Triterpenes having human antifungal and antiyeast activity

Details Triterpenes having human antifungal and antiyeast activity Triterpenes having human antifungal and antiyeast activity

2001-10-01

2003-11-04

Barts, Samuel (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S182000, C514S468000, C549S297000, C549S456000, C552S510000

Reexamination Certificate

active

06642217

ABSTRACT:

BACKGROUND OF THE INVENTION
Betulin is a pentacyclic triterpenoid derived from the outer bark of paper birch trees (
Betula paperifera
). It can be present at concentrations of up to about 24% of the bark of white birch.
Merck Index,
twelfth edition, page 1236, 1996. Lupeol is a related compound also found in birch bark and in other plant sources. Lupeol is present at concentrations of about 1.5-3% of birch bark and at up to about 8.2% in
Canavalia ensiformis,
a plant widespread in the humid tropics of Asia, India, and Africa. Allobetulin is another triterpenoid found in birch bark. A typical pulp mill that processes birch produces enough bark waste to allow for the inexpensive isolation of significant quantities of these triterpenoids.
Fungi infect humans and are a major cause of human health problems. They also infect plants and cause enormous losses in agricultural productivity. One class of fungal infections of mammals are the dermatophytic infections. These are fungal infections of the hair, nails, and skin. They are caused by fungi called “dermatophytes,” which include species belonging to the genera Epidermophyton, Microsporum, and Trichophyton. Among the species of dermatophytes are the following:
Microsporum canis,
which results in scalp and skin infections, mostly in children;
Microsporum gypseum,
which also results in scalp and skin infections in animals and humans;
Trichophyton tonsurans,
the major agent causing scalp ringworm;
Trichophyton rubrum,
causing skin, nail, hair, and scalp infections; and
Trichophyton mentagrophytes,
which can occur on all parts of the body surface.
Other fungal infectious agents include the opportunists that are likely to infect immunodeficient persons. These include Cryptococcus, Candida, and Aspergillus.
Betulin and related compounds have been shown to have anti-viral activity against herpes simplex virus. Carlson et al., U.S. Pat. No. 5,750,578.
Current agents used to treat fungal infections include the polyene antibiotics, including nystatin; synthetic azoles; and griseofulvin. Fungal infections are difficult to treat because, like humans, they are eukaryotes.
Currently, there is a need for new anti-fungal and anti-yeast agents. A need particularly exists for agents that will act against a range of species, including dermatophytic fungi, yeasts, and Candida. New anti-fungal agents would be less expensive to manufacture if they were abundant natural products or easily synthesized from abundant natural products.
SUMMARY OF THE INVENTION
The present invention provides a therapeutic method of treating a mammal afflicted with a fungal or yeast infection comprising administering to the mammal an effective anti-fungal or anti-yeast amount of a triterpene of formula (I):
wherein
R
1
is hydrogen or hydroxy;
R
2
is a direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C
6
-C
10
)aryl, or (C
1
-C
6
)alkyl;
R
3
is hydrogen, hydroxy, (C
1
-C
6
)alkyl, O═P(OH)
2
, O═P(OH)
2
OP(O)(OH)—, (C
1
-C
5
)alkanoyl, Si(R)
3
wherein each R is H, phenyl or (C
1
-C
6
)alkyl, C(O)N(R)
2
, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C
1
-C
4
)alkoxy](C
1
-C
4
)alkyl, or a glycoside;
R
4
is hydrogen, hydroxy, (C
1
-C
6
)alkyl, O═P(OH)
2
, O═P(OH)
2
OP(O)(OH)—, (C
1
-C
5
)alkanoyl, Si(R)
3
wherein each R is H, phenyl or (C
1
-C
6
)alkyl, C(O)N(R)
2
, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C
1
-C
4
)alkoxy](C
1
-C
4
)alkyl, or a glycoside; or R
4
and R
5
together are oxo; and
R
5
is direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C
6
-C
10
)aryl, or (C
1
-C
6
)alkyl; or R
4
and R
5
together are oxo;
wherein any alkyl can optionally be substituted with one or more halo, hydroxy, (C
6
-C
10
)aryl, nitro, cyano, (C
1
-C
6
)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR
7
R
8
, wherein R
7
and R
8
are each independently hydrogen, (C
1
-C
6
)alkyl or polyethyleneimine; or C(═O)OR
9
, wherein R
9
is hydrogen, (C
1
-C
6
)alkyl, or polyethyleneimine;
each of the bonds represented by — is independently absent or is present;
wherein any alkyl is optionally interrupted on carbon with one or more oxy, thio, sulfinyl, sulfonyl, polyethyleneimine, or poly(ethylene glycol);
wherein any alkyl is optionally partially unsaturated;
wherein any aryl can optionally be substituted with one or more halo, hydroxy, nitro, cyano, (C
1
-C
6
)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR
7
R
8
, wherein R
7
and R
8
are each independently hydrogen, (C
1
-C
6
)alkyl or polyethyleneimine; or C(═O)OR
9
, wherein R
9
is hydrogen, (C
1
-C
6
)alkyl, or polyethyleneimine;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a therapeutic method of treating a mammal afflicted with a fungal or yeast infection comprising administering to the mammal an effective anti-fungal or anti-yeast amount of a triterpene of formula (II):
wherein
one of R
1
and R
2
is —O—Y and the other is hydrogen or (C
1
-C
6
)alkyl optionally substituted by hydroxy, (C
1
-C
6
)alkoxy, halo, halo(C
1
-C
6
)alkoxy or NR
j
R
k
wherein R
j
and R
k
are independently H, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkonyl; or R
1
and R
2
together are oxo (═O);
R
3
is hydrogen, halo, carboxy, mercapto, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, or —O—Y;
R
4
and R
5
are each independently hydrogen, (C
1
-C
6
)alkyl, or hydroxy(C
1
-C
6
)alkyl;
R
6
is hydrogen or is absent when the adjacent — is a bond;
R
7
is hydrogen or (C
1
-C
6
)alkyl;
R
8
is hydrogen, (C
1
-C
6
)alkyl, or hydroxy(C
1
-C
6
)alkyl and R
11
is hydrogen, (C
1
-C
6
)alkyl, carboxy, or hydroxy(C
1
-C
6
)alkyl; or R
8
and R
11
together are —O—C(═X)—;
R
9
and R
10
, are each independently hydrogen or (C
1
-C
6
)alkyl;
each of the bonds represented by — is independently absent or is present;
X is two hydrogens, oxo (═O) or thioxo (═S);
each Y is independently H, aryl, P(O)(Cl)
2
, (C
3
-C
8
)cycloalkyl, adamantyl, —SO
2
R
a
O═P(R
b
)
2
, O═P(R
c
)
2
OP(O)(R
d
)—, Si(R
e
)
3
, tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and —N(R
f
)—; wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (═O), hydroxy, carboxy, halo, mercapto, nitro, —N(R
g
)(R
h
), (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide; and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
R
a
is (C
1
-C
6
)alkyl or aryl;
R
b
, R
c
, and R
d
are each independently hydroxy, (C
1
-C
6
)alkoxy, hydroxy(C
2
-C
6
)alkoxy, adamantyloxy, adamantyl(C
1
-C
6
)alkoxy, norbornyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C
1
-C
6
)alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C
3
-C
8
)cycloalkyloxy, NR
x
R
y
, or aryloxy;
R
e
is H, aryl or (C
1
-C
6
)alkyl;
R
f
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl;
R
g
and R
h
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, adamantyl, adamantyl(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, aminosulfonyl, (C
1
-C
6
)alkanoyl, aryl and benzyl; or R
b
and R
c
together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical; and
R
x
and R
y
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, aryl or benzyl;
wherein each aryl of Y, R
a
-R
d
, R
g
-R
h
, R
x
, and R
y
may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NR
i
R
j
, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, or (C
1
-C
6
)alkanoyloxy; wherein R
i
and R
j
are each indepe

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