Cyclohexapeptides having antimicrobial activity

Details Cyclohexapeptides having antimicrobial activity Cyclohexapeptides having antimicrobial activity

1999-05-21

2004-06-01

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S009100, C530S317000, C530S323000

Reexamination Certificate

active

06743776

ABSTRACT:

TECHNICAL FIELD
The present invention relates to new polypeptide compound and a salt thereof which are useful as a medicament.
BACKGROUND ART
In U.S. Pat. No. 5,376,634, 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 include Aspergillus, Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophyte, Malassezia, Fusarium and the like.], inhibitory activity on &bgr;-1,3-glucan synthase, and further which are expected to be useful for the prophylactic and/or therapeutic treatment of
Pneumocystis carinii
infection (e.g.
Pneumocystis carinii
pneumonia) in a human being or an animal, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for the prophylactic and/or therapeutic treatment of infectious diseases including
Pneumocystis carinii
infection (e.g.
Pneumocystis carinii
pneumonia) in a human being or an animal.
The object polypeptide compound of the present invention are new and can be represented by the following general formula [I] (SEQ ID No: 1):
wherein
R
1
is aroyl substituted with heterocyclic group which has a suitable substituent selected from the group consisting of
aryl having cyclo(lower)alkyloxy,
aryl having morpholinyl,
aryl having aryloxy(lower)alkoxy,
heterocyclic group having cyclo(lower)alkyl,
heterocyclic group having higher alkyl,
ar(lower)alkyl having lower alkoxy, and
cyclo(lower)alkyl which may have one or more suitable substituent(s);
aroyl substituted with heterocyclic group which has hydroxy and may have additional one or more suitable substituent(s);
aroyl substituted with piperidyl which has aryl having lower alkoxy;
aroyl substituted with thiadiazolyl which has a suitable substituent selected from the group consisting
of aryl having pentyl,
aryl having hexyl,
aryl having methoxy,
aryl having butoxy, and
aryl having higher alkoxy;
aroyl substituted with aryl which has aryl having pentyloxy;
aroyl substituted with piperazinyl which has 3-hexyloxyphenyl;
aroyl substituted with 1,2,3,6-tetrahydropyridyl which may have one or more suitable substituent(s);
aroyl substituted with thienyl which may have one or more suitable substituent(s);
aroyl substituted with furyl which may have one or more suitable substituent(s);
aroyl substituted with heterocyclic(lower)alkyl which may have one or more suitable substituent(s);
aroyl substituted with ar(lower)alkynyl which may have one or more suitable substituent(s);
lower alkanoyl substituted with thiazolyl which may have one or more suitable substituent(s);
aroyl substituted with imidazothiadiazolyl which may have one or more suitable substituent(s);
aroyl substituted with isoxazolyl having halogen which may have one or more suitable substituent(s); or
4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl; and
R
2
is hydroxy, hydroxysulfonyloxy or lower alkoxy, with proviso that
R
2
is not hydroxysulfonyloxy, when R
1
is 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl.
The new polypeptide compound [I] and a salt thereof can be prepared by the process as illustrated in the following reaction scheme.
wherein R
1
and R
2
are as defined above,
R
a
2
is hydroxysulfonyloxy,
R
b
2
is hydroxy or
R
c
2
is lower alkoxy.
The starting compound [IIb] and [IIc] or a salt thereof are novel and can be prepared by the following schemes.
Wherein R
d
2
is lower alkoxy.
Suitable salts of the object polypeptide compound [I] are pharmaceutically acceptable, conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt;
a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,NI-dibenzylethylenediamine salt, etc.);
an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.);
an organic carboxylic sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions 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 20 carbon atoms, unless otherwise provided.
Suitable example of “one or more” may be the number of 1 to 6, in which the preferred one may be the number of 1 to 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.
Suitable example of “suitable substituent(s)” may include lower alkoxy as mentioned below, higher alkoxy as mentioned below, lower alkyl as mentioned below, higher alkyl as mentioned below, higher alkoxy(lower)alkyl, lower alkoxycarbonyl, oxo, aryl which may have one or more lower alkoxy, aryl which may have one or more higher alkoxy, aryl which may have one or more lower alkyl, aryl which may have one or more higher 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 alkyl, aryl substituted with aryl which may have one or more higher alkyl, aroyl which may have one or more lower alkoxy, aroyl which may have one or more higher alkoxy, aroyl which may have one or more lower alkyl, aroyl which may have one or more higher alkyl, heterocyclic group which may have one or more lower alkoxy, heterocyclic group which may have one or more higher alkoxy, aryl having heterocyclic(higher)alkoxy, heterocyclic group which may have aryl having higher alkoxy, heterocyclic group which may have aryl having lower alkoxy(higher)alkoxy, heterocyclic group which may have aryl having lower alkoxy, lower alkoxy(lower)alkyl, halo(lower)alkoxy, lower alkenyloxy, halo(higher)alkoxy, lower alkoxy(higher)alkoxy, aryl which may have one or more lower alkoxy(lower)alkoxy, heterocyclic group, aryl which may have one or more lower alkoxy(higher)alkoxy, aryl which may have one or more higher alkenyloxy, cyclo(lower)alkyl which may have aryl, aryl substituted with heterocyclic group which may have lower alkyl and oxo, cyclo(lower)alkyl which may have one or more lower alkyl, aryl which may have cyclo(lower)alkyl, aryl which may have heterocyclic group, 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, 3,5-dimethyloctyloxy, 3,7-dimethyloctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, and the like,
in which the preferred one may be (C
7
-C
14
)alkoxy, and the more preferred one may be heptyloxy and o

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