Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-10-20
2001-01-30
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S009100, C514S011400, C514S030000, C514S616000, C514S617000
Reexamination Certificate
active
06180679
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the fields of pharmaceutical and organic chemistry and provides cryptophycin compounds useful for treating fungal infections.
The incidence of serious, life-threatening, fungal infections is increasing at an alarming rate. 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% in the same time period. With the exception of coagulase negative staphylococci, statistically,
C. albicans
represents the fastest growing area of concern in hospital acquired bloodstream infections (Banerjee et al., 1991,
American Journal of Medicine
91 (3B): 86S-89S).
The rising incidence of nosocomial fungal infections is being fueled by changing medical practices, including invasive surgical procedures addressing such problems as joint replacement and open heart surgery, increased use of cancer chemotherapy, and the AIDS epidemic. All of these processes compromise the immune system and provide an environment in which fungal infections can be established.
Unfortunately, the diagnosis of fungal infections is difficult and time consuming. Rather than waiting for the results of diagnostic tests, empirical antifungal therapy must frequently be initiated with a compound such as amphotericin B (which may have safety/toxicity issues) or one of the azoles to which fungal species are developing resistance. Thus, having an antifungal with a broad spectrum of activity coupled with a low toxicity profile would be very desirable.
Further, the existence of multiple drug resistance (mdr)-related genes in a non-pathological as well as in key opportunistic pathological fungi has been discovered. These genes have been termed “mdr-like” because of the homology that exists between the proteins encoded by these genes and the human mdr-1 gene product.
With the discovery of mdr-like genes in a variety of fungi, including key pathogenic fungi, such as
Aspergillus flavus, Aspergillus fumigatus
and
Cryptococcus neoformans
the prospect of discovering an antifungal agent that can have fungal mdr inhibitor activity becomes extraordinarily desirable.
Applicants have discovered agents which can be useful antifungal agents. Two particularly desired compounds are known as Cryptophycin 52 and Cryptophycin 55.
Further, Applicants provide compounds which can provide useful mdr inhibitor activity.
SUMMARY OF THE INVENTION
The presently claimed invention provides a method for controlling fungal growth comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V.
or a pharmaceutically acceptable salt thereof.
The presently claimed invention provides a method for providing mdr inhibitor activity comprising administering a therapeutically effective amount of a compound of the formula:
wherein
Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group;
R
1
is halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, or phosphate;
R
2
is OH or SH; or
R
1
and R
2
may be taken together to form an epoxide ring, and aziridine ring, an episulfide ring, a sulfate ring, or monoalkylphosphate ring; or
R
1
and R
2
may be taken together to form a second bond between C
18
and C
19
;
R
3
is a lower alkyl group;
R
4
is H;
R
5
is H;
R
4
and R
5
may be taken together to form a second bond between C
13
and C
14
;
R
6
is benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group, a substituent selected from the group consisting of B-ring heteroaromatic, substituted heteroaromatic, B-ring
(C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, substituted C
3
-C
8
cycloalkyl, substituted (C
1
-C6)alkyl, a group of the formula III′:
R
7
is H or a lower alkyl group;
R
8
is H or a lower alkyl group;
R
9
is H or a lower alkyl group;
R
10
is H or a lower alkyl group;
R
14
is H or a lower alkyl group;
R
15
, R
16
, and R
17
are each independently selected from the group consisting of hydrogen, OR
18
, halo, NH
2
, NO
2
, OPO
4
H
2
,
OR
19
phenyl, and ZZ;
R
18
is C
1
-C
6
alkyl;
R
19
is C
1
-C
6
alkyl;
R
30
is C
1
-C
6
alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2;
m is 0, 1, or 2;
X is O, NH
−
or alkylamino;
Y is C, O, NH, S, SO, SO
2
or alkylamino;
Z is selected from the group consisting of —(CH
2
)
n
—, —(CH
2
)
p
—O—(CH
2
)
m
— and (C
3
-C
5
)cycloalkyl;
ZZ is selected from the group consisting of a simple substituted aromatic group and a simple unsubstituted aromatic group; or
a pharmaceutically acceptable salt or solvate thereof. The compounds of formula IA are disclosed in PCT International Publication Number WO 96/40184, published Dec. 19, 1996. The compounds of formula IA also include to known cryptophycin compounds such as Cryptophycin 1, 3, 5, 13, 15. Such cryptophycin compounds are disclosed in U.S. Pat. Nos. 4,946,835, 4,845,085, 4,845,086, and 4,868,208, which are hereby incorporated by reference. The term shall also refer to other known cryptophycin compounds such as cryptophycin 8.
The present invention provides an antifungal composition comprising at least five percent (5%) by weight of a compound selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V in admixture with one or more pharmaceutically acceptable carriers or excipients therefor.
The present invention further provides a method for controlling a mycotic infection comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V. Additionally, the present invention provides a method for controlling a yeast infection comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V. Finally, the present invention provides a method for controlling a parasitic infection comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “simple alkyl” shall refer to C
1
-C
7
alkyl wherein the alkyl may be saturated, unsaturated, branched, or straight chain. Examples include, but are in no way limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, propenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, methylated pentyl groups and the like.
As used herein, the term “B-ring C
1
-C
6
alkyl” refers to saturated, unsaturated, branched and straight chain alkyl wherein the B-ring C
1
-C
6
alkyl group may include up to three (3) non-carbon substituents. Such non-carbon substituents are most preferredly selected from the group consisting of OH, SCH
2
phenyl, NH
2
, CO, CONH
2
, CO
2
H, PO
3
H
2
, SO
2
R
21
wherein R
21
is selected from hydrogen and C
1
-C
3
alkyl.
As used herein, the term “substituted phenyl” shall refer to a phenyl group with from one to three non-hydrocarbon substituents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I.
As used herein, the term “substituted benzyl” shall refer to a benzyl group with from one to three non-hydrocarbon substitutents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I wherein such substituents may be attached at any available carbon atom.
As used herein “B-ring heterocyclic group” refers to aromatic rings which contain one or more non-carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur. Especially preferred B-ring heterocyclic groups are selected from, but not limited to, the group consisting of:
R
20
is
Shih Chuan
Williams Daniel Charles
Eli Lilly and Company
Engelmann John H.
Jagoe Donna
Krass Frederick
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