8Hz), 7.23 (1H, mn), 7.3-7.5 (2H, mn), 7.67 (1H1, mn), 7.90 (2H, di, J=8. 8Hz) 7. 96 (4H, s) 8. 07 (1H, d, J=7. 8Hz) 8.57 (1H, d, J=7.8Hz), 8.8,5 (1H, 8.95 (1H, s) MASS :1392.65 (M-Na') Elemental Analysis Calcd. For C 6 1
H
7 7
N
1 2 NaO 2 2
S
3 -1OH 2 0 C 45.86, H 6.12, N 10.52 Found C 45.75, H- 5.83, N 10.46 Example 137 IR (KBr) :3347, 2935, 1666, 1631, 1523, 1463, 1255, 1078, 1047 cmitC NNR (DMSO-d 6 5) :0.95 (3H, d, J=6.7Hz), 1.03 (6H, d, J=6.3Hz), 1.11 (3H, d, J=5.7Hz), 1.3-1.6 mn), 1.6-2.15 (5H, mn), 2.2-2.5 (6H, mn), 2.71 (2H, d, J=10.2Hz), 2.97 (2H, mn), 3.20 (1H, mn) 3.56 (2H, mn) 3. 71 (2H, mn), 3.8B-4. 6 (14H, in), 4. 6-5. 4 (9H, mn), 6.7 4 (1H, d, J=8.2Hz), 6.85 (1H, d, J=8.2Hz), 6.93 (1H, 7.04 (1H, 7.14 (2H, d, J=8.8Hz), 7.23 (1H, in), 7.3-7.5 (2H, in), 7.67 (1H, mn), 7.90 (2H, di, J=8.8Hz), 7.96 (4H, 8.07 (1H, di, J=7.8Hz), 8.57 (1H, di, J=7.8Hz), 8.85 (1H, 8.95 (1H, s) MASS :1420.94 (M-Na+) Elemental Analysis Calci. For C 63
H
81
N
12 NaO 2 2
S
2 -8H 2
O
C 47.60, H 6.15, N 10.57 Found C 47.84, H 6.06, N 10.50 Example138 IR (KBr) :3347, 2937, 1666, 1631, 1521, 1465, 1257, 1074, 1047 cm- 1 NNR (DMSO-d 6 6) :0.95 (3H, di, J=6.7Hz), 1.03 (6H, di, C=6.3Hz), 1.08 (3H, di, J=5.7Hz), 1.3-1.6 (6H, in), 1. 6-2. 15 (5H, mn), 2.2-2. 5 (6H, in), 2.45 (2H, in), 2.71 (2H, di, J=10.2Hz), 2.97 (2H, in), 3.20 (1H, mn) 3.56 (2H, mn) 3.71 (2H, in), 3. 8-4. 6 (13H, in), 4. 6-5.4 (8H, WO 99/40108 PCT/JP99/00538 443 in6.68 (1H, d, j=8.2Hz), 6.76 (1H, di, J=8.2Hz), 6.86 (1H, 6.97 (1H, 7.14 (2H, d, J=8.9Hz), 7.23 (1H, mn), 7.3-7.S (2H, mn), 7.67 (1H, mn), 7.90 (2H, mn), 7.96 (4H, 8.07 in), 8.60 (1H, in), 8.85 (1H, 8.95 (1H, s) MASS (in/z) :1405.74 (M-Na+) Elemental Analysis Calcd. For C 63
H
81
N
12 NaO 21
S
2 '9H 2
O
C 47.54, H 6.27, N 10.56 Found C 47.68, H 6.21, N 10.50 Example 139 MASS (in/z) :1435.29 (M-Na+) Example 140 IR (KBr) :3328, 2939, 1664, 1633, 1525, 1465, 1442, 1257, 1047 cm-i 1 NMR (DMSO-d 6 6) :0.95 (3H, di, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.3-1.6 (6H, in), 1.6-2.15 (5H, mn), 2.2-2.5 (6H, in), 2.5-2.7 (2H, in), 2.59 (4H, 2.97 (2H-, in), 3.20 (1H, m) 3.73 (2H, in), 3.8-4.6 (14H, in), 4.6-5.4 (9H, mn), 6.69 (1H, d, J=8.2Hz), 6.80 (1H, di, J=8.2Hz), 6.88 (1H, 7.05 (1H, 7.14 (2H, d, J=8.8Hz), 7.23 (1H, m) 7.3-7.5 (2H, m) 7. 67 (1H, in), 7.90 (2H, d, J=8.8Hz), 7.96 (4H, 8.07 (1H,d, J=7.8Hz), 8.57 (1H, d, J=7.8Hz), 8.85 (1H, 8.95 (1H, s) MASS (in/z) :1408.94 (M-Na+) Elemental Analysis Calcd.'*For C 6 1
H
7 7 Nl 2 NaO 2 1
S
3 -10H 2 0 C 45.40, H 6.06, N 10.42 Found C 45.49, H 5.59, N 10.26 Examne 1 IR (KBr) :3340, 2939, 1631, 1523, 1465, 1442, 1257, 1047 cm- 1 MR (DMSO-d 6 5) :0.96 (3H, d, J=6.7Hz), 1.10 (3H, di, 7Hz) 1. 3-1. 6 (4H, in), 1. 6-2.15 (5H, in), 2 (4H, in), 2.97 (2H, mn), 3.20 (1H, in) 3.23 (3H, s), 3.34 (2H, t J=6.2Hz), 3.73 (2H, in), 3.8-4.6 (14H, WO 99/40108 PCT/JP99/00538 444 mn), 4. 6-5. 4 (9H, m) 6. 69 (1H, d, J=8. 2Hz) 6. 76 (1H, d, J=8.2Hz), 6.88 (1H, 7.04 (1H, 7.14 (2H, d, J=8.8Hz) 7.23 (1H, in), 7.3-7.5 (2H, mn), 7. 67 (1H, in), 7. 90 (2H, d, J=8. 8Hz) 7. 95 (4H, s) 8. 07 (1H,in) 8. 57 (1H, mn), 8. 85 (1H, 8.95 (1H, s) MASS (in/z) :1338.33 (M-Na+) Elemental Analysis Caici. For C 5 8
H
7 2
N,
1 NaO 2 2
S
2 '10H 2
O
C 45.16, H 6.01, N 9.99 Found C 45.39, H 5.80, N 10.02 Fxamnlle 142 1K (KBr) :3340, 2935, 1648, 1631, 1537, 1515, 1456, 1257, 1047 cm- 1 NNR (DMSO-d 6 6) :0.96 (3H, d, J=6.7Hz), 1.10 (3H, di, J=5.7Hz) 1. 3-1. 6 (4H, in), 1. 6-2. 15 (5H, mn), 2.2-2. (6H, in), 2.97 (2H, mn), 3.20 (1H, in) 3.23 (3H1, s), 3.34 (2H, t J=6.2Hz), 3.74 (2H, mn), 3.8-4.6 (13H, mn), 4. 6-5.4 (8H, in), 6. 68 (1H, di, J=8.2Hz) 6.-76 (1H, di, 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,im) 7. 67 (1H, in), 7.90 (2H, mn), 7.96 (4H, 8.07 8.60 (1H, mn), 8.85 (1H, 8.95 (1H, s) MASS (in/z) :1322.3 (M-Na+) Elemental Analysis Calcd. For C 58 1{ 72
N
11 NaO 2 1
S
2 *9H 2
O
C 46.18, H 6.01, N 10.21 Found C 45.96, H 5.86, N 10.12 IR (KBr) :3349, 2937, 1666, 1631, 1523, 1465, 1257, 1047 cm- 1 NNR (DMSO-d 6 6) :0.96 (3H, di, J=6.7Hz), 1.10 (3H, d, J=5.7Hz) 1.3-1. 6 (6H, in), 1 .6-2.15 (SH, mn), 2.2-2.5 (4H, in), 2.97 (2H1, in), 3.20 (1H1, in) 3.23 (3H, s), 3.34 (2H, t J=6.2Hz), 3.73 (2H, mn), 3.8-4.6 (14H, mn), 4. 6-5. 4 (9H, in), 6. 69 (1H, d, J=8. 2Hz) 6. 76 (1H1, d, J=8.2Hz), 6.88 (1H, 7.04 (1H, 7.14 (2H, d, J=8. 8Hz) 7.23 (1H, m) 7. 3-7.5 (2H, m) 7. 67 (1H, WO 99/40108 PCT/JP99/00538 445 mn), 7. 90 (2H, d, J=8. 8Hz) 7. 95 (4H, s) 8. 07 (1H, m) 8. 57 (1 H, in), 8. 85 (1 H, s) 8. 95 (1KH, s) MASS :1352.48 (M-Na t Elemental Analysis Calcd. For C 5 9
H
7 4 N 1 1 NaO 2 2
S
2 -12H 2
O
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-i NMR (DMSO-d 6 6) :0.96 d, J=6.7Hz), 1.10 (3H, d, 7 Hz) 3 6(8H, 1 6-2. 15S(5H,im) 2 -2 mn), 2.97 (2H, in), 3.20 (1H, in) 3.23 (3H, s), 3.34 (2H, t J=6.2Hz), 3.73 (2H, mn), 3.8-4.6 (14H, in), 4. 6-5. 4 (9H, m) 6. 69 (1H, d, J=8. 2Hz) 6. 76 (1H, d, J=8.2Hz), 6.88 (1H, 7.04 (1H, 7.14 (2H, d, J=8.8Hz) 7.23 (1H, mn) 7. 3-7.5 (2H, in), 7. 67 (1H, mn), 7. 90 (2H, d, J=8. 8Hz) 7. 95 (4H, s) 8. 07 (1H,im) 8.57 (1H, mn), 8.85 (1H, 8.95 (1H, s) MASS (in/z) :1366.46 (M-Na+) Elemental Analysis Calcd. For C 6 0
H
7 6
N
1 1 NaO 2 2
S
2 '13H 2
O
C 44.36, H 6.33, N 9.48 Found C 44.40, H 5.88, N 9.30 Exai~ple 145 IR (KBr) 3324, 2933, 1666, 1631, 1523, 1465, 1257, 1047 cm-i NMR (DMSO-d 6 :0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=5.7Hz), 1.3-1.6 (10H, in), 1.6-2.15 (5H, in), 2.2-2.5 (4H, in), 2. 97 (2H, mn), 3.20 (1H, mn) 3.23 (3H, s) 3.34 (2H, t J6.2Hz) 3.73 (2H, m) 3.8-4. 6 (14H, in), 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,im) 7. 3-7.5 (2H,im) 7. 67 (1H, mn), 7. 90 (2H, d, J=8. 8Hz), 7. 95 (4K, s) 8. 07 (1H,im) 8.57 (1H, in), 8.85 (1H, 8.95 (1H, s) WO 99/40108 PCT/JP99/00538 446 MASS 1380.30 (M-Na') Elemental Analysis Calcd. For C 61
H
7 8
N
11 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 Example 146 IR (KBr) 3351, 3330, 2935, 1664, 1633, 1606, 1529, 1465, 1446, 1267, 1238 cm- 1 NMR (DMSO-d 6 6) 0.96 (3H, d, J=6.4Hz), 1.10 (3H, d, J=5.4Hz), 1.60 (6H, 1.7-2.1 (3H, 2.1-2.6 (4H, 2.98 (2H, 3.20 (1H, m) 3.4 (4H, 3.73 (2H, 3.8-4.6 (12H, 4.6-5.6 (9H, 6.70 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, 7.06 (2H, d, J=8.9Hz), 7.2-7.7 (4H, 7.74 (2H, d, J=8.9Hz), 7.94 (4H, 8.07 8.56 (1H, 8.79 (1H, 8.95 (1H, s) MASS 1304.84 (M-Na+) Elemental Analysis Calcd. For C 5 7
H
69
N
12 NaO 2 0
S
2 -7H 2 O C 47.04, H 5.75, N 11.55 Found C 47.32, H 5.75, N 11.67 Example 147 IR (KBr) 3351, 3330, 2933, 1668, 1631, 1515, 1454, 1268, 1236 cm- 1 NMR (DMSO-d 6 6) 0.96 (3H, d, J=6.4Hz), 1.11 (3H, d, J=5.4Hz), 1.6-2.1 (3H, 2.1-2.6 (4H, 2.98 (2H, 3.20 (1H, m) 3.4 (4H, 3.76 (6H, 3.8- 4.6 (12H, 4.6-5.6 (9H, 6.70 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.89 (1H, 7.05 (1H, s), 7.06 (2H, d, J=8.9Hz), 7.2-7.7 (4H, 7.74 (2H, d, J=8.9Hz), 7.94 (4H, 8.07 8.56 (1H, 8.79 (1H, 8.95 (1H, s) MASS 1306.85 (M-Na') Example 148 IR (KBr) 3355, 2975, 2935, 1666, 1631, 1610, 1523, 1465, 1241 cm- 1 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, in), 2.1-2. 6 (6H, mn), 2. 98 (2H, mn), 3.20 (1H, in) 3. 4 (2H, in), 3.73 (4H, in), 3. 8-4. 6 (12H1, mn), 4. 6-5. 6 (911, 6.70 (1H1, d, J=8.2Hz) 6. 81 (1H, d, J=8.2Hz) 6. 89 (1H, s) 7. 04 (1H, s) 7. 11 (2H, d, J=8. 9Hz) 7.2-7. 7 (4H1, mn), 7.78 (2H, di, J=8. 9Hz) 7. 95 (4H, s) 8. 07 (lH,in), 8.54 (1H, mn), 8.80 (1H1, 8.95 (1H, s) MASS (in/z) :1334.95 (M-Na+) Elemental Analysis Caici. For C 5 8
H
7 1 Nl 2 NaO 2 lS 2 -1OH 2 0 C 45.25, H 5.96, N 10.92 Found C 45.25, H 5.76, N 10.94 Exm~ple 49 IR (KBr) :3355, 2971, 2933, 1668, 1648, 1631, 1610, 1535, 1515, 1463, 1241 cm- 1 NMR (DMSO-d 6 6) :0.96 (3H, d, J=6.7Hz), 1.10 (311, di, J=5.7Hz), 1.18 (6H, d, J=6.2Hz), 1.6-2.1 (3H, mn), 2. 1-2. 6 (8H, mn), 2. 98 (2H, mn), 3.20 (1H1, mn) 3.4 (2H, mn), 3.73 (4H, mn), 3.8-4.6 (1lH, mn), 4.6-5.6 (8H, mn), 6.70 (1H1, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.89 (1H1, 6.96 (1H, 7.12 (2H, d, J=8.9Hz), 7.2-7.7 (4H, mn), 7.78 (2H1, d, J=8.9Hz), 7.95 (4H, 8.12 (1H, m) 8. 56 (1H, mn), 8. 80 (1H1, s) 8. 95 (1H, s) MASS (in/z) :1319.3 (M-Na+) Elemental Analysis Calcd. For C 58
H
7 lNl 2 NaO 2 0
S
2 *9H 2
O
C 46.27, H 5.96, N 11.16 Found C 46.03, H 5.85, N 11.02 IR (KBr) :3353, 2927, 1666, 1631, 1608, 1535, 1465, 1432, 1265, 1193, 1047 cm- 1 NMR (DMSO-d 6 :0.96 (311, di, J=6.7Hz), 1.10 (3H, d, J=5.7Hz) 1. 6-2. 1 (3H, mn) 2. 1-2. 6 (4H, mn) 2. 66 (4H, mn), 2.98 (211, mn), 3.20 (1H, mn), 3.73 (2H, mn), 3.79 (4H, mn), 3. 8-4 .6 (1211, mn), 4. 6-5. 6 (9H, mn), 6.72 (1H, di, J=8.2Hz), 6.81 (1H1, d, J=8.2Hz), 6.88 (1H, s), 7.04 (1H1, 7.11 (211, d, J=8.9Hz), 7.2-7.7 (4H, WO 99/40108 PCT/JP99/00538 448 7.77 (2H, d, J=8.9Hz), 7.94 (4H, 8.07 (IH,m), 8.54 (1H, 8.80 (1H, 8.95 (1H, s) MASS 1322.96 (M-Na') Example 151 IR (KBr) 3353, 1666, 1629, 1523, 1454, 1378, 1268, 1238 cm- NMR (DMSO-d 6 5) 0.9-1.4 (9H, 1.4-2.1 (3H, m), 2.1-2.6 (10H, 2.98 (2H, 3.20 (1H, 3.4 (4H, 3.74 (2H, 3.8-4.6 (12H, 4.6-5.6 (9H, 6.72 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.88 (1H, 7.05 (1H, 7.09 (2H, d, J=8.9Hz), 7.2-7.7 (4H, 7.78 (2H, d, J=8.9Hz), 7.94 (4H, 8.07 (1H, 8.54 (1H, 8.80 (1H, 8.95 (1H, s) MASS 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 6) 0.95 (3H, d, J=6.7Hz), 1.0-1.4 (8H, 1.58 (1H, 1.78 (4H, 1.8-2.1 (3H, m), 2.1-2.6 (5H, 2.63 (4H, 2.98 (2H, 3.20 (1H, 3.4 (4H, 3.74 (2H, 3.8-4.6 (12H, 4.6-5.6 (9H, 6.72 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.88 (1H, 7.04 (1H, 7.08 (2H, d, J=8.9Hz), 7.2-7.7 (4H, 7.77 (2H, d, J=8.9Hz), 7.94 (4H, 8.10 8.58 (1H, 8.80 (1H, 8.95 (1H, s) MASS 1388.3 (M-Na Example 153 IR (KBr) 3353, 2931, 1668, 1650, 1631, 1537, 1513, 1456, 1396,1270, 1238, 1197 cm- 1 NMR (DMSO-d 6 6) 0.97 (3H, d, J=6.7Hz), 1.0-1.4 (8H, 1.58 (1H, 1.75 (4H, 1.7-2.1 (3H, m), 2.1-2.6 (7H, 2.63 (4H, 2.98 (2H, 3.20 (1H, 3.4 (4H, 3.74 (2H, 3.8-4.6 (11H, WO 99/40108 PCT/JP99/00538 449 4.6-5.6 (8H, 6.72 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.88 (1H, 7.04 (1H, 7.08 (2H, d, J=8.9Hz), 7.2-7.7 (4H, 7.77 (2H, d, J=8.9Hz), 7.94 (4H, 8.11 8.58 (1H, 8.80 (1H, 8.95 (1H, s) MASS 1372.3 (M-Na') Example 154 IR (KBr) 3353, 2935, 1666, 1633, 1540, 1513, 1461, 1440, 1247 cm- 1 NMR (DMSO-d 6 6) 0.9-1.1 (6H, 1.10 (3H, d,J=5.7Hz), 1.47 (2H, 1.6-2.1 (5H, 2.1-2.6 (4H, 2.98 (2H, 3.20 (1H, 3.71 (2H, 3.8-4.6 (14H, 4.6-5.6 (9H, 6.67 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.88 (1H, 6.99 (2H, d, J=8.8Hz), 7.05 (1H, 7.2-7.7 (4H, 7.82 (2H, d, J=8.8Hz), 7.97 (4H, 8.10 8.58 (1H, 8.66 (1H, 8.78 (1H, s) MASS 1294.53 (M-Na Elemental Analysis Calcd. For C 5 6
H
6 8 11 NNaO 2 1
S
2 -9H 2 0 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 NMR (DMSO-d 6 5) 0.9-1.1 (6H, 1.10 (3H, d,J=5.7Hz), 1.2-1.5 (4H, 1.6-2.1 (5H, m) 2.1-2.6 (4H, m), 2.98 (2H, 3.20 (1H, 3.71 (2H, 3.8-4.6 (14H, 4.6-5.6 (9H, 6.69 (2H, d, J=8.2Hz), 6.80 (1H, d, J=8.2Hz), 6.87 (1H, 6.99 (2H, d, J=8.8Hz), 7.05 (1H, 7.2-7.7 (4H, 7.82 (2H, d, J=8.8Hz), 8.06 (4H, 8.10 8.58 (1H, 8.67 (1H, 8.76 (1H, s) MASS 1308.25 (M-Na*) Elemental Analysis Calcd. For C 57
H
7 0 11 NNaO 2 1
S
2 '8H 2 0 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 IR (KBr) :3359, 2933, 1666, 1631, 1540, 1513, 1463, 1440, 1295, 1247, 1047 cm- NMR (DMSO-d 6 6) 9-1. 1 (6H, in), 1. 10 (3H, d, J=5. 7Hz) 1. 2-1. 5 (6H, mn), 1. 6-2. 1 (5H, mn), 2. 1-2. 6 (4H, mn), 2.98 (2H, mn), 3.20 (1H, in), 3.71 (2H, in), 3.8-4.6 (14H, in), 4.6-5.6 (9H, mn), 6.69 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz) 6.87 (1H, 6.98 (2H, d, J=8.8Hz), 7.04 (1H, 7.2-7.7 (4H, mn), 7.82 (2H, d, J=8.8Hz), 8.06 (4H, 8.10 8.58 (1H, mn), 8.67 (1H, 8.77 (1H, s) MASS (in/z) :1322.61 (M-Na+) Elemental Analysis Calcd. For C 5 8
H
7 2 N,,NaO 2 lS 2 -11H 2 0 C 45.10, H 6.13, N 9.98 Found C 45.31, H 5.81, N 9.84 IR (KBr) :3351, 2933, 1631, 1523, 1465, 1440, 1255, 1178, 1047 cin 1 NMR (DMSO-d 6 6) :0.8-1.0 (6H, in), 1.10 (3H, d,J=5.7Hz), 1.2-1.6 (6H, in), 1.6-2.1 (5H, in), 2.1-2.5 (4H, in), 2.98 (2H, in), 3.20 (1H, in), 3.73 (2H, in), 3.8-4.6 (14H, in), 4.6-5.4 (9H, in), 6.69 (1H, d, J=8.2Hz), 6.79 (1H, d, J=8.2Hz), 6.88 (1H, 7.05 (1H, s), 7.14 (2H, d, J=8.8Hz), 7.23 (1H, in), 7.3-7.5 (2H, in), 7.67 (1H, mn), 7.89 (2H, d, J=8.8Hz), 7.96 (4H, 8.07 (1H, in), 8.54 (1H, in), 8.85 (1H, 8.95 (1H, s) MASS (in/z) :1322.12 (M-Na+) Elemental Analysis Calcd. For C 58
H
72 NllNaO 2 lS 2 '8H 2
O
C 46.74, H 5.95, N 10.34 Found C 46.81, H 5.67, N 10.23 Exampl1e 158 IR (KBr) :3359, 2935, 1652, 1631, 1538, 1523, 1429, 1382, 1299, 1253, 1047 cm- 1 WO 99/40108 PCT/JP99/00538 451 NMR (DMSO-d 6 6) 0.8-1.0 (6H, 1.10 (3H, d,J=5.7Hz), 1.3-1.5 (4H, 1.6-2.1 (5H, 2.1-2.5 (4H, m), 2.98 (2H, 3.20 (1H, 3.75 (2H, 3.8-4.6 (14H, 4.6-5.4 (9H, 6.69 (1H, d, J=8.2Hz), 6.77 (1H, d, J=8.2Hz), 6.85 (1H, 7.01 (2H, d, J=8.8Hz), 7.05 (1H, 7.23 (1H, 7.43 (2H, d, J=8.2Hz), 7.69 (1H, 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, 8.61 (1H, d, J=6.7Hz), 8.82 (1H, s) MASS 1312.10 (M-Na+) Elemental Analysis Calcd. For C 5 6
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 Example 159 MASS 1429.04 (M-Na 4 Example 160 To a solution of l-hydroxybenzotriazole (26 mg) and 4-[5-[4-(4-propoxypiperidin-l-yl)phenyl]-1,3,4-thiadiazol- 2-yl]benzoic acid hydrochloride (60 mg) in N,Ndimethylformamide (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) and N,N'-diisopropylethylamine (34 pl) 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 reduced pressure. The solid 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 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 5) 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, 6.70 (1H, d, J=8.2Hz), 6.81 (1H, d, J=8.2Hz), 6.87 (1H, 7.04 (1H, 7.09 (2H, d, J=9.2Hz), 7.26-7.76 (3H, 7.84 (2H, d, J=8.8Hz), 7.97-8.14 (6H, 8.64-8.95 (2H,m) MASS 1347.44 (M-Na The following compounds [Examples 161 and 162] were 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, 2.80-5.50 (34H, m), 6.71 (1H, d, J=8.2Hz), 6.80 (1H, d, J=8.2Hz), 6.86 (1H, 6.76-6.94 (1H, 6.94-7.09 (3H, m), 7.09-7.34 (4H, 7.34-7.78 (3H, 7.90 (2H, d, J=8.7Hz), 7.96-8.17 (6H, 8.49-8.88 (2H-,m) MASS 1343.23 (M-Na Example 162 IR (KBr) 1655, 1527 cm i NMR (DMSO-d 6 5) 0.97 (3H, d, J=6.8Hz), 1.10 (3H, d, J=5.7Hz), 1.8-2.6 (12H, 2.8-3.6 (7H, 3.7-4.6 (14H, 4.7-5.5 (8H, 6.6-6.85 (4H, m), 6.85-6.95 (1H, 6.97 (1H, 7.15-7.25 (1H, m), 7.4-7.8 (3H, 7.72 (2H, d, J=8.9Hz), 8.0-8.2 8.30 (1H, 8.71 (1H, 8.7-8.9 (1H, 9.11 (1H, s) MASS 1302 (M -23) Elemental Analysis Calcd. For C 57
H
68
N
13 NaO 9
S
2 '9H 20 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 IN hydrochloric acid (8 ml) with stirring at ambient temperature. The mixture was WO 99/40108 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 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 30% aqueous acetonitrile (3 and 40% aqueous acetonitrile (4 The 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) (1.02 g).
NMR (DMSO-d 6
+D
2 0 6) 0.96 (3H, d, J=6.7Hz), 1.09 (3H, 1.25-1.60 (8H, 1.60-2.45 (10H, m), 2.80-3.10 (1H, 3.21 (3H, 3.30 (2H, t, J=6.4Hz), 3.60-4.50 (15H, 4.65-4.95 (2H, m), 6.41 (1H, d, J=8.3Hz), 6.50-6.70 (2H, 7.11 (1H, 7.16 (1H, 7.25-7.60 (2H, 7.85-8.25 (8H,m) ESI-MASS 1255.08 (M'+Na Elemental Analysis Calcd. For C 58
H
76
N
10 0 18 S-4H 2 0 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 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 stood at 2-5°C overnight and evaporated in vacuo. The residue WO 99/40108 PCT/JP99/00538 454 was dissolved in a mixture of hexane (50 ml) and ethyl acetate ml) 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 acetate v/v) and a mixture of hexane and ethyl acetate 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 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 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 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 phase silica gel, YMC-gel ODS-AM 120-S50 (Trademark, made by YMC) (700 ml) eluting in turn with 20% aqueous acetonitrile 30% aqueous acetonitrile (3.5 L) and 40% aqueous acetonitrile (3.5 The 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 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 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 L) and 50% aqueous acetonitrile (3.5 The 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-I) (1.37 g).
The other Object Compound (164-II) was chromatographed on reverse phase silica gel, YMC-gel ODS-AM 120-S50 (Trademark, made by YMC) (700 ml) eluting in turn with 20% aqueous acetonitrile (3.5L) and 50% aqueous acetonitrile The 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) 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, 2.85-3.00 (1H, m), 3.74 (3H, 3.31 (2H, t, J=6.4Hz), 3.75-4.55 (17H, 4.70-5.00 (2H, 6.40-6.70 (3H, 7.14 (2H, d, J=8.9Hz), 7.98 (2H, d, J=8.9Hz), 8.05 (2H, d, J=8.7Hz), 8.12 (2H, d, J=8.7Hz) ESI-MASS 1269.4 (M (positive) 1246.4 (M (negative) Elemental Analysis Calcd. For C 59
H
78
N
10
O
18 S 3H 2 O C 54.45, H 6.51, N 10.76 Found C 54.11, H 6.74, N 11.18 Object Compound (164-II) NMR (DMSO-d 6
+D
2 0 6) 0.96 (3H, d, J=6.7Hz), 1.10 (3H, d, J=6.1Hz), 1.20-2.45 (19H, 3.72 (3H, 3.73 (3H, 3.80-5.00 (15H, 6.55-6.90 (3H, 7.13 (2H, d, J=8.9Hz), 7.97 (2H, d, J=8.9Hz), 8.00-8.20 (4H, m) ESI-MASS 1283.4 (positive) The following compound was obtained according to a similar manner by using tert-butyldimethylsilane instead of tert-butylsilane of Example 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 W097/32975.
Example 166 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, 1.88-5.83 (35H, 6.68-8.71 (10H, m) MASS 903.17 (M-Na') Example 167 To a solution of Starting Compound (167) (0.1 g) and 4-[5-[4-(7-methoxyheptyloxy)phenyl]-1,3,4-thiadiazol-2yl]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 temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration and dried under reduced pressure to give Object Compound (16-7) (159 mg).
IR (KBr) 3344, 1648.8, 1637.3, 1513.8, 1257.4, 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, 1.6-2.6 (12H, m), 2.9-4.6 (25H, 4.7-5.5 (9H, 6.71 (1H, d, J=8.2Hz), 6.78 (1H, d, J=8.2Hz), 6.88 (1H, 6.97 (1H, 7.13 (2H, d, J=8.8Hz), 7.16 (1H, 7.44 (1H, d, J=8.0Hz), 7.59 (1H, br 7.70 (1H, brs), 7.97 (2H, d, J=8.8Hz), 7.9-8.2 (6H, 8.72 (1H, 8.79 (1H, d, J=7.3Hz) MASS 1311 (M-diisopropylamine-1) Elemental Analysis Calcd. For C 66
H
95
N
11
O
21
S
2 -5H20 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 NNP. CDMSO-d 6 5) :0.91 (3H, t, JTh7.0Hz), 0.97 (3H, d, J=6. 6Hz) 1. 10 (3H, d, J=5. 6Hz) 1. 0-1 .5 (19H, in), 1. 6-2. 7 (10H, in), 3. 0-3. 3 (3H, mn), 3. 7-4. 6 (15H-, in), 4.8-5.3 (11H, mn), 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) 7.2-7.5 (3H, in), 7.23 (1H, 7.56 (1H, 7.58 (1H, in), 7. 85 (2H, d, J=8. 8Hz) 7. 9-8. 1 (5H, in), 8.2 6 (1H, d, J=8.7Hz),8. 85 (1H, s) 8. 87 (1H1, d, J=7. 3Hz) MASS :1268 (M-diisopropylanine-1) The following compound was obtained in a manner similar to that of ExaMple 2-3 of W097/32975.
IR (KBr) :1664, 1627, 1234, 1086, 1043 cm- 1 NNR (DMSO-d 6 6) :0.96 O3H, d, J=6.7Hz), 1.14 (3H, d, J=5.9Hz), 1.3-2.55 mn), 2.6-3.6 (3H, in), 3.65-4.5 (15H, in), 4.7-5.4 (7H, in), 6.65-7.05 (411, in), 7.07 (1H, 7.4-8.25 (7H1, in), 8.71 (1H, s) MASS (in/z) :903 (M-1)
Claims (14)
1. A polypeptide compound of following the general formula [I] wherein 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); 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; 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); amino protective group; WO 99/40108 PCT/JP99/00538 459 heptylnaphthoyl; hexylnaphthoyl; aroyl substituted with heterocyclic carbamoyl which may have one or more suitable substituent 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 substituent(s); or lower alkenoyl substituted with heterocyclic group which may have one or more suitable substituent(s), R 2 is hydrogen or hydroxy, R 3 is hydroxy, hydroxysulfonyloxy or lower alkoxy, and R 4 is hydroxy or lower alkoxy, or a salt thereof.
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 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- 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 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 phenyl which has lower alkoxy.
4. A compound of claim 3, wherein R1 is benzoyl substituted with thiadiazolyl which has phenyl having piperidyl, 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 phenyl which has piperazinyl substituted with cyclohexyl, benzoyl substituted with thiadiazolylhaving phenyl substituted with phenyl which has morpholino having di(lower)alkyl, or benzoyl substituted with imidazothiadiazolyl having phenyl which has lower alkoxy.
A compound of claim 4, wherein R 1 is benzoyl substituted with thiadiazolyl which 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.
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 WO 99/40108 PCT/JP99/00538 461 OH HO H3C 0 HO O HN OH O NH 0 CH 3 [Ib] H 2 N O N R 2 NH OH ROH O R 3 R4 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 R1 OH [III] wherein R1 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 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; 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; 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 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 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: HO 0 NH H 3 C NH- R 1 a N 0 HO O HN OH 25OPI [Ia] NH 0 CH 3 H 2 N O N R 2 NH OH OH O R3 R 4 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: [II] wherein KI R 1 R 3 and R 4 are as defined above, or a salt thereof, to give a compound [Ia] of the formula: OH HO 0 NH H 3 C NH- RI a N 0 HO =o HN OH 0 0\ [Ia] 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, a or a salt thereof, or iii) reducing a compound [IV] of the formula [IV] wherein R 4 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 H 3 C HNH 2 N q0 HO o HN OH \[Ib] P:\OPERIKbmn22998-99 spccdoc-9/I 102 -465- wherein R 2 R 3 and R 4 are as defined in Claim 1, or a salt thereof.
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.
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.
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.
11. Use of a compound of Claim 1 in the manufacture of a medicament for prophylactic and/or therapeutic treatment of infectious diseases caused by pathogenic 25 microorganisms.
12. A polypeptide compound of Claim 1, substantially as hereinbefore described with reference to the Examples.
13. A process for preparing a polypeptide compound according to Claim 6, substantially as hereinbefore described with reference to the Examples. P:\OPER\Ybn2998-99 speoAdo-19/l 1/02 466
14. A polypeptide compound produced by the process of claim 6 or Claim 13. DATED this 1 9 1h day of November, 2002 Fujisawa Pharmaceutical Co., Ltd. By DAVIES COLLISON CAVE Patent Attorneys for the Applicants
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU22998/99A AU756792B2 (en) | 1998-02-09 | 1999-02-05 | New compound |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPP1728A AUPP172898A0 (en) | 1998-02-09 | 1998-02-09 | New compound |
| AUPP1728 | 1998-02-09 | ||
| AUPP3138A AUPP313898A0 (en) | 1998-04-23 | 1998-04-23 | New compound |
| AUPP3138 | 1998-04-23 | ||
| PCT/JP1999/000538 WO1999040108A1 (en) | 1998-02-09 | 1999-02-05 | New compound |
| AU22998/99A AU756792B2 (en) | 1998-02-09 | 1999-02-05 | New compound |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0000644A2 (en) * | 1977-07-19 | 1979-02-07 | Fujisawa Pharmaceutical Co., Ltd. | Lower cycloalkyl substituted-benzene derivatives, the preparation thereof and their pharmaceutical compositions |
| WO1996011210A1 (en) * | 1994-10-07 | 1996-04-18 | Fujisawa Pharmaceutical Co., Ltd. | Cyclic hexapeptides having antibiotic activity |
-
1999
- 1999-02-05 AU AU22998/99A patent/AU756792B2/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0000644A2 (en) * | 1977-07-19 | 1979-02-07 | Fujisawa Pharmaceutical Co., Ltd. | Lower cycloalkyl substituted-benzene derivatives, the preparation thereof and their pharmaceutical compositions |
| WO1996011210A1 (en) * | 1994-10-07 | 1996-04-18 | Fujisawa Pharmaceutical Co., Ltd. | Cyclic hexapeptides having antibiotic activity |
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