Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-06
2001-09-25
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06294565
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods useful in combatting infectious diseases. Specifically, this invention relates to methods of combatting infectious diseases using dicationic bis-benzimidazole compounds.
BACKGROUND OF THE INVENTION
The need for new antifungal agents has become more pronounced because of the increase in the number of fungal infections which occur in patients who are immunocompromised. There is an increased incidence of fungal infections attributed, for example, to the aggressive use of cancer chemotherapy, organ transplantation, and opportunistic infections associated with acquired immunodeficiency syndrome (AIDS) patients. Fungal infections are among the most common complications of AIDS, as well as of cancer chemotherapy. The major opportunistic fungal pathogens causing disseminated mycoses in immunocompromised hosts include Candida and Cryptococcus.
Currently used antifungal agents for the treatment of systemic mycoses can be classified as polyene antibiotics, including Amphotericin B, flucytosine and synthetic azoles. There can, however, be significant drawbacks to the use of these agents, including limited efficacy and/or toxicity. Accordingly, it is an object of the present invention to provide new compounds useful in the treatment of fungal infections.
SUMMARY OF THE INVENTION
As a first aspect, the present invention provides a method of treating
Crytococcus neoformans
in a patient in need of such treatment. The method comprises administering to a patient in need of such treatment an amount effective to treat
C. neoformans
of a compound of Formula I:
wherein:
R
1
and R
2
are each independently selected from the group consisting of H, lower alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, hydroxyalkyl, aminoalkyl, or alkylaminoalkyl, or R
1
and R
2
together represent a C
2
to C
10
alkyl, hydroxyalkyl, or alkylene or R
1
and R
2
together are:
wherein n is a number from 1 to 3, and R
10
is H or —CONHR
11
NR
15
R
16
wherein C
11
is lower alkyl and R
15
and R
16
are each independently selected from the group consisting of H and lower alkyl; and
R
3
is H, hydroxy, lower alkyl, cycloalkyl, aryl, alkylaryl, alkoxyalkyl, hydroxycycloalkyl, alkoxycycloalkoxy, hydroxyalkyl, aminoalkyl or alkylaminoalkyl;
A is a heterocyclic aromatic group selected from the group consisting of:
wherein R
4
, R
5
, and R
6
are each independently selected from the group consisting of H, lower alkyl, halogen, aryl, arylalkyl, aminoalkyl, aminoaryl, oxyalkyl, oxyaryl, or oxyarylalkyl;
R
12
is hydrogen, lower alkyl, hydroxy, aminoalkyl or alkylaminoalkyl, or a physiologically acceptable salt thereof.
In a preferred embodiment of the invention, R
1
and R
2
together represent a C
2
to C
4
alkylene, and R
3
, R
4
, R
5
and R
6
are H and R
12
is H or lower alkyl. In one aspect of this embodiment of the invention, R
1
and R
2
together represent
and R
3
is H.
In another aspect of this embodiment of the invention, R
1
and R
2
together represent
and R
3
is H.
In yet another preferred embodiment of the invention, each of R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are H and R
12
is H or lower alkyl.
In yet another preferred embodiment of the invention, each of R
1
, R
3
, R
4
, R
5
and R
6
are H, R
2
is lower alkyl, preferably isopropyl, and R
12
is H or lower alkyl.
In yet another preferred embodiment of the invention, A is:
wherein R
4
, R
5
, and R
6
are each H.
In another preferred embodiment of the invention, A is:
wherein R
4
and R
5
are each H and R
12
is H or lower alkyl.
In yet another preferred embodiment of the invention, A is:
wherein R
4
and R
5
are each H.
As a second aspect, the present invention provides a method of treating
Candida albicans
in a patient in need of such treatment. The method comprises administering to a patient in need of such treatment a compound of Formula I above in an amount effective to treat
C. albicans.
As a third aspect, the present invention also provides a method of treating a tumor bearing patient in need of such treatment. The method comprises administering to a patient in need of such treatment a compound of Formula I above in a therapeutically effective amount.
As a fourth aspect, the present invention provides compounds useful for the treatment of
C. neoformans.
The compounds have the structural Formula (I), described above. Currently preferred compounds of Formula I include, but are not limited to, 2,5-bis(5-amidino-2-benzimidazolyl) pyrrole; 2,5-bis-[5-(2-imidazolinyl)-2-benzimidazolyl]pyrrole; 2,6-bis[5-(2-imidazolinyl) -2-benzimidazolyl]pyridine; 1-methyl-2,5-bis(5-amidino-2-benzimidazolyl)pyrrole; 1-methyl-2,5-bis[5-(2-imidazolyl)-2-benzimidazolyl]pyrrole; 1-methyl-2,5-bis[5-(1,4,5,6-tetrahydro-2-pyrimidinyl)-2-benzimidazolyl]pyrrole; 2,6-bis(5-amidino-2-benzimidazoyl)pyridine; 2,6-bis[5-(1,4,5,6-tetrahydro-2-pyrimidinyl)-2-benzimidazolyl]pyridine; 2,5-bis(5-amidino-2-benzimidazolyl)furan; 2,5-bis[5-(2-imidazolinyl)-2-benzimidazolyl]furan; 2,5-bis(S-N-isopropylamidino-2-benzimidazolyl)furan; and physiologically acceptable salts thereof. Novel compounds useful for treating
C. albicans
and for combatting tumors are also disclosed.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “lower alkyl,” refers to C1 to C6 linear or branched alkyl, such as methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, tert-butyl, butyl, pentyl, isopentyl, and hexyl. The term “cycloalkyl” as used herein refers to C3 to C6 cyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “aryl” as used herein refers to C3 to C10 cyclic aromatic groups such as phenyl, naphthyl, and the like, and includes substituted aryl groups such as tolyl. The term “hydroxyalkyl” as used herein refers to C1 to C4 linear or branched hydroxy-substituted alkyl, i.e., —CH
2
OH, —(CH
2
)
2
OH, etc. The term “aminoalkyl” as used herein refers to C1 to C4 linear or branched amino-substituted alkyl, wherein the term “amino” refers to the group NR′IR″, wherein R′ and R″ are independently selected from H or lower alkyl as defined above, i.e., —NH
2
, —NHCH
3
, —N(CH
3
)
2
, etc. The term “alkoxyalkyl” as used herein refers to C1 to C6 linear or branched alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, and t-butyloxy.
As noted above, the methods of the present invention are useful for treating
Cryptococcus neoformans.
The methods of the present invention are useful for treating these conditions in that they inhibit the onset, growth, or spread of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject inflicted with, or at risk of contracting the condition.
Subjects to be treated by the methods of the present invention are typically human subjects although the methods of the present invention may be useful with any suitable subject known to those skilled in the art.
As noted above, the present invention provides pharmaceutical formulations comprising the aforementioned compounds of Formula I, or pharmaceutically acceptable salts thereof; in pharmaceutically acceptable carriers for aerosol, oral, and parenteral administration as discussed in greater detail below. Also, the present invention provides such new compounds or salts thereof which have been lyophilized and which may be reconstituted to form pharmaceutically acceptable formulations for administration, as by intravenous or intramuscular injection.
The therapeutically effective dosage of any specific compound, the use of which is in the scope of present invention, will vary somewhat from compound to compound, patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.1 to about 50 mg/kg will have therapeutic efficacy, with still hig
Boykin David W.
Dykstra Christine C.
Perfect John
Tidwell Richard R.
Wilson W. David
Cook Rebecca
Myers Bigel & Sibley & Sajovec
University of North Carolina at Chapel Hill
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