Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-04
2003-08-05
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S339000, C514S414000, C514S451000, C514S459000, C514S460000
Reexamination Certificate
active
06602879
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention relates to Pyrrole-Type compounds, compositions comprising Pyrrole-Type compounds, and methods useful for treating or preventing cancer or a neoplastic disorder comprising administering a composition comprising a Pyrrole-Type compound. The compounds, compositions, and methods of the invention are also useful for inhibiting the growth of a cancer cell or neoplastic cell. The present invention also relates to Pyrrole-Type compounds, compositions, and methods useful for treating or preventing a viral infection. The compounds, compositions, and methods of the invention are also useful for inhibiting the replication or infectivity of a virus.
2. BACKGROUND OF THE INVENTION
2.1. Cancer and Neoplastic Disease
Cancer affects approximately million adults and children worldwide, and this year, more than 9 million new cases will be diagnosed (International Agency for Research on Cancer; www.irac.fr). According to the American Cancer Society, about 563,100 Americans are expected to die of cancer this year, more than 1500 people a day. Since 1990, in the United States alone, nearly five million lives have been lost to cancer, and approximately 12 million new cases have been diagnosed.
Currently, cancer therapy involves surgery, chemotherapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998, “Principles of Cancer Patient Management”, in
Scientific American: Medicine
, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health of the patient or may be unacceptable to the patient. Additionally, surgery may not completely remove the neoplastic tissue. Radiation therapy is effective only when the irradiated neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue, and radiation therapy can also often elicit serious side effects. (Id.) With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of neoplastic disease. However, despite the availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks (see, for example, Stockdale, 1998, “Principles Of Cancer Patient Management” in
Scientific American Medicine
, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10). Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous, side effects, including severe nausea, bone marrow depression, immunosuppression, etc. Additionally, many tumor cells are resistant or develop resistance to chemotherapeutic agents through multi-drug resistance.
Tamura et al., JP93086374, discloses metacycloprodigiosin and/or prodigiosin-25C as being useful for treating leukemia, but provides data for only prodigiosin-25C activity against L-5178Y cells in vitro. Hirata et al., JP-10120562, discloses the use of cycloprodigiosin as an inhibitor of the vacuolar ATPase proton pump and states that cycloprodigiosin may have anti-tumor enhancing activity. Hirata et al., JP-10120563 discloses the use of cycloprodigiosin as a therapeutic drug for leukemia, as an immunosuppressant, and as an apoptosis inducer. JP61034403, to Kirin Brewery Co. Ltd, describes prodigiosin for increasing the survival time of mice with leukemia. Boger, 1988, J. Org. Chem. 53:1405-1415 discloses in vitro cytotoxic activity of prodigiosin, prodigiosene, and 2-methyl-3-pentylprodigiosene against mouse P388 leukemia cells. The National Cancer Institute, http://dtp.nci.nih.gov, discloses data obtained from the results of a human-tumor-cell-line screen, including screening of butylcycloheptyl-prodiginine HCl; however, the screen provides no indication that the compounds of the screen are selective for cancer cells (e.g., as compared to normal cells).
Therefore, there is a significant need in the art for novel compounds and compositions, and methods that are useful for treating cancer or neoplastic disease with reduced or without the aforementioned side effects. Further, there is a need for cancer treatments that provide cancer-cell-specific therapies with increased specificity and decreased toxicity.
2.2. Viruses and Disease
In addition to cancer, an enormous number of human and animal diseases result from virulent and opportunistic viral infections (see Belshe (Ed.) 1984
Textbook of Human Virology
, PSG Publishing, Littleton, Mass.). Viral diseases of a wide array of tissues, including the respiratory tract, CNS, skin, genitourinary tract, eyes, ears, immune system, gastrointestinal tract, and musculoskeletal system, affect a vast number of humans of all ages (see Table 328-2 In: Wyngaarden and Smith, 1988,
Cecil Textbook of Medicine,
18
th
Ed.
, W. B. Saunders Co., Philadelphia, pp. 1750-1753).
Although considerable effort has been invested in the design of effective anti-viral therapies, viral infections continue to threaten the lives of millions of people worldwide. In general, attempts to develop anti-viral drugs have focused on several stages of viral life cycle (See e.g., Mitsuya, H., et al., 1991, FASEB J. 5:2369-2381, discussing HIV). However, a common drawback associated with using of many current anti-viral drugs is their deleterious side effects, such as toxicity to the host or resistance by certain viral strains.
Accordingly, there is a need in the art for anti-viral compounds, compositions, and methods that allow for safe and effective treatment of viral disease without the above-mentioned disadvantages.
Citation or identification of any reference in Section 2 of this application is not an admission that such reference is available as prior art to the present invention.
3. SUMMARY OF THE INVENTION
FORMULA I
The present invention encompasses novel compounds having the general Formula (I):
and pharmaceutically acceptable salts thereof, wherein:
each R
1
is independently selected from the group consisting of —H, —CH
3
, —CH
2
CH
3
, —CH
2
C
6
H
5
, —C(O)OC(CH
3
)
3
, —C(O)OCH
2
C
6
H
5
, and —C(O)CH
3
;
R
2
is selected from the group consisting of —H, C
1
-C
12
straight chain alkyl, —CH
2
C
6
H
5
, —SiR
10
R
11
R
12
, —C(O)CH
3
, —C(O)C
6
H
5
, -2-tetrahydropyranyl, —OCH
2
OCH
3
, and —C(O)OCH
2
CCl
3
;
R
3
is selected from the group consisting of —H, C
1
-C
12
straight chain alkyl, —CH(R
14
)(R
15
) wherein R
14
and R
15
are independently C
1
-C
12
straight chain alkyl, —C(O)C
1
-C
9
straight chain alkyl, —CH(OH)C
1
-C
9
straight chain alkyl, —CH(Cl)C
1
-C
9
straight chain alkyl, -(2-pyridyl)methyl, -(3-pyridyl)methyl, -(4-pyridyl)methyl, and —CH
2
C
6
H
5
, the —CH
2
C
6
H
5
being unsubstituted or substituted on phenyl with one cyano or one or more halo, methoxyl, or trifluoromethyl groups;
R
10
is selected from the group consisting of C
1
-C
4
straight or branched chain alkyl and —C
6
H
5
;
R
11
and R
12
are independently C
1
-C
3
straight or branched chain alkyl;
R
16
and R
17
is —H; and
m is an integer ranging from 1 to 5;
with the proviso that the compound of Formula (I) is not:
butyl-meta-cycloheptylprodiginine,
metacycloprodigiosin,
4-ethoxy-5-((3,5-nonamethylene-2H-pyrrol-2-ylidene)methyl)-2,2′-bi-1H-pyrrole, or
4-propoxy-5-((3,5-nonamethylene-2H-pyrrol-2-ylidene)methyl)-2,2′-bi-1H-pyrrole.
The compounds of Formula (I) and pharmaceutically acceptable salts thereof are useful for treating or preventing cancer or neoplastic disease in a patient in need of such treatment or prevention. The compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful for inhibiting the growth of a cancer cell or neoplastic cell. The compounds of Formula (I) and pharmaceutically acceptable salts thereof are useful for treating or preventing a viral infection in a patient in need of such treatment or prevention. The compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful for inhibiting the replication or infectivity of a virus.
The present invention provides compositions comprising a pharmaceutically accepta
Johnson Roy A.
Murthy Madiraju S. R.
Shore Gordon C.
Steenaart Nancy A. E.
Gemin X Biotechnologies Inc.
McKane Joseph K.
Pennie & Edmonds LLP
Small Andrea D.
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