Triterpenes having antibacterial activity

Details Triterpenes having antibacterial activity Triterpenes having antibacterial activity

2001-10-01

2004-02-10

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

Reexamination Certificate

active

06689767

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.
Several triterpenoids have been found to have utility. For example, 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.
Bacteria are very common pathogens of humans. Among the bacterial species that cause serious disease are the gram negative bacterium
Escherichia coli
and gram positive bacteria of the genus Staphylococcus.
Staphylococcus aureus
is the most serious pathogen of the Staphylococcus bacteria, It is estimated to causes 13% of the 2 million hospital infections each year, and result in 80,000 deaths in the United States. Staphylococcal infections occur most commonly in persons weakened by poor health or immunodeficiency.
Antibiotic resistance of bacteria is a growing problem. New agents active against bacteria are needed. A need particularly exists for agents that will act against a range of species, including gram-negative and gram-positive species. Ideally, new agents would also be inexpensive to manufacture. New anti-bacterial agents would be less expensive to manufacture if they were abundant natural products or were easily synthesized from abundant natural products.
SUMMARY OF THE INVENTION
The present invention provides a therapeutic method of treating a mammal afflicted with a bacterial infection, the method comprising administering to the mammal an effective antibacterial 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
, 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, a glycoside, or amino; or R
4
and R
5
together are oxo or (═NOH); 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, together are oxo or (═NOH);
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; —OP(═O)(OH)
2
; 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 bacterial infection, the method comprising administering to the mammal an effective antibacterial 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
)alkanoyl; 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(Rf)—; 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, norbomyloxy, 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 independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl, or benzyl;
wherein any alkyl can optionally be substituted with one or more polyethyleneimine or poly(ethylene glycol); and wherein any alkyl can optionally be interrupted with one or more polyethyleneimine or poly(ethylene glycol);
or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of inhibiting or killing a bacterium, the method comprising contacting the bacterium with an effective antibacterial amount of

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