Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-12-30
2004-02-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S183000, C514S266100, C514S266200, C514S266300, C544S287000, C544S322000, C544S253000, C544S283000, C544S358000, C544S359000
Reexamination Certificate
active
06689782
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the fields of organic chemistry, biochemistry, medicinal chemistry, microbiology and medicine. In particular, it relates to organic compounds that are fungal efflux pump inhibitors.
BACKGROUND OF THE INVENTION
The information provided and the references cited herein are not admitted, nor should they be construed, to be prior art to the present invention; rather, they are provided solely to assist the reader in understanding the present invention.
Fungal infections are relatively rare in immuno-competent patients. In fact, a number of Candida species are often present as benign commensal organisms in the digestive system of healthy individuals (Shepherd, et al.,
Ann. Rev. Microbiol.,
1985, 39:579-614). Fungal infections, however, can be life threatening for immuno-compromised patients. There are three major groups of immuno-compromised individuals that are at risk: (1) cancer patients undergoing chemotherapy, (2) organ transplant patients being treated with immuno-suppressants, and (3) AIDS patients. Data from the National Nosocomial Infections Surveillance System conducted in the United States showed a 487 percent increase in Candida bloodstream infections between 1980 and 1989 (Rinaldi, et al.,
Antimicrob. Ag. Chemother.,
1995, 39:1-8). Oropharyngeal candidiasis is the most common fungal infection complication associated with AIDS with up to 90% of AIDS patients having had at least one episode of the infection (Powderly,
AIDS research and Human Retroviruses,
1994, 10:925-929).
There are relatively few clinically useful anti-fungal agents. Among those available are amphotericin B, flucytosine, fluconazole, itraconazole and ketoconazole (Odds,
J. Antimicrob. Chemother.,
1993, 31: 463-471). However, resistance to all of these drugs is developing rapidly. Take, for example, fluconazole.
Fluconazole is currently the most extensively used anti-fungal agent for the treatment of patients with severe candidiasis. It has higher water solubility and a longer plasma half-life than other azole fungicides and has relatively low toxicity. Between 1988 and 1993, fluconazole was used to treat over 15 million patients, including at least 250,000 AIDS patients (Hitchcock,
Biochem. Soc. Trans.,
1993, 21:1039-1047). Given such wide-spread use, it comes as no surprise that fluconazole-resistant Candida strains have been reported (Rex, et al.,
Antimicrob. Ag. Chemother.,
1995, 39:1-8; Vanden Bossche, et al., 1994, supra). In some cases the resistance was found to be due to mutations in
C. albicans
itself while in other cases
C. albicans
was simply displaced by Candida species less susceptible to fluconazole, namely,
C. glabrata
and
C. krusei
(Odds, 1993, supra).
The mechanism of resistance to fluconazole appears to be multifaceted. In one study, amplification of the CYP51 gene (encoding the fluconazole target P-450 protein C14 demethylase) was implicated (Vanden Bossche, et al.,
Antimicrob. Agents and Chemother.,
1994, 36: 2602-2610). In another study, resistance was correlated with the appearance of an altered P-450 target protein with decreased affinity for fluconazole (Hitchcock,
Biochem Soc. Trans.,
1993, 21:1039-1047). However, fluconazole resistance appears to be primarily due to decreased accumulation of the drug in resistant cells (Vanden Bossche, et al., 1994; Odds, 1993, supra). Species intrinsically resistant to fluconazole such as
C. glabrata, C. krusei
and
Aspergillus fumigatus
have also been shown to accumulate less fluconazole (Vanden Bossche, et al., 1994, supra).
C. glabrata
and
C. krusei,
on the other hand, have been shown to accumulate itraconazole and to be susceptible to that compound (Marichal et al.,
Mycoses,
1995, 38:111-117). Thus, it appears that both intrinsic and acquired resistance may be due to decreased drug accumulation in the cell. There are several ways in which a cell can manipulate the intracellular concentration of a compound. One is preventing the compound from gaining access to the interior of the cell in the first place. Another is metabolic decomposition of the compound once it is in the cell. A further means is simply excreting the intact compound before it can have any effect on the cell. This latter approach is called efflux and the cell components involved in efflux, i.e., membrane transporter proteins, are called efflux pumps.
Efflux pumps are ubiquitous in all types of cells, from bacterial to mammalian (Higgins,
Ann. Rev. Cell Biol.,
1992, 8:67-113). Efflux is driven either by the energy of ATP hydrolysis (ABC-transporter superfamily) or by proton transfer (Major Facilitator superfamily). Efflux pumps exhibit differing degrees of specificity.
Some efflux pumps are extremely specific, such as the TetA pump in gram-negative bacteria, which effluxes tetracycline only. Others are less specific; e.g., the MsrA protein in
Staphyloccus aureus
effluxes not only erythromycin but related macrolides as well. There are also efflux pumps that are quite general in their efflux capability, excreting a variety of structurally unrelated compounds from a cell. Many efflux pumps are clinically significant.
Resistance to chemotherapeutics in some mammalian cancer cells has been attributed to a multi-drug resistant efflux pump known as P-glycoprotein (Pgp) (Gottesman, et al.,
Ann. Rev. Biochem.,
1993, 62:385-427).
Pseudomonas aeruginosa,
which causes respiratory infections, adventitious infection in burn patients, etc., uses Mex efflux pumps to eliminate quinolones, as well as other structurally unrelated antibiotics (Nikaido,
Science,
1994, 264:382-388). Multiple-drug resistant (MDR) efflux pumps have been implicated in fluconazole resistance in
C. albicans
and
C. glabrata
(Parkinson, et al.,
Antimicrob. Agents Chemother.,
1995, 39:1696-1699; Sanglard, et al.,
Antimicrob. Agents Chemother.,
1995, 39:2378-2386; Albertson, et al.,
Antimicrob. Agents Chemother.,
1996, 40:2835-2841).
Based on the above, it would clearly be desirable to be able to inhibit the activity of fungal efflux pumps so that anti-fungal agents can accumulate in fungal cells in sufficient quantity to exert their effect. The present invention provides compounds that achieve this goal.
SUMMARY OF THE INVENTION
The present invention relates to compounds that are fungal efflux pump inhibitors. When administered to a patient suffering from an infection caused by a fungal species that employs efflux pump(s) as a resistance mechanism, the compounds inhibit the activity of the pump(s) allowing a co-administrated anti-fungal agent to accumulate in sufficient concentration to inhibit fungal cells and treat the infection.
Thus, in one aspect the present invention relates to a compound having the chemical formula:
or a pharmaceutically acceptable salt thereof, wherein:
A
1
is carbon or nitrogen, provided that when A
1
is nitrogen, R
5
does not exist;
R
2
and R
3
are independently selected from the group consisting of hydrogen, halo and —O(1C-4C)alkyl;
R
4
and R
6
are independently selected from the group consisting of hydrogen, halo, —O(1C-4C)alkyl, —OCF
3
, and O—CH
2
(3C-6C)cycloalkyl;
R
5
is selected from the group consisting of hydrogen and
R
7
and R
8
are independently selected from the group consisting of hydrogen, halo, —C≡N, —O(1C-4C)alkyl, —OCHF
2
, —OCF
3
and, taken together, —OCH
2
O—;
R
1
is selected from the group consisting of —(1C-4C)alkyl, -(3C-6C)cycloalkyl,
wherein:
A
4
is selected from the group consisting of —NH, oxygen and sulfur;
A
2
, A
3
and A
5
are independently selected from the group consisting of carbon and nitrogen provided that no more than two of A
2
, A
3
and A
5
are nitrogen at the same time;
or,
R
1
is —C(O)(CH
2
)
n
(R
22
)R
9
, wherein,
n is 0, 1, 2 or 3;
R
9
is selected from the group consisting of hydrogen, —OH, —(1C-4C)alkyl, -(3C-6C)cycloalkyl, —CH
2
(3C-6C)cycloalkyl,
wherein:
A
6
, A
7
and A
8
are independently selected from the group consisting of carbon, oxygen, sulfur and NR
15
;
A
9
, A
10
and A
11
are independently
Cho Aesop
Lemoine Remy
Palme Monica
Watkins William J.
Bingham & McCutchen LLP
Essential Therapeutics, Inc.
Patel Sudhaker B.
Rose Bernard F.
Shah Mukund J.
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