CA2433263A1 - Stabilized pharmaceutical composition in lyophilized form - Google Patents

Abstract

A stabilized pharmaceutical composition in lyophillized form comprising: a cyclic polypeptide compound represented by the following general formula (I) , wherein R1 is hydrogen or acyl group, R2 is hydrogen or acyl group, R3 is lower alkyl which has one or more hydroxy or protected hydroxy, R4 is hydrog en or hydroxy, R5 is hydrogen, hydroxy, lower alkoxy or hydroxysulfonyloxy, and R6 is hydroxy or acyloxy, or a salt thereof, and a stabilizer.

Description

DESCRIPTION
STABILIZED PHARMACEUTICAL COMPOSITION
IN LYOPHILIZED FORM
TECHNICAL FIELD
The present invention relates to a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound. More particularly, the present invention relates to a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptida compound or a salt thereof and a stabilizer.
The cyclic polypeptide compound of the present invention is represented by the following general formula (I) OH
OH O
N

R~ HO 0 H OH
\N (I) R 3"~ H O=_~C H 3 R

r wherein R1 is hydrogen or aryl group, R~ is hydrogen or.acyl group, R3 is lower alkyl which has one or more hydroxy or protected hydroxy, R4 is hydrogen or hydroxy, R5 is hydrogen, hydroxy, lower alkoxy or hydroxysulfonyloxy, and R6 is hydroxy or acyloxy, or a salt thereof.
The cyclic polypeptide compound (I) or a salt thereof has an antimicrobial activity, particularly an antifungal activity and a (3 -1, 3-glucan synthase inhibiting action, and is useful for preventing and treating various kinds of infectious diseases including Pneumocystis carinii infection, e.g., carinii pneumonia.
BACKGROUND ART
The cyclic polypeptide compound represented by the above formula (I) are disclosed by WO 01/60846.
The cyclic polypeptide compound ( I ) or a salt thereof is generally unstable to light, humidity, acids, heat and the like. Therefore, there is desired development of pharmaceutical preparations in which the cyclic polypeptide compound (I) or a salt thereof is stabilized.
DISChOSURE OF INVENTION
The present invention provides a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound (I) or a salt thereof and a stabilizer.
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.
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, and .the most preferred one may be the number of 1 or 2.
Suitable example of "halogen" may be fluorine, chlorine, bromine, iodine 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, tent-pentyloxy, neo-pentyloxy, hexyloxy, isohexyloxy and the like.
Suitable example of "higher alkoxy" may include straight or branched one such as heptyloxy, octyloxy, 3,5-dimethyloctyloxy, 3,7-dimethyloctyloxy, nonyloxy, decyloxy,.undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, and the like.
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, tert-butyl, pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like.
Suitable example of "higher alkyl" may include straight or branched one such as heptyl, octyl, 3,5-dimethyloctyl, 3,7-dimethyloctyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and the like.
Suitable example of "aryl" and "ar" moiety may include phenyl which may have lower alkyl (e. g., phenyl, mesityl, xylyl, tolyl, etc. ) , naphthyl, anthryl, indanyl, fluorenyl, and the like, and this "aryl" and "ar" moiety may have one or more halogen.
Suitable example of "aroyl" may include benzoyl, toluoyl, naphthoyl, anthrylcarbonyl, and the like.
Suitable example of "heterocyclic group" may include unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e. g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e. g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) hetero~nonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, azetidinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,~ indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom ( s ) and 1 to 3 nitrogen atom ( s ) , for example, oxazolyl, isoxazolyl, oxadiazolyl (e. g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom ( s ) and 1 to 3 nitrogen atom ( s ) , for example, morpholinyl, sydnonyl, morpholino, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 oxygen atoms) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom ( s ) and 1 to 3 nitrogen atom ( s ) , for example, thiazolyl, isothiazolyl, thiadiazolyl (e. g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom ( s ) and 1 to 3 nitrogen atom ( s ) , for example thiazolidinyl, thiomorpholinyl, thiomorpholino, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;, unsaturated condensed heterocyclic group containing 1 or 2 sulfur atoms) and l to 3 nitrogen atoms) , for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclicgroupcontaininganoxygenatom, for~example, furyl etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s), for example, tetrahydrofuran, tetrahydropyran, dioxacyclopentane, dioxacyclohexane, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclicgroupcontaininganoxygenatom and 1 or 2 sulfur atoms) , for example, dihydrooxathiinyl, etc. ;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom ( s ) , for example benzothienyl, ben~zodithiinyl, 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" may have one or more suitable substituent (s) selected from the group consisting of lower alkyl, oxo, cyclo(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkanoyl which may have amino and heterocycliccarbonyl.
Suitable example of "cyclo(lower)alkyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and this "cyclo (lower) alkyl" may have one or more lower alkyl.

Suitable example of "cyclo (lower) alkyloxy" may include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. '.
Suitable example of "acyl group" may include carboxy;
carbamoyl; mono or di(lower)alkylcarbamoyl (e. g., methylcarbamoyl, dimethylcarbamoyl,~, ethylcarbamoyl, diethylcarbamoyl, etc.); aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid; and the like.
Aliphatic acyl such as lower or higher alkanoyl (e. g. , 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 (e. g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower alkenyloxycarbonyl (e. g., vinyloxycarbonyl, propenyloxycarbonyl, allyloxycarbonyl, butenyloxycarbonyl, butedienyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e. g., methylsulfonyl, ethylsulfonyl, etc.);
lower or higher alkoxysulfonyl (e. g., methoxysulfonyl, ethoxysulfonyl, etc.); or the like;
Aromatic acyl such as aroyl (e. g., benzoyl, toluoyl, naphthoyl, etc.);
ar(lower)alkanoyl [e. g., phenyl(C1-C6)alkanoyl (e. g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl,phenylpentanoyl,phenylhexanoyl,etc.), naphthyl(C1-C6)alkanoyl (e. g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];
G

ar(lower)alkenoyl [e. g., phenyl(C3-C6)alkenoyl (e. g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentanoyl, phenylhexenoyl, etc.), naphthyl(C3-C6)alkenoyl (e. g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]:
ar(lower)alkoxycarbonyl [e.g., phenyl(C1-C6 )alkoxycarbonyl (e. g., benzyloxycarbonyl, etc.), fluorenyl(C1-C6)alkoxy-carbonyl (e.g., fluorenylmethyloxycarbonyl, etc.), etc.]o aryloxycarbonyl (e. g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl (e. g., phenoxyacetyl, phenoxypropionyl, etc.);
arylcarbamoyl (e. g., phenylcarbamoyl, etc.);
arylthiocarbamoyl (e. g., phenylthiocarbamoyl, etc.);
arylglyoxyloyl (e. g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);
arylsulfonyl which may have 1 to 4 lower alkyl (e. g., phenylsulfonyl, p-tolylsulfonyl, etc.);
aroyl (e.g., beIlZOy1) substituted with one or more suitable substituent(s); or the like; .
Heterocyclic acyl such as heterocycliccarbonyl;
heterocyclic(lower)alkanoyl (e. g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic(lower)alkenoyl~(e.g., 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.

Suitable example of "acyl group" of R1 can be referred to aforementioned "acyl group", in which the preferred one may be lower alkoxycarbonyl, higher alkanoyl and benzoyl substituted with one or more suitable substituent(s).
Suitable example of "suitable substituent (s) " in the term of "benzoyl substituted with one or more suitable substituent(s)" maybe thiadiazolyl substituted with phenyl having phenylsubstituted with morphlinohaving loweralkyl, thiadiazolyl substituted with phenyl having a suitable substituent selected from the group consisting of lower alkoxy(lower)alkoxy and lower alkoxy(higher)alkoxy, piperazinyl substituted with phenyl having piperidyl substituted with a suitable substituent selected from the group consisting of phenyl having lower alkoxy (lower) alkoxy, cyclo(lower)alkyloxy and lower alkoxy(lower)alkylthio, piperazinyl substituted with phenyl having phenyl substituted with morpholino having lower alkyl, imidazothiadiazolyl substituted with phenyl having piperidyl substituted with a suitable substituent selected from the group consisting of lower alkoxy (lower) alkoxy and lower alkoxy(lower)alkylthio, imidazothiadiazolyl substituted with phenyl having lower alkoxy(lower)alkoxy, ' phenyl subsutituted with piperazinyl having phenyl substituted with morpholino having lower alkyl, isoxazolyl substituted with phenyl having lower alkoxy(lower)alkoxy, isoxazolyl ,substituted with phenyl having higher alkoxy substituted with morpholino having lower alkyl, thiadiazolyl substituted with phenyl having piperazinyl substituted with cyclo(lower)alkyl which has . one or more suitable substituent (s) selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy(higher)alkoxy and phenyl, thiadiazolyl substituted with phenyl having piperazinyl substituted with lower alkyl having cyclo(lower)alkyl, thiadiazolyl substituted with phenyl having piperidyl substituted with one ormore suitable substituent ( s) selected from the group consisting of cyclo(lower)alkyloxy, lower alkoxy(lower)alkoxy and lower alkoxy(lower)alkoxy(lower)alkyl, thiadiazolyl substituted with phenyl having piperidyl substituted with cyclo(lower)alkyl and lower alkoxy, thiadiazolyl substituted with pyridyl having piperazinyl substituted withcyclo(lower)alkylhavinglower alkyl, imidazothiadiazolyl substituted with phenyl having piperidyl substituted with cyclo(lower) alkyl, imidazothiadiazolyl substituted with phenyl having piperazinylsubstituted withcyclo(lower)alkyl havinglower alkyl, phenyl substituted with plperazinyl navly cyclo(lower)alkyl substituted with one or more suitable substituent(s) selected from the group consisting of cyclo (lower) alkyl which may have lower alkoxy, lower alkyl, lower alkoxy and phenyl which may have lower alkoxy, in which the preferred one may be thiadiazolyl substituted with phenyl having phenyl substituted with morpholino having dimethyl, thiadiazolyl substituted with phenyl having a substituent selected from the group consisting of methoxyhexyloxy and methoxyheptyloxy, piperazinyl substituted with phenyl having piperidyl substituted with a substituent selected from the group consisting of phenyl having methoxybutoxy, cyclohexyloxy and methoxyhexylthio, piperazinyl substituted with phenyl having phenyl substituted with morpholino having dimethyl, imidazothiadiazolyl substituted with phenyl having piperidyl substituted with a substituent selected from the group consisting of methoxypropox~y, methoxybutoxy, methoxypentyloxy and methoxyhexylthio, imidazothiadiazolyl substituted with phenyl having methoxybutoxy, .
phenyl subsutituted with piperazinyl having phenyl substituted with morpholino having dimethyl, isoxazolyl substituted with phenyl having methoxyhexyloxy, isoxazolyl substituted with phenyl having heptyloxy substituted with morphlino having dimethyl, thiadiazolyl substituted with phenyl having piperazinyl substituted with cyclohexyl which has one or two substituent(s) selected from the group consisting of methyl, methylene, methoxyheptyloxy, methoxyoctyloxy and phenyl, thiadiazolyl substituted with phenyl having piperazinyl substituted with methyl which has a substituent selected from the group consisting of cyclopentyl and cyclohexyl, thiadiazolyl substituted with phenyl having piperidyl substituted with one or two substituent(s) selected from the group consisting of cyclohexyl, methoxy, cyclohexyloxy, methoxypentyloxy,methoxyhexyloxy,methoxybutoxymethyland methoxypentyloxymethyl, thiadiazolyl substituted with pyridyl having piperazinyl substituted with cyclohexyl which has a substituent selected from the group consisting of methyl and ethyl, imidazothiadiazolyl substituted with phenyl having piperidyl substituted with cyclohexyl, imidazothiadiazolyl substituted with phenyl having piperazinyl substituted with cyclohexyl having methyl, phenyl substituted with piperazinyl having cyclohexyl substituted with one or two substituent(s) selected from thegroup consistingofethyl,t-butyl,methoxy,cyclopentyl, cyclohexyl which may have methoxy or dimethyl, and phenyl which may have methoxy.
The suitable example of ~~acyl group" for R1 may be benzoyl which has thiadiazolyl substituted with phenyl . having phenyl substituted with morpholino having dimethyl, benzoyl which has thiadiazolyl substituted with phenyl having a substituent selected from the group consisting of methoxyhexyloxy and methoxyheptyloxy, benzoyl which has piperazinyl substituted with phenyl having piperidyl substituted with a substituent selected from the group consisting of phenyl having methoxybutoxy, cyclohexyloxy and methoxyhexylthio, benzoyl which has piperazinyl substituted with phenyl having phenyl substituted with morpholino having dimethyl, benzoyl whichhas imidazothiadiazolyl substituted with phenyl having piperidyl substituted with a substituent selected from the group consisting of methoxypropoxy, methoxybutoxy, methoxypentyloxy and methoxyhexylthio, benzoyl which has imidazothiadiazolyl substituted with phenyl having methoxybutoxy, benzoyl which has phenyl subsutituted with piperazinyl having phenyl substituted with morpholino having dimethyl, benzoyl which has isoxazolyl substituted with phenyl having methoxyhexyloxy, benzoyl which has isoxazolyl substituted with phenyl havingheptyloxysubstituted withmorphlinohavingdimethyl, benzoyl which has thiadiazolyl substituted with phenyl having piperazinyl substituted with cyclohexyl which has one or two substituent (s) selected from the group consisting of methyl, methylene, methoxyheptyloxy, methoxyoctyloxyand phenyl, benzoyl which has thiadiazolyl substituted with phenyl having piperazinyl substituted with methyl which has a substituent selected from the group consisting of cyclopentyl and cyclohexyl, benzoyl which has thiadiazolyl substituted with phenyl having piperidyl substituted with one or two substituent ( s ) selected from the group consisting of cyclohexyl, methoxy, cyclohexyloxy, methoxypentyloxy, methoxybutoxymethyl and methoxypentyloxymethyl, l0 benzoyl which has thiadiazolyl substituted with pyridyl having piperazinyl substituted with cyclohexyl which has a substituent selected from the group consisting of methyl and ethyl, benzoyl which has imidazothiadi~azolyl substituted with phenyl having piperidyl substituted with a substituent selected from the group consisting of methoxyhexyloxy, cyclohexyl and methoxyhex~yl, benzoyl which has imidazothiadiazolyl substituted with phenylhaving piperazinylsubstituted withcyclohexylhaving methyl, benzoyl which has phenyl substituted with piperazinyl having cyclohexyl substituted with one or two substituent ( s ) selected from the group consisting of ethyl, t-butyl, methoxy, cyclopentyl, cyclohexyl which may have methoxy or dimethyl, and phenyl which may have methoxy.
The suitable example of "lower alkyl" in the term of "lower alkyl which has one or more hydroxy or protected hydroxy" may be methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.
The suitable example of ~~hydroxy protective group"
in the term of unprotected hydroxy" may be phenyl (lower) alkyl which may have one or more suitable substituent(s) (e. g., benzyl, 4-methoxybenzyl, trityl, etc.), tri-substituted silyl [e. g., tri(lower)alkylsilyl(e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
The suitable example of "lower alkyl which has one or more hydroxy or protected hydroxy" may be dihydroxypropyl, dihydroxyisopropyl, trihydroxybutyl, tetrahydroxypentyl, pentahydroxyhexyl and diacetyloxyisopropyl.
The suitable example of "acyl group" of R2 may be acetyl, 2-acetyloxypropionyl, metylsulfonyl, 2,5-diaminopentanoyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl and tert-butoxycarbonyl.
The suitable example of "acyl" moiety of "acyloxy" may be lower alkenyloxycarbonyl, and the most preferred one may be allyloxycarbonyl.
The suitable example of "acyloxy" may be lower alkenyloxycarbonyloxy, and the more preferred one may be allyloxycarbonyloxy.
Particularly, the preferred examples of the cyclic polypeptide compound (I) of the present invention are as follows the compound (I), wherein R1 is hydrogen, lower alkoxycarbonyl, higher alkanoyl or benzoyl substituted with one or more suitable substituent(s), R~ is hydrogen, R3 is lower alkyl which has one or more hydroxy, R4 is hydrogen or hydroxy;
R5 is hydroxy or hydroxysulfonyloxy; and R6 is hydroxy.
And, more preferred one may be the compound (I) wherein R1 is hydrogen, lower alkoxycarbonyl, higher alkanoyl or benzoyl substituted with one or more suitable substituent(s), R~ is hydrogen, R3 is lower alkyl which has. two hydroxy, R4 is hydrogen or hydroxy;
R5 is hydroxy or hydroxysulfonyloxy; and R6 is hydroxy.
And, still more preferred one may be the compound ( I ) wherein R1 is benzoyl substituted with a suitable substituent selected from the group consisting of thiadiazolyl substituted with phenyl having phenyl substituted with morphlino having lower alkyl, thiadiazolyl substituted with phenyl havingasuitable substituent selected from the group consisting of lower alkoxy(lower)alkoxy and lower alkoxy(higher)alkoxy, piperazinyl substituted with phenyl having piperidyl substituted with a suitable substituent selected from the group consisting of phenyl having lower alkoxy (lower)'alkoxy, cyclo(lower)alkyloxy and lower alkoxy(lower)alkylthio, piperazinyl substituted with phenyl having phenyl substituted with morpholino having lower alkyl, imidazothiadiazolyl~substituted with phenyl having piperidyl substituted with a suitable substituent selected from the group consisting of lower alkoxy (lower) alkoxy and lower alkoxy(lower)alkylthio, imidazothiadiazolyl substituted with phenyl having lower alkoxy(lower)alkoxy, phenyl subsutituted with piperazinyl having phenyl substituted with morpholino having lower alkyl, isoxazolyl substituted with phenyl having lower alkoxy(lower)alkoxy, , isoxazolyl substituted with phenyl having higher alkoxy substituted with morpholino having lower alkyl, thiadiazolyl substituted with phenyl having piperazinyl substituted with cyclo(lower)alkyl which has one or more suitable substituent ( s ) selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy(higher)alkoxy and phenyl, thiadiazolyl substituted with phenyl having piperazinyl substituted with lower alkyl having cyclo (lower) alkyl, thiadiazolyl substituted with phenyl having piperidyl substituted with one or more suitable substituent ( s ) selected from the group consisting of cyclo(lower)alkyloxy, lower alkoxy(lower)alkoxy and lower alkoxy(lower)alkoxy(lower)alkyl, thiadiazolyl substituted with phenyl having piperidyl substituted with cyelo(lower)alkyl and lower alkoxy, thiadiazolyl substituted with pyridyl having piperazinylsubstituted withcyclo(lower)alkylhavinglower alkyl, imidazothiadiazolyl substituted with phenyl having piperidyl substituted with cyclo(lower) alkyl, imidazothiadiazolyl substituted with phenyl having piperazinylsubstituted withcyclo(lower)alkylhavinglower alkyl, and phenyl substituted with piperazinyl having cyclo(lower)alkyl substituted with one or more suitable substituent(s) selected from the group consisting of cyclo (lower) alkyl which may have lower alkoxy, lower alkyl, lower alkoxy and phenyl which may have lower alkoxy, R' is hydrogen, R3 is lower alkyl which has two hydroxy, R4 is hydrogen or hydroxy;
R5 is hydroxy or hydroxysulfonyloxy; and R6 is hydroxy.

And, the most preferred one may be the compound (I) Wherein R1 is benzoyl which has thiadiazolyl substituted with phenyl having piperazinyl substituted with cyclo(lower)alkyl which has lower alkyl, benzoyl which has thiadiazolyl substituted with phenyl having piperidyl substituted with cyclo(lower)alkyloxy, benzoyl which has phenyl substituted with piperazinyl having cyclo(lower)alkyl substituted with cyclo(lower)alkyl and lower alkoxy, benzoyl which has thiadiazolyl substituted with phenylhaving piperidylsubst,ituted with cyclo(lower)alkyl, R~ is hydrogen, R3 is lower alkyl which has two hydroxy, R4 is hydrogen or hydroxy;
R5 is hydroxy or hydroxysulfonyloxy~ and R6 is hydroxy.
The suitable salt of the cyclic polypeptide compound (I) is soluble in water, and a pharmaceutically acceptable salt including salt with base and acid addition salt. Such a salt may be prepared by treating the cyclic polypeptide compound ( I ) with an appropriate base or acid according to the conventional method.
As a salt with bases, may be mentioned salt with inorganic base such as alkali metal salt (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salt (e. g., calcium salt, magnesium salt, etc.), ammonium salt and the like; salt with organic base such as organic amine salt (e. g. , triethylamine salt, diisopropyleth ylamine salt, pyridine salt,picolinesalt, ethanolaminesalt, triethanolaminesalt, dicyclohexylaminesalt,N,N'-dibenzylethylenediaminesalt, etc.)~ and the like.
As acid addition salt, may be mentioned inorganic acid addition salt (e. g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); and organic carboxylic or sulfonic acid addition salt (e. g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methnesulfonate, benzenesulfonate, toluenesulfonate, etc.). Further, may also be mentioned salt with basic or acidic amino acid (e.g., salt with arginine, aspartic acid, glutamic acid, etc.).
The cyclic polypeptide compound (I) of the present invention may also include possible conformers and a pair or more of stereoisomers such as geometric isomers and optical isomers which may exist due to asymmetric carbon atoms.
The amount of the cyclic polypeptide compound (I) or a salt thereof contained in the composition for a single unit dosage of the present invention is 0.1 to 400 mg, more preferably 1 to 200 mg, still more preferably 5 to 100 mg, specifically 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 75, 80, 85, 90, 95 and 100 mg.
Thepreferredlyophilizedcomposition may beconsisting of the cyclic polypeptide compound (I) or a salt thereof and a stabilizer, optionally adding a pH adjuster and/or a pH buffer.
As the stabilizer, po.lysaecharides may be mentioned.
The suitable examples of the polysaccharide are dextran (e. g. , dextran 40, dextran 70, etc. ) , starch, cellulose and hyaluronic acid. The polysaccharide contained in the pharmaceutical composition of the present invention may be a -monohydrate, a -anhydride, (3 -anhydride or a combination thereof.
The amount of the stabilizer used in the pharmaceutical composition of the present invention should be at least sufficient for stabilizing the cyclic polypeptide compound (I) or a salt thereof in the composition. In order to 1~

stabilize the cyclic polypeptide compound ( I ) , one part by weight of the stabilizer with respect to one part by weight of the cyclic polypeptide compound (I) or a salt thereof in the present composition is sufficient at least. The stabilizer may also serve as a carrier or an excipient. Thus the use amount of stabilizer does not have a particular upper limit and may be determined in consideration of the weight or volume of the composition with respect to a unit dose of the compound and the like. However, such amount is preferably 1 to 50 parts by weight, more preferably 5 to parts by weight, with respect to one part by weight of the cyclic polypeptide compound (I) or a salt thereof, though it varies depending upon the kind and the used amount of the cyclic polypeptide compound (I) or a salt thereof, its 15 preparation form and/or the like.
Thepharmaceuticalcompositionofthepresentinvention may be produced according to methods known in the art with using additives if necessary. Here, Basic Lecture on Development of Pharmaceuticals XI 20 Production of 20 Pharmaceuticals (the second volume) (editedbyKyo7aunn Tsuda and Hisashi Nogami and published by Chi~yo Shoten) is mentioned for reference.
The lyophilized composition may be obtained by preparing an aqueous solution of the cyclic polypeptide compound ( I ) or a salt thereof and a stabilizer, optionally adding a pH
buffer and/or a pH adjuster.
Suitable example of the pH buffer may be amino acid (e . g. , glycine,h-arginine,h-asparticacid,h-glutamieacid, etc.), sodium L-glutamate monohydrate, ethanolamine, trometamol, and the like, and the amount of the pH buffer is preferably 1 to 30 parts by weight, more preferably 10 to 20 parts by weight, with respect to one part by weight of the cyclic polypeptide compound ( I ) or a salt thereof, though i~t varies depending upon the kind and the used amount of the cyclic polypeptide compound (I) or a salt thereof, its preparation form and/or the like.
Suitable example of the pH adjuster may be inorganic base (e. g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide), organic base (e. g., triethylamine, diisopropylethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.), inorganic acid (e. g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. ) , organic carboxylic or sulfonic acid (e . g. , formic acid, acetic acid, trifluoroacetic acid, malefic acid, tartaric acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc), citric acid anhydrous, and the like, as required to attain pH 9.0 to 10.0, preferably pH 9.5 to 10.0, and then lyophilizing the resulting solution in vial according to a conventional method. Thus, the stabilized pharmaceutical composition in lyophilized form, when dissolved in purified water, preferably gives a solution of pH 9. 0 to 10. 0, more preferably pH 9.5 to 10Ø
It is preferable that the thus prepared composition in lyophilized form is sealed and stored with shading. The lyophilized composition can be loaded in each vial in the solution form before lyophilizing or in lyophilized powder form after lyophilizing.
Since the cyclic polypeptide compound (I) or a salt thereof is not satisfactorily stable to humidity, it is necessary that the lyophilized composition of the present invention contains 3. 4 % by weight or less of water, preferably 3.0 0, more preferably 2.0 0.
Usually the stabilized pharmaceutical composition in lyophilized form is dissolved in isotonic sodium chloride solution as required and used as an injection solution. The pharmaceutical composition of the present invention may be used as an .injection preparation which requires some compounding before use.

The present invention is now described in further detail by way of example and test examples, which should not be construed to limit the scope of the invention.
Compositional Example 1 The compound of Example 2 0.2g Dextran 40 ~g Glycine 0.3g Sodium hydroxide in a suitable amount Dextran 40 and glycine were dissolved in purified water (30mL) at ambient temperature, and the compound of Example _2 was dispersed into the solution. The compound of Example _2 was dissolved at pH of approximately 9. 8 with adding 0. 4 0 aqueous sodium hydroxide solution. After adding purified water, total 40mL of the solution was obtained. Each 2mL
of the resulting solution was filled into a lOmL size of Type I tubing glass vial. The solution in the respective vials was lyophilized by using the lyophilizer (Hull 2FS5C
manufactured by Hull Corp. ) by the conventional method to obtain lyophilized compositions each containing lOmg of the compound of Example 2.
Compositional Example 2 Lyophilized compositions each containing l0mg of the compound of Example 1 are obtained in the similar manner as Compositional Example 1.
Compositional Example 3 'Lyophilized compositions each containing l0mg of the compound of Example 3 are obtained in the similar manner as Compositional Example 1.
Compositional Example 4 Lyophilized compositions each containing lOmg of the compound of Example 4 are obtained in the similar manner as Compositional Example 1 .
Compositional Example 5 The compound of Example 2 0.1258 Dextran 40 1.258 Glycine 0.18758 Sodium hydroxide in a suitable amount Dextran 40 and glycine were dissolved in purified water (20mL) at ambient temperature, and the compound of Example 2 was dispersed into that solution. The compound of Example 2 was dissolved at pH of approximately 9. 8 with adding 0 . 4 0 15 aqueous sodium hydroxide solution. After adding purified water, total 25mL of the solution was obtained.
Each 1mL of the resulting solution was filled into a lOmL size of Type I tubing glass vial. The solution in the respective vials was lyophilized by using the lyophilizer 20 (Hull 2FS5C manufactured by Hull Corp. ) by the conventional method to obtain lyophilized compositions each containing 5m8 of the compound of Example 2.
Compositional Example 6 25 The compound of Example 2 5g Dextran 40 508 L-arginine 17.48 Anhydrous Citric Acid in a suitable amount 30 Dextran 40 and L-arginine were dissolved in purified water (800mL) at ambient temperature, and the solution was added with.the compound of Example 2 avoiding bubbling under gently stirring. After adding 21o aqueous citric acid solution (about 0.5mL) to adjust pH 9.8 and adding purified 35 water for injection, total 1000mL of the solution was obtained.
Each 1mL of the resulting solution was filled into a lOmL size of Type I tubing glass vial. The solution in the respective vials was lyophilized by using the lyophilizer (Hull 2FS5C manufactured by Hull Co.) by the conventional method to obtain lyophilised compositions each containing 5mg of the compound of Example 2.
Compositional Example 7 Lyophilized compositions each containing 5mg of the compound of Example 4 are obtained in the similar manner as Compositional Example 6 . "
Compositional Example 8 Lyophilized compositions each containing 5mg of the compound of Example 5 are obtained in the similar manner as Compositional Example ~ except that trometamol is used instead of L-arginine.
Compositional Example 9 Lyophilized compositions each containing 5mg of the compound of Example 1 are obtained in the similar manner as Compositional Example 5 except that trometamol is used instead of L-arginine.
Compositional Example 10 The compound of Example 2 5g Dextran 40 50g L-arginine 70g Anhydrous Citric Acid in a suitable amount Dextran 40 and L-arginine were dissolved in water for injection (800mL) at ambient temperature, and the solution was added with the compound of Example 2 avoiding foaming under gently stirring. After adding 20o aqueous citric acid solution (about 25mL) to adjust pH 9.8 and adding water for injection, tota1s1000mL of the solution was obtained.
Each 1mL of the resulting solution was filled into a lOmL size of Type I tubing glass vial. The solution in the respective vials was lyophilized by using the lyophilizer (Hu11~2FS5C manufactured by Hull Co.) by the conventional method to obtain lyophilized compositions each containing 5mg of the compound of Example 2.
Compositional Example 11 Lyophilized compositions each containing 5mg of the compound of Example 7 are obtained in the similar manner as Compositional Example 10 .
Test Example 1 Effect of stabilizer in stabilizing lyophilized compositions of the compound of Example 2 The compound of Example 2 and dextran 40, lactose, as a stabilizer, were dissolved completely in 1 or 2mL of glycine-NaOH buffer solution (pH 9.8). The resulting solutions were lyophilized and maintained at 70°C in glass vials. Nine days after, the resulting compositions were tested on their appearance, the residual amount of the compound of Example 2, and pH. As a control, a solution of the compound of Example 2 without any stabilizers was used.
The results are shown in Table 1.

Table 1 Stabilizers Test Items 0 hours After 9 days Control: nil Appearance Yellow mass Yellow mass Residual 100.0 56.5 Amount (%) pH* 9.78 9.75 Dextran 40 Appearance Yellow mass Yellow mass (100mg) Residual 100.0 >90 Amount ( o ) pH* 9.80 9.71 Lactose Appearance Yellow mass Brown melt (100mg) Residual 100.0 <80 Amount (%) pH* 9.71 4.70 Each vial was contained l0mg of the compound of Example _2.
*pH of reconstituted solutions of compositions in 2mZ
of purified water.
As is obvious from Table 1, the lyophilized composition of the compound of Example 2 and dextran 40 was significantly stable as compared with the one not containing any stabilizer or containing other stabilizers, such as lactose.
Test Example 2 Stability test of lyophilized composition containing 5mg of the compound of Example 2 The pharmaceutical compositions obtained in Compositional Example6were storedat varioustemperatures.
The results are shown in Table 2.

TahlP 7 Storage Test Items Conditions Residual Appearance pH*

Amount ( o ) 0 hours Yellow 100.0 9.69 mass After 3 months Yellow at 40C and a 75 >95 9. 72 mass humidity After 3 months Yellow at 25C and a 60 >95 9 . 71 mass humidity Each vial was contained 5mg of the compound of Example _2.
*pH of reconstituted solutions of compositions in 1mZ of purified water As is obvious from Table 2, the residual amount of the compound of Example 2 after stored at 40°C or 25°C for 3 months was more than 950.
The following Examples are given for the purpose of illustrating the present invention in more detail.
The Starting Compounds used and the Object Compounds obtained in the following Examples 1 to 7 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.

Example Formula No.

HO HO 0 ' N.N . _ HO~H3C'~~.... N H \ / l~ ~ \ / ~O~CH2)50CH3 N S
0 o H~ OH
b ' HO' H O~H3 0 l~
1('u'0H
D QH
H03S0 .
l OH O
HO 0 - N,N _ HO H3C'~~ N -I~,. H \ / / J~S~ \ / ~O I CH2 ) 50CH3 NH ~ 0 HO o H~ OH
HO'~ H o : H3 0 g l~
~~''OH
DH
H03S0 \
HO
OH O
HO 0 ~--~' H3C~. ~. Nn ? H ~ N

o H~ OH
H2N HO" H o 'CH3 0 g ~~(~ N
~~''OH
~D H ~
H03S0 \. ! - 'CHg OH O
HO O ~-i N~ ~N
HO H3C,...~ O ~ ~I
HO~ 0 H~ OH
H HO' H o~Hg l \
O ~~''OH
_ ~DH ~
H03S0 \ / - 'CH3 HO

Example Formula No.

HO 0 - ~' HO H30'" N j q \ / \ / ~ \ /
~--N :..~ ~O
HOJ p H OH
O~ HO' ~H O~H3 O H ~(~
~~~'OH .

Na03S0 \

OH
HO ~ ' 0 N
H 0 H 3 C".. H '--' ~--~ H ~ O
HO-i o H~ OH
H0~ H O .CH3 ~~~''OH
~DH
H03S0 \ / .
HO
OH O

HO H3C'~N H \ / ~ .
HON ~NY O

O'~OHO
H o~H3 J o H l~
N~'OH
DH

o~ . ~N~.
4 =Lo-~o OH p H3CH~:. 0 N~ H \ / ~ \
HO ~ 0 o H~ OH
HO~HH~,. H O~H3 0 l~
~''OH
_ DH
H03S0 \ /
. HO

Example Formula No.
OH
HO O ~
HgC~, '. N~ NHS
O
HO 0 H~ OH
HO-J I HO' H O~CH3 Fmoc O
N~"'OH
DH

HO
OH
O
HO O ~ ~,~ ~
NH \ H!~~5~(CH2)qOCHg H3C "...~~ ~ ~ NO
HO o HN OH
J H HO,; H O . H3 HO O H
N ~""OH
_ OH

HO
OH
HO O
......~N~ NH2 HO
O
HO~ p H~ OH
0 HO g 0 r ~0 0 ' 1 / ~ ~~""OH
OH

HOr OH O , HO HO O N~ H ~~ NSN ~ ~ N~O
...... O

H H O" g 0 ~ 1'~
"'OH
_ OH
H03SO ~
HO
2~

Example Formula No.
OH
HO ~ ~' NH ? NHS
H O ,....
O
H0~ o HN OH
HO' H O
O p H
= 1 / ~ N~~"OH
_ OH

OH 0 N-N OMe / \
HO 0 N--IO_ ~~ / S ~ / N
HO ......~ ~O O
HO~ ~O HN OH
H HO H o N
"~OH
_ OH
H03S0 ~ !
HO
Example 1 To a solution of the starting compound ( 1 ) ( 610 . 6 mg ) in a mixture of methanol ( 10 ml ) a'nd tetrahydrofuran (25 ml) were successively added triphenylphosphine (32 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg) and morpholine (106 ~.1) with stirring, and the mixture was stirred at ambient temperature for 3.5 hours. Ethyl acetate (100 ml) was added, and the resulting precipitate collected, washed with isopropyl ether, and dried to give a crude pale yellow powder (535 mg). The crude powder was dissolved sodium hydroxide aqueous solution and subjected to column chromatography on ODS (YMC-gel ODS-AM-S-50 (Trademark:
prepared by YMC Co., Ztd.)) (37% acetonitrile aqueous solution). The fractions containing the object compound were combined, and evaporated under reduced pressure to remove acetonitrile. The residue was lyophi 1i zed to give the obj ect compound ( 1 ) ( 293 . 7 mg ) .
IR (KBr) : 3355.5, 1633.4, 1608.3, 1529.3, 1517.7, 1463.7, 1444.4, 1267.0, 1230.4 cm-1 NMR ( DMSO-d6, b) : 0 . 98 ( 3H, d, J=6 . 7Hz ) , 1 . 10 ( 3H, d, J=5 . 6Hz ) , 1 . 2-5 . 6 ( 65H, m) , 6. 71 ( 1H, d, J=8 . 1Hz ) , 6.78 (1H, d, J=9.7Hz), 7.00 (1H, s), 7.09 (2H, d, J=9.lHz) , 7.75 (2H, d, J=8. 7Hz) , 7 . 95 (4H, s) , 7. 3-8. 7 (7H, m) , 8.79 (1H, s) MASS (m/z) : 1465.5 (M-H)-Elemental Analysis Calcd.for C66H90N1202252'7H20:
C 49.74, H 6.58, N 10.55 Found : C 49.72, H 6.43, N 10.40 Example 2 The suspension of a mixture of the starting compound ( 2 ) ( 10 0 mg ) , 1 , 3-dihydroxyacetate ( 13 . 5 mg ) and acetic acid (0.13 ml) in a mixture of methanol (1.5 ml) and dimethylformamide(0.7m1)wasaddedsodiumcyanoborohydride ( 9 . 4 mg ) with stirring at ambient temperature, and the mixture was stirred at the same temperature overnight. To the reaction mixture was added ethyl acetate (20 ml). The resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of water and 1N sodium hydroxide and the solution was subjected to column chromatographyon ODS (Daiso-gel, SP-120-40/60-ODS-B
(Trademark: prepared by Daiso Co., Ltd.)) (50 ml) eluting with 40o acetonitrile in water. The fractions containing the object compound were collected and evaporated under reduced pressure to remove acetonitrile. ,The residue was lyophilized to give the object compound (2) (55 mg).
NMR ( DMSO-d6, 8) : 0 . 90 ( 3H, d, J=6 . 8Hz ) , 0 . 98 ( 3H, d, J=6. 7Hz) , 1.11 (3H, d, J=5. 5Hz) , 1. 43-5.24 (62H, m), 6.69-8.85 (17H, m) ESI MASS (m/z) (Negative) : 1408.3 (M+) Example 3 To a solution of starting compound (3) (0.22 g) in a mixture of methanol (4 ml) and THF (1 ml) were successively added triphenylphosphine (14 mg), tetrakis(triphenylphosphine)palladi'um(0) (8 mg) and morpholine (40 ~.l) with stirring and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in a mixture of pH
6.86 standard buffer solution and 1N sodium hydroxide, insoluble materials were filtered off and the solution was subj ected to column chromatography on ODS (Daiso-gel, SP-120-40/60-ODS-B (Trademark:
prepared by Daiso Co. , htd. ) ) (100 ml) eluting with 30 o acetonitrile in water. The fractions containing the object compound were collected and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give object compound (3) (85 mg).
IR (KBr): 1633, 1537, 1516, 1450, 1234 cm-1 NMR (DMSO-d6 + D20, 8): 0.98 (3H, d, J=7.09Hz), 1.05 (3H, d, J=7.OOHz), 1.15 (6H, d, J=6.21Hz), 1.60-2.30 (8H, m), 2.75-3.45 (14H, m), 3.80-4.50 (10H, m), 4.81 (1H, br s), 6.65-7.20 (8H, m), 7.50-7.80 (5H, m), 7.94 (2H, d, J=8.49Hz) ESI MASS (m/z)(Negative): 1416.4 (M++1) Elemental Analysis Calcd. for C67H91N110215'7H20:
C 52.10, H 6.85, N 9.97 Found: C 52.29, H 6. 60, N 9. 61 The following comopound was obtained according to a similar manner to that of Example 3.
Example 4 IR (KBr): 2931, 2854, 1632, 1510, 1446, 1385, 1325 cm-1 NMR (DMSO-d6, b): 0.97 (3H, d, J=6.7Hz), 1.12 (3H, d, J=5. 5Hz) , 1. 08-2. 62 (23H, m) , 2. 62-4.50 (37H, m) , 4 . 66-5. 45 ( 10H, m) , 6 . 70 ( 1H, d, J=8 . 1Hz ) , 6. 78 ( 1H, d, J=8 . 1Hz ) , 6. 83-7 . 09 (7H, m) , 7 .34-8 . 00 (3H, m) , 7 . 80 (2H, d, J=8. 7Hz) , 8.00-8.49 (2H, m), 8.71 (1H, s) MASS (m/z): 1408.4 (M++1) Elemental Analysis Calcd. for C66H95N110215'7H20v C 51.59, H 7.15, N 10.03 Found: C 51.77, H 7.05, N 9.82 Example 5 To a solution of starting compound (5) (12.50 g) and diisopropyleth.ylamine (3.67 ml) in N,N-dimethylformamide (250 ml) was added 4-[2-[4-(4-methoxybutoxy)phenyl]imidazo-[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid benzotriazol-1-yl ester at room temperature. The solution was stirred for 4 hours at the same temperature, during which period additional 4-[2-[4-(4-methoxybutoxy)phenyl]imidazo[2,1-b][1,3 ,4]-thiadiazol-6-yl]benzoic acid benzotriazol-1-yl ester was added to the mixture. The reaction mixture was then filtered. To the filtrate was added piperidine (9.33 ml) at room temperature. The solution was stirred for 1 hour at the same temperature.
Ethyl acetate was added to the reaction mixture. The powder was collected by filtration to give crude material (16.12 g). The crude material was purified by column chromatography on ODS to give obj ect compound (5) (11.10 g). ~ ' IR (KBr)~: 1659, 1633, 1529, 1518, 1466, 1444, 1255 cm-1 NMR (DMSO-d6, 8): 0.98 (3H, d, J=6.7Hz), 1.00 (3H, d, J=5 . 8Hz) , 1 . 5-2 . 6 ( 12H, m) , 2 . 8-3 . 6 ( 33H, m) , 4 . 7-5 . 4 ( 10H, m) , 6 . 65-6 . 85 ( 2H, m) , 7 . 00 ( 1H, s ) , 7 . 15 ( 2H, d, J=8 . 9Hz ) , 7. 3-7. 7 (2H, m) , 7. 90 (2H, d, J=8. 8Hz) , 7. 96 (4H, s) , 8. 0-8.5 (2H, m) , 8.71 (1H, s) , 8.85 (1H, s) MASS (m/z) : 1392 (M++23) Elemental Analysis Calcd.forC60H79N11022S2~5H20:
C 49.34, H 6.14, N 10.55 Found: C 49.30, H 6.23, N 10.53 The following compounds [Example 6 and 7] were obtained according to a similar manner to that of Example 5.
Example 6 IR (F~Br) : 1664, 1635, 1605, 1446, 1410, 1350, 1329, 1281 cm-1 NMR (DMS~-d6, D20, ~) : 0. 98 (3H, d, J=6.7Hz) , 1. 10 (3H, d, J=5.9Hz), 1.1-2.6 (21H, m), 2.8-4.5 (31H, m), 4.7-4.9 (2H, m) , 6. 7-~. 9 (2H, m) , 7. 0-7. 2 (3H, m) , 7. 85 (2H, d, J=8.9Hz), 8.0-8.2 (4H, m) ESI MASS (m/z) (Negative) : 1409.4 (M--1) Elemental Analysis Calcd. for C~4H87N11021S2~6H2Q:
C 50.62, H 6.57, N 10.15 Found: C 50.40, H 6.61, N 9.92 Example 7 IR (I~Br) : 1664, 1628, 1605, 1446, 1417, 1279, 1084, 1047 cm-1 NMR (DMSO-d6+D20, 8): 0.8-1.3 (12H, m), 1.5-2.6 (16H, m) , 2. 8-4 . 5 (32H, m) , 4 .7-4 . 9 (2H, m) , 6. 7-6. 9 (2H, m) , 7 . 0-7 .2 (3H, m), 7.85 (2H, d, J=8.6Hz), 8.0-8.2 (4H, m) ESI MASS (m/z)(Negative): 1423.5 (M--1) The cyclic polypeptide compound ( I ) or a salt thereof has an antifungal activity, particularly against the following fungi.
Ac.remonium;
Absidia (e. g., Absidia corymbifera, etc);
Aspergillus (e. g. , I~spergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, etc);
Blastomyces (e. g. , Blastomyces derma titidis, etc) ;
Candida (e. g. , Candida albicans, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida parapsilosis, Candida stellatoides, Candida tropicalis, Candida utilis, etc.);
Cladosporium (e. g. , Cladosporium trichoides, etc) ;
Coccidioides (e. g., Coccidioides immitis, etc);
Cryptococcus (e. g., Cryptococcus neoformans, etc);
Cunninghamella (e. g. , ' Cunninghamella elegans, etc) ;
Dermatophyte;
Exophiala (e. g., Exophiala dermatitidis, Exophiala spinifera, ete);
Epidermophyton (e. g. , Epidermophyton floccosum, etc) ;
Fonsecaea (e. g. , Fonsecaea pedrosoi, etc) ;
Fusarium (e. g. , Fusarium solani, etc) ;
Geotrichum (e. g., Geotrichum candiddum, etc);
Histoplasma (e. g., Histoplasma capsulatum var.
capsulatum, etc);
Malassezia (e. g. , Malassezia furfvr, etc) ;
Microsporum (e. g. , Microsporum cams, Microsporum gypseum, etc);
Mucor;
Paracoccidioides (e. g. , Paracoccidioides brasiliensis, etc) ;
Penicillium (e. g., Penicillium marneffei, etc);
Phialophora;
Pneumocystis (e. g. , Pneumocystis carinii, etc) ;
Pseudallescheria (e. g. , Pseudallescheria boydii, etc) Rhizopus (e. g., Rhizopus microsporus var.
rhizopodiformis, Rhizopus oryzae, etc) ;
Saccharomyces (e. g., Saccharomyces cerevisiae, etc);
Scopulariopsis;

Sporothrix (e. g. , Sporothrix schenchii, etc) ;
Trichophyton (e. g. , Trichophyton mentagrophytes, Trichophyton rubrum, etc);
Trichosporon (e. g., Trichosporon asahii, Trichosporon cutaneum, etc).
The above fungi are well known to cause various infection diseases in skin, hair, nail, oral mucosa, gastrointestinal tract, bronchus,lung,endocardium,brain,meninges,urinary organ, vaginal protion, oral cavity, ophthalmus, systemic, kidney,bronchus,heart,externalauditorycanal,bone,nasal cavity, paranasal cavity, spleen, liver, hypodermal tissue, lymph duct, gastrointestine, articulation, muscle, tendon, interstitial plasma cell in lung, and so on.
Therefore, the cyclic polypeptide compound (I) or a salt thereof of the present composition is useful for preventing and treating various infectious diseases, such as dermatophytosis (e. g., trichophytosis, etc), pityriasis versicolor, candidiasis, cryptococcosis, geotrichosis, trichosporosis, aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis, chromomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotic keratrtis, otomycosis, pneumocystosis, and so on.
A commercialpackage comprisingthe cyclic polypeptide compound (I) or a salt thereof of the present composition and a written matter associated therewith, wherein the written matter states that the pharmaceutical composition can or should be used for preventing or treating infections disease.

Claims (13)

1. A stabilized pharmaceutical composition in lyophilized form which comprises:

a cyclic polypeptide compound represented by the following general formula (I) :

wherein R1 is hydrogen or acyl group, R2 is hydrogen or acyl group, R3 is lower alkyl which has one or more hydroxy or protected hydroxy, R4 is hydrogen or hydroxy, R5 is hydrogen, hydroxy, lower alkoxy or hydroxysulfonyloxy, and R6 is hydroxy or acyloxy, or a salt thereof as an active ingredient, and a polysaccharide as a stabilizer.

2. A composition according to claim 1, which further comprises a pH adjuster and /or a pH buffer.

3. A composition according to claim 2, in which the polysaccharide is dextran.

4. A composition according to claim 3, in which the dextran is dextran 40.

5. A composition according to claim 2, in which the pH buffer is amino acid.

6. A composition according to claim 5, in which the amino acid is L-arginine.

7. A composition according to claim 1, which contains to 50 parts by weight of the polysaccharide with respect to one part by weight of the polypeptide compound (I) or a salt thereof.

8. A composition according to claim 1, which contains 0.1 to 400 mg of the polypeptide compound (I) or a salt thereof in a single unit dose.

9. A composition according to claim 1 prepared by the steps of:

dissolving the polypeptide compound (I) or a salt thereof, the stabilizer and optionally a pH adjuster and/or a pH buffer in a purified water, and lyophilizing the solution.

10. A composition of claim 1, which, when dissolved in purified water, gives a solution of pH 9.0 to 10Ø

11. A composition of claim 1 containing 3.4 % by weight or less of water.

12. An injection preparation prepared by dissolving the composition of claim 1 in isotonic sodium chloride solution.

13. A commercial package comprising the pharmaceutical composition of any one of claim 1 to claim 11 and a written matter associated therewith, wherein the written matter states that the pharmaceutical composition can or should be used for preventing or treating infections disease.