Cyclic hexapeptides with antimicrobial activity

Details Cyclic hexapeptides with antimicrobial activity Cyclic hexapeptides with antimicrobial activity

1999-12-22

2001-05-15

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S317000

Reexamination Certificate

active

06232290

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 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 Aspergillus, Cryptococcus, Candida, Mucor, Actinonyces, 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 methods for the prophylactic and/or therapeutic treatment of infectious disease including
Pneumocystis carinii
infection (e.g.
Pneumocystis carinii
pneumonia) in a human being or an animal.
The object polypeptide compounds of the present invention are new and can be represented by the following general formula [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;
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),
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.
The new polypeptide compound [I] and a salt thereof can be prepared by the process as illustrated in the following reaction schemes.
The starting compound [II] and [IV], or a salt thereof can be prepared by the process as illustrated in the following reaction schemes.
wherein
R
2
, R
3
and R
4
are as defined above,
R
a
1
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),
R
a
3
is lower alkoxy, and
R
a
4
is hydroxy or lower alkoxy.
Suitable salt of the new polypeptide compound [I] is a pharmaceutically acceptable and conventional non-toxic salt, and may include a salt with a base or an acid addition salt 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, diisopropylethylamine salt pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediame 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.).
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 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)” in the R
1
and R
a
1
may include higher alkoxy, aryl which have 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 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 m

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