Thio derivatives of sordarin as antifungal agents

Details Thio derivatives of sordarin as antifungal agents Thio derivatives of sordarin as antifungal agents

2001-09-14

2002-08-20

Sololu, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C549S418000, C549S419000, C549S420000, C548S240000, C514S378000, C514S455000, C514S460000, C544S231000, C544S237000

Reexamination Certificate

active

06436930

ABSTRACT:

BACKGROUND
Infections by
Candida albicans
, which include systemic, mucosal and cutaneous infections, are a common and often serious health problem.
Candida albicans
is part of the normal flora of the skin, mucous membranes in the mouth, throat, intestine and genital tract. Normally Candida fungus lives in a healthy balance with the other bacteria and yeasts in the body as part of the normal flora.
However, a number of environmental stimuli can trigger the growth of Candida. Further, abnormal physiological changes in the epithelium may be involved together with a host of other factors, including genetics, nutrition, stress and other factors that result in infections of various organs of the body, particularly in immunosuppressed individuals or in individuals that have had the normal floral balance changed by the taking of wide spectrum antibiotics.
In addition, cancer patients, organ transplant patients and patients with immunologic disorders, chronic infections, leukemia, acquired immunodeficiency deficiency syndrome (AIDS), Hodgkin's disease, neutropenia and other hematologic diseases and endocrinopathies including diabetes are particularly susceptible to fungal infections by
Candida albicans
. Such immunologically compromised patients are at a risk of systemic candidiasis resulting from the inability of their immune system to destroy ubiquitous fungus of
Candida albicans
which is part of the normal environment. In fact, systemic candidiasis is one of the major causes of morbidity and mortality in immunocompromised individuals, particularly those patients who are neutropenic, suffering from AIDS, or who are undergoing immunosuppression for transplantation or therapy for cancer.
Recently, the incidence of serious, life-threatening, fungal infections has been increasing at an alarming rate. For example, the number of
Candida albicans
bloodstream infections in non-teaching hospitals increased by 370% between 1980 and 1990. At the same time the incidence of bloodstream infections by
C. albicans
in teaching hospitals increased by 487%. With the exception of coagulase negative staphylococci, statistically,
C. albicans
represents the fastest growing area of concern in hospital acquired bloodstream infections (Banejee et al., 1991, American Journal of Medicine 91 (3B): 86S-89S).
The natural product sordarin, its aglycone sordaricin, shown below
and its semi-synthetic derivatives have been discovered to selectively inhibit fungal protein synthesis. A broad spectrum of fungicidal activity has been demonstrated against a range of pathogens, and several sordarin derivatives have displayed excellent bioavailability and low mammalian toxicity.
Despite the prior identification of compounds having antifungal activity, what is needed are new compounds with improved activity against
Candida albicans.
SUMMARY OF THE INVENTION
The present invention relates to antifungal compounds having the following structural formula:
and pharmaceutically acceptable salts or solvates thereof, wherein X is S, SO, SO
2
, or S(O) (NR
1
) and Y is CHO or CN.
R is selected from H, C(═O)OR
1
, C(═O)NR
2
R
3
, C(═O)R
4
, (CH
2
)
m
(C═O)R
4
, CH(R
2
)OR
5
, CH(R
2
)SR
5
, C(R
6
)(R
7
)(R
8
),
R
1
is C
1
-C
14
alkyl, C
2
-C
14
alkenyl, C
2
-C
14
alkynyl, C
3
-C
20
cycloalkyl, aryl or aryl-C
1
-C
6
alkyl-.
R
2
and R
3
are independently H or R
1
, R
4
is H, R
1
, or —(CH
2
)
m
NR
2
R
3
.
R
5
is H, R
1
, or —(CH
2
)
x
O(CH
2
)
y
H.
R
6
is H, C
1-14
alkyl, aryl, aryl -C
1
-C
6
alkyl-, —(CH
2
)
y
CHR
9
(CH
2
)
Z
H, —(CH
2
)
y
C(R
7
)═CH(CH
2
)H, —(CH
2
)
y
C(R
7
)≡CH(CH
2
)
m
R
9
, —(CH
2
)
y
C═C(CH
2
)
Z
H, —(CH
2
)
y
C≡C(CH
2
)
m
R
9
,or —(CH
2
)
y
C(R
7
)═CHC≡C (CH
2
)
Z
H.
R
7
and R
8
are independently H or C
1
-C
14
alkyl.
R
9
is OH or NR
2
R
3
.
R
10
is H, C
1
-C
6
alkyl, C
3
-C
6
alkenyl, CH
2
(═O)OR
1
, CH
2
(═O)NR
2
R
3
, CH
2
(═O)R
4
, or CH(R
2
)OR
5
.
R
a
is H, halogen, OH, OR
1
, or OC(═O)R
1
.
R
b
and R
c
are each independently hydrogen, C
1-6
alkyl or C
1-4
alkoxy-C
1-4
alkyl-, or R
b
and R
c
together with the carbon atom to which they are attached represent C═O, C═S, or C
3-8
cycloalkyl.
R
d
is hydrogen or —CH
2
R
a
, where R
a
is defined as above.
R
e
and R
f
are each independently hydrogen, C
1-6
alkyl or C
1-4
alkoxy-C
1-4
alkyl-, or R
e
and R
f
together with the carbon atom to which they are attached represent C═O, C═S, or C
3-8
cycloalkyl.
A and B are each independently oxygen, sulfur, or CR
11
R
12
in which R
11
and R
12
are each independently hydrogen, C
1-6
alkyl, C
1-4
alkoxy, or C
1-4
alkoxy-C
1-4
alkyl-, or R
11
and R
12
together with the carbon atom to which they are attached represent C═O, C═S, C
3-8
cycloalkyl, or C═CHR
13
where R
13
represents hydrogen or C
1-4
alkyl; or when A or B is oxygen and n is zero then —B—CR
b
R
c
or —A—CR
b
R
c
respectively may also represent —N═CR
c
— or —NR14—CR
b
R
c
— in which CR
b
and CR
c
are C═O and R
14
is C
1-4
alkyl or an acyl group COR
15
where R
15
is C
1-6
alkyl or when B is oxygen and n is zero A may represent the group CR
13
in which CR
13
has the meanings defined above which is attached to the pyran ring by a double bond.
R
g
is hydrogen, halogen, azido, C
1-6
alkyl, hydroxy, C
1-6
alkoxy, C
1-6
alkoxy substituted by one or two hydroxy groups or a ketal thereof or one or two C
1-3
alkoxy groups, aryl-C
1-4
alkoxy, C
3-6
alkenyloxy, a group OCOR
16
in which R
16
is aryl C
1-4
alkoxy or a C
1-10
alkyl group optionally containing one or two double bonds or C
1-6
alkoxycarbonyl-C
1-4
alkoxy, and R
h
represents hydrogen or R
g
and R
h
may, together with the carbon atom to which they are attached, represent C═O or C═CH
2
. R
i
is CH
2
R where R
17
is hydrogen, hydroxyl, C
1-14
alkoxy, or a group OCOR
18
wherein R
18
is C
1-4
alkyl. R
j
is O(CO)CH
3
or CH
3
. W is oxygen, sulfur, or CH
2
. The dotted line in group (i) denotes the optional presence of an additional bond.
R
1a
is hydrogen, halogen, hydroxy, or C
1-4
alkoxy.
R
2a
is hydrogen, halogen, hydroxy, C
1-10
alkoxy, C
1-10
alkylthio, C
1-6
alkoxy-C
1-4
alkoxy, aryl-C
1-6
alkyloxy, aryl-C
3-6
alkenyloxy, azido, NR
5a
COR
5a
in which each
R
5a
is independently hydrogen or C
1-6
alkyl, OR
6a
in which R
6a
is a cyclic ether containing four to eight atoms linked to the oxygen atom via a ring carbon atom adjacent to the ring oxygen atom or a group Z
a
C═O—Z
b
—R
7a
where Z
a
is oxygen, sulfur, or NH, Z
b
is either a bond, an oxygen atom, or a moiety NR
8a
in which R
8a
is hydrogen or C
1-6
alkyl, and R
7a
is C
1-10
alkyl optionally containing one or two double bonds, aryl, aryl-C
1-4
alkyl, aryl-C
2-4
alkenyl, halo-C
1-6
alkyl, or C
1-6
alkoxy- C
1-4
alkyl.
R
3a
represents hydrogen, or R
2a
and R
1a
together with the carbon atom to which they are attached represent C═O or C═NOR
9a
in which R
9a
is C
1-6
alkyl.
R
4a
is hydroxyl, C
1-6
alkoxy or O(C═O)R
7a
in which R
7a
is defined as above.
R
20
is C
1-6
alkyl, C
1-6
alkoxy, phenoxy, C
3-6
alkenyloxy optionally substituted by one or two halogen atoms, C
1-4
alkoxy substituted by an optionally substituted phenyl group, C
3-8
alkynyl, C
3-6
alkenyl optionally substituted by C
1-4
alkoxy or one or two halogen atoms, optionally substituted phenyl, optionally substituted C
3-7
cycloalkyl, C
5-7
cycloalkenyl, C
2-4
alkyl substituted by C
1-4
alkoxy, C
1-4
alkylthio or halogen, C
1-4
alkyl substituted by C
1-4
alkoxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, propadienyl, cyano, optionally substituted C
3-7
cycloalkyl, optionally substituted 5 or 6 membered heteroaryl, or 1 or 2 optionally substituted phenyl groups, or methyl substituted by C
1-6
alkanoyl or benzoyl.
In addition, n is 0 or 1, m is 1-6, x is 2-6, y is 0-6 and z is 0-6.
This invention also relates to a pharmaceutical composition comprising an antifungal effective amount of a compound of the

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