Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-24
2001-01-09
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S468000, C549S048000, C549S460000, C549S461000
Reexamination Certificate
active
06172104
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns dicationic dibenzofurans and dicationic dibenzothiophenes, and the use thereof in the treatment of
Pneumocystis carinii
pneumonia.
BACKGROUND OF THE INVENTION
A number of aromatic diamidines have been shown to bind to the minor-groove of DNA, and to exhibit useful antimicrobial activity. Various hypotheses of the mode of antimicrobial action of the aryl amidines have been proposed. However, evidence is growing that these compounds function by complex formation with DNA and subsequent selective inhibition of DNA dependent microbial enzymes. Intervention in transcription control has been demonstrated and seems to be a plausible mode of action for structurally diverse minor groove binders. (Das, B. P.; Boykin, D. W.,
J. Med. Chem.
1977, 20, 531-536; Boykin, D. W. et al.,
J. Med. Chem.
1995, 36, 912-916; Kumar, A. et al.,
Eur. J. Med. Chem.
1996, 31, 767-773; Lombardy, R. J. et al.,
J. Med. Chem.
1996, 31, 912-916; Tidwell, R. R. et al.,
Antimicrob. Agents Chemother.
1993, 37, 1713-1716; Tidwell, R. R.; Bell, C. A., Pentamidine and Related Compounds in Treatment of
Pneumocystis carinii
Infection, in
Pneumocystis carinii
, Ed Marcel Decker; New York, 1993, 561-583; Henderson, D.; Hurley, L. H.,
Nature Med.
1995, 1, 525-527; Mote, J. Jr., et al.,
J. Mol. Biol.
1994, 226, 725-737; Boykin, D. W., et al.,
J. Med. Chem.
1998, 41, 124-129).
PCT Application No. WO96/40117 (Dec. 19, 1996) describes dicationic substituted carbazoles and the use thereof in treating
Pneumocystis carinii
pneumonia (PCP),
Cryptococcus neoformans, Cryptosporidium parvum
, and
Candida albicans.
J. Moffatt,
J. Chem. Soc.
1951, 625-626, describes 3:6-diamidinodibenzofuran, and the use thereof in the treatment of as a trypanocide.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a compound having the formula:
wherein:
R
1
, R
2
, R
3
, and R
4
are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, oxyaryl, oxyarylalkyl, or halogen;
A and B are each selected from the group consisting of H, loweralkyl, oxyalkyl, and
wherein:
each R
5
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R
5
groups together represent C
2
to C
10
alkyl, hydroxyalkyl, or alkylene; and
R
6
is H, hydroxy, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
or a pharmaceutically acceptable salt thereof; subject to the proviso that said compound is not 3:6-diamidinodibenzofuran.
A second aspect of the present invention is a method of treating
Pneumocystis carinii
pneumonia in a subject in need of such treatment, comprising administering to said subject a compound having the formula:
wherein:
R
1
, R
2
, R
3
, and R
4
are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, oxyaryl, oxyarylalkyl, or halogen;
A and B are each selected from the group consisting of H, loweralkyl, oxyalkyl, and
wherein:
each R
5
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R
5
groups together represent C
2
to C
10
alkyl, hydroxyalkyl, or alkylene; and
R
6
is H, hydroxy, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
or a pharmaceutically acceptable salt thereof.
A third aspect of the present invention compound having the formula:
wherein:
R
1
, R
2
, R
3
, and R
4
are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, oxyaryl, oxyarylalkyl, or halogen;
A and B are each selected from the group consisting of H, loweralkyl, oxyalkyl, and
wherein:
each R
5
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R
5
groups together represent C
2
to C
10
alkyl, hydroxyalkyl, or alkylene; and
R
6
is H, hydroxy, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
or a pharmaceutically acceptable salt thereof.
A fourth aspect of the present invention is a method of treating
Pneumocystis carinii
pneumonia in a subject in need of such treatment, comprising administering to said subject a compound having the formula:
wherein:
R
1
, R
2
, R
3
, and R
4
are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, oxyaryl, oxyarylalkyl, or halogen;
A and B are each selected from the group consisting of H, loweralkyl, oxyalkyl, and
wherein:
each R
5
is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R
5
groups together represent C
2
to C
10
alkyl, hydroxyalkyl, or alkylene; and
R
6
is H, hydroxy, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;
or a pharmaceutically acceptable salt thereof.
Compounds according to formula (I) or (II) above and the pharmaceutically acceptable salts thereof, pharmaceutical formulations containing the same, and the use of compounds of formula (I) or (II) and the pharmaceutically acceptable salts thereof for the preparation of a medicament for treating
Pneumocystis carinii
pneumonia, are also an aspect of the present invention.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth below.
DETAILED DESCRIPTION OF THE INVENTION
The term “loweralkyl,” as used herein, refers to C
1
-C
6
linear or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Isoalkyl groups, such as isopropyl, isobutyl, isopentyl, and the like are currently preferred. The term “loweralkoxy” or “oxyalkyl” as used herein, refers to C
1
-C
6
linear or branched alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, and t-butyloxy. Methoxy is currently preferred.
As noted above, the methods of the present invention are useful for treating
Pneumocystis carinii
pneumonia. 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.
In one embodiment of the foregoing, A and B are each:
wherein:
R
1
is H, R
2
is H or loweralkyl, R
3
is H, R
4
is H, R
5
is H, and R
6
is isoalkyl; and the pharmaceutically acceptable salts thereof.
In another embodiment of the foregoing, A and B are each:
wherein:
R
1
is H, R
2
is H, R
3
is H, R
4
is H, R
5
is H, and R
6
is C
3
-C
8
alkoxyalkyl; and the pharmaceutically acceptable salts thereof.
In another embodiment of the foregoing, A and B are each:
wherein:
R
1
is H, R
2
is H or loweralkyl, R
3
is H, R
4
is H, R
5
is H, and R
6
is alkylhydroxy; and the pharmaceutically acceptable salts thereof.
In another embodiment of the foregoing, A and B are each:
wherein:
R
1
is H, R
2
is H or loweralkyl, R
3
is H, R
4
is H, R
5
is H, and R
6
is propoxyethyl; and the pharmaceutically acceptable salts thereof.
In another embodiment of the foregoing, A and B are each:
wherein:
R
1
is H, R
2
is H or loweralkyl, R
3
is H, R
4
is H, R
5
is H, and R
6
is propoxyisopropyl; and the pharmaceutically acceptable salts thereof.
In another embodiment, A and B are each:
wherein:
R
1
is H, R
2
is H
Hall James Edwin
Tidwell Richard R.
Lambkin Deborah C.
Myers Bigel & Sibley & Sajovec
The University of North Carolina at Chapel Hill
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