Antifungal activity of dicationic molecules

Details Antifungal activity of dicationic molecules Antifungal activity of dicationic molecules

1999-09-15

2001-12-04

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S200000, C549S210000

Reexamination Certificate

active

06326395

ABSTRACT:

FIELD OF THE INVENTION
The invention generally relates to methods for treating fungal infections.
BACKGROUND OF THE INVENTION
The incidence of fungal infections in the immunocompromised population has significantly increased over the past several years. In particular, Candida species, especially
Candida albicans,
are often significant pathogens in patients infected with human immunodeficinecy virus (HIV). As an example, infections can range from somewhat mild oropharyngeal or vulvovaginal candidiasis to severe debilitating mucocutaneous candidiasis. Moreover, AIDS patients suffering from oral candidiasis may also experience esophageal candidiasis which has been known to lead to gastrointestinal bleeding and perforation.
Candida albicans
is a species which is commonly isolated from patients with the above-mentioned infections.
Treatment of candidiasis has typically involved two classes of drugs: (1) polyenes such as amphotericin B and nystatin; and (2) azoles such as clotrimazole, ketoconozole, fluconozole, and itraconazole. Since immunosuppression in AIDS-infected patients often occurs over an extended period of time, fungal reinfection may be common. Accordingly, these patients commonly receive prolonged antifungal therapy. Widespread antifungal therapy, however, has raised issues regarding the increased level of resistance among isolates of the Candida species, especially with respect to fluconozole. See Pfaller, M. A., et al.,
Journal of Clinical Microbiology,
January 1994, pp. 59-64; and Cameron, M. L., et al.,
Antimicrobial Agents and Chemotherapy,
November 1993, pp. 2449-2453.
In view of the above, there remains a need in the art to develop new antifungal treatment methods utilizing compounds which address the problems noted above. It would especially be desirable if the use of such compounds displayed increased fungal activity at acceptable dosage levels. Accordingly, it is an object of the present invention to provide new antifungal treatment methods exhibiting increased fungal activity at acceptable dosage levels.
SUMMARY OF THE INVENTION
The above object as well as others is provided by the present invention.
In one aspect,the invention provides a method of combating a fungal infection in a subject in need of such a treatment. The method comprises administering to the subject an effective fungal infection-combating amount of a compound [(I)-(VI)] selected from the group consisting of:
wherein R
1
and R
2
may be the same or different and selected from the group consisting of H, loweralkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, oxyalkyl, oxyaryl, and oxyarylalkyl; and
wherein Y
5
and Y
6
are present in the meta or para positions and may the same or different and are represented by the formula (a) or (b) selected from the group consisting of:
wherein:
each R
22
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R
22
groups together represent C
2
-C
10
alkyl, hydroxyalkyl, or alkylene; and
R
23
is H, hydroxy, loweralkyl, alkoxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl; and
wherein Y
3
is selected from the group consisting of NR′″ and O;
wherein R′″ is selected from the group consisting of H and loweralkyl;
and wherein Y
4
is represented by the formula:
wherein R
20
is selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl;
wherein R
21
is selected from the group consisting of hydroxy, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, and alkylaryl;
wherein Y
15
and Y
16
may be the same or different and represented by the formula:
wherein:
each R
22
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkylamino, cycloalkyl, aryl, or alkylaryl or two R
22
groups together represent C
2
-C
10
alkyl, hydroxyalkyl, or alkylene; and
R
23
is H, hydroxy, loweralkyl, alkoxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
wherein each R
25
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R
25
groups together represent substituted or unsubstituted C
2
-C
10
alkyl, hydroxyalkyl, or alkylene; and
R
26
is H, hydroxy, loweralkyl, alkoxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
R″ is hydroxy, alkoxyalkyl, hydroxyalkyl, alkoxyaryl, aryl, or the substituent selected from the formula (i) and (ii) consisting of:
wherein:
n and m may be independently selected and each range from 0 to 6; each R
22
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R
22
groups together represent C
2
-C
10
alkyl, hydroxyalkyl, or alkylene; and R
23
is H, hydroxy, loweralkyl, alkoxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
wherein:
is from 2 to 6;
X is selected from the group consisting of O, NH, and S;
Y
9
and Y
10
may be in the meta or para position, are independently selected and are each represented by the formula:
wherein each R
30
is selected from the group consisting of H, hydroxy, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl; and wherein each of the two R
30
groups together may represent C
2
-C
10
alkyl, hydroxyalkyl, or alkylene;
wherein R
31
is selected from the group consisting of H, hydroxy, loweralkyl, alkoxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
wherein R
3
and R
4
may be the same or different and are selected from the group consisting of H, amino nitro, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl;
wherein X may be O, NH, or S; n and m may be the same or different and range from 2 to 6;
wherein Y
11
and Y
12
may be the same or different and represented by the formula:
wherein each R
30
is selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl; and wherein each of the two R
30
groups together may represent represent C
2
-C
10
alkyl, hydroxyalkyl, or alkylene;
wherein R
31
is selected from the group consisting of H, hydroxy, loweralkyl, alkoxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
wherein R
5
is selected from the group consisting of H, hydroxy, and
wherein n ranges from 0 to 3;
wherein X is C
1
to C
12
linear or branched, saturated or unsaturated alkyl containing up to four double bonds, or is substituted or unsubstituted aryl;
wherein Y
13
and Y
14
may be the same or different and are represented by the formula:
wherein R
40
and R
42
are each independently selected from the group consisting of H, loweralkyl, cycloalkyl, substituted aryl, and unsubstituted aryl, or wherein R
40
and R
42
together may represent represent C
2
-C
10
alkyl, hydroxyalkyl, alkylene, substituted aryl, or unsubstituted aryl; and wherein R
41
may be H, hydroxy, loweralkyl, alkoxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl.
In yet another aspect,the invention provides compounds for administering to a subject in need of fungal treatment. The compounds are represented by the formula:
wherein Y
15
and Y
16
may be the same or different and represented by the formula:
wherein:
each R
22
is independently selected from the group consis

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