Cyclic compounds

Details Cyclic compounds Cyclic compounds

1999-07-23

2002-12-03

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C530S327000, C530S332000, C514S011400, C514S014800

Reexamination Certificate

active

06489440

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel cyclic compounds having antifungal activity (hereinafter referred to as Aerothricins), the use of Aerothricins in the medical therapy, pharmaceutical compositions containing Aerothricins as well as to processes and intermediates for the preparation of Aerothricins.
BACKGROUND
Azole antifungal agents are currently widely used for the treatment of systemic mycoses. However, long term prophylactic use of azole antifungals resulted in generation of azole resistant Candida spp. due to their fungistatic action. Therefore, fungicidal agents are particularly important for treatment of severe systemic mycoses. Furthermore, the currently available antifungal agents are not effective against Fusarium spp. which is one of the emerging pathogens among immunocompromised patients. Amphotericin B is a highly effective fungicidal agent currently used clinically, but its therapeutic index (effective dose vs. toxic dose) is rather narrow. Certain cyclic compounds such as LY303366 (EP 736 541), WF11243 (EP 584 360) are known to show fungicidal activity through inhibition of &bgr;-1,3-glucan synthase. However, they have still some disadvantages in terms of antifungal spectrum and/or safety profile. Thus, development of new fungicidal agents with better safety profile and efficacy against major systemic pathogens including newly emerging pathogens like Fusarium spp. is urgently required.
SUMMARY OF THE INVENTION
The present invention relates to novel Aerothricins represented by the Formula (I), wherein
R
1
is guanidino, tri-lower alkylammonio, —N(R
10
)—R
11
, —N(R
15
)—CO—R
14
, —N(R
15
)—CO—CH[N(R
10
)R
11
]—R
13
, —NHCOCH(R
13
)—NHCOCH(NH
2
)—R
13
,
R
10
and R
11
are each independently selected from hydrogen; heteroaryl substituted with one or two amino; lower alkyl optionally substituted with one or more, preferably one or two, amino, amino-lower alkyl, cyano, guanidino, nitrogen containing heterocycle(s) or phenyl group(s) containing an amino, amidino or guanidino group;
R
13
is a residue derived from natural or unnatural amino acids;
R
14
is lower alkyl substituted with one or more, preferably one or two, amino, guanidino, nitrogen containing heterocycle(s) or phenyl group(s) containing an amino, amidino or guanidino group;
R
15
is hydrogen, lower alkyl optionally substituted with one or more, preferably one or two, amino, guanidino, nitrogen containing heterocycle(s) or phenyl group(s) containing an amino, amidino or guanidino group;
R
2
is hydrogen, hydroxysulfonyl, lower alkyl or lower alkenyl, wherein lower alkyl and lower alkenyl may be optionally substituted with acyl, carbamoyl, amino, mono-lower alkylamino or di-lower alkylamino;
R
3
is hydrogen, hydroxy, nitro, amino, acylamino, (lower alkylcarbamoyl)amino, carboxyl, lower alkoxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl or lower alkynyl, wherein lower alkyl, lower alkenyl and lower alkynyl may be optionally substituted with hydroxy, amino, mono-lower alkylamino, di-lower alkylamino, lower alkoxycarbonyl or carbamoyl;
R
4
is alkyl, alkenyl, alkoxy or alkenyloxy which may be optionally substituted with lower alkyl, aryl, cycloalkyl or fluorine atom(s);
R
5
is —CONH
2
, —CN or —CH
2
NH
2
;
X is a single bond, or an aryl, biphenyl or terphenyl group optionally containing one or more hetero atom(s) and/or being substituted with halogen atom(s) or lower alkyl;
Y is a single bond, —CH
2
—, —CH(lower alkyl)-, —CONH— or —CON(lower alkyl)-;
Z is —O—, —NH—or —N(lower alkyl)-;
m is an integer of 0 to 4; and
n is an integer of 2 to 5;
with the proviso that when —Y—(CH
2
)
m—X—R
4
is unsubstituted alkyl or aralkyl, then R
1
is not amino, R
2
and R
3
are not hydrogen, R
5
is not —CONH
2
, and Z is not —O— or —NH— at the same time;
and pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition comprising an Aerothricin of Formula (I) and a pharmaceutically acceptable carrier. Furthermore, the present invention relates to the use of such Aerothricins for the preparation of medicaments, as well as to processes and intermediates for the preparation of the Aerothricins of Formula (I). Additionally, the present invention relates to a method for the prophylactic and/or therapeutic treatment of infectious diseases caused by pathogenic microorganisms.


REFERENCES:
patent: 5446022 (1995-08-01), Fujie
patent: 5547934 (1996-08-01), Fujie
patent: 584 360 (1994-03-01), None
patent: 736 541 (1996-10-01), None
patent: 96/30399 (1996-10-01), None
Davies et al.,Tetrahedron Asymmetry 2(3), pp. 183-186 (1991).
Bouffard et al.,J. Med. Chem. 37:222-225(1994).
Black et al.,Biorg. Med. Chem. Lett 7(22) pp. 2879-2884 (1997).
Futaki et al,J. Chem. Soc. Perkins Trans. (6), pp. 1739-1744 (1990).
Abstract of Japanese Patent No. 09176189 published Aug. 7, 1997.

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