Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-24
2001-04-03
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S242000, C514S255050, C514S269000, C514S333000, C514S338000, C514S394000
Reexamination Certificate
active
06211177
ABSTRACT:
TECHNICAL FIELD
This invention relates to methods for inducing or promoting apoptosis and for arresting uncontrolled neoplastic cell proliferation, methods that are specifically useful in the arresting and treatment of neoplasias, including precancerous and cancerous lesions.
BACKGROUND OF THE INVENTION
Pharmaceuticals that are effective against early stage neoplasias comprise an emerging and expanding area of research and potential commercial development. Such pharmaceuticals can delay or arrest development of precancerous lesions into cancers. Each year in the United States alone, untold numbers of people develop precancerous lesions, which exhibit a strong statistically significant tendency to develop into malignant tumors, or cancer. Such lesions include lesions of the breast (that can develop into breast cancer), lesions of the skin (that can develop into malignant melanoma or basal cell carcinoma), colonic adenomatous polyps (that can develop into colon cancer), cervical displasia (cervical cancer) and other such neoplasms.
Such compounds and methods are particularly beneficial to sub-populations of patients who repeatedly develop precancerous lesions, and therefore have a statistically higher probability of getting cancer. Many cancer types (e.g., breast, colon, prostate etc.) have such patient sub-populations.
The search for drugs useful for treating and preventing neoplasias in their earliest stages is intensive because chemotherapy and surgery on cancer itself is often not effective, and current cancer chemotherapy has severe side effects. Such cancer-preventative compounds are also envisaged for recovered cancer patients who retain a risk of cancer reoccurrence, and even for cancer patients who would benefit from compounds that selectively induce apoptosis in neoplastic, but substantially not in normal cells.
Because it is believed that chronic administration of cancer-preventative pharmaceuticals is necessary to inhibit or arrest the development of neoplasia, standard cancer chemotherapeutic drugs are not considered appropriate drugs for cancer chemoprevention because whatever cancer preventative (as opposed to cancer-fighting) capabilities those drugs may possess do not outweigh their severe side effects. Most standard chemotherapeutics are now believed to kill cancer cells by inducing apoptosis (also sometimes referred to as “programmed cell death”). Apoptosis naturally occurs in many tissues in the body. Apoptosis plays a critical role in tissue homeostasis, that is, it ensures that the number of new cells produced are correspondingly offset by an equal number of cells that die. Apoptosis is especially pronounced in self-renewing tissues such as bone marrow, immune cells, gut, and skin. For example, the cells in the intestinal lining divide so rapidly that the body must eliminate cells after only three days to protect and prevent the overgrowth of the intestinal lining.
Standard chemotherapeutics promote apoptosis not only in cancer cells, but also in normal human tissues, and therefore have a particularly severe effect on tissues where apoptosis is especially pronounced (e.g. hair, gut and skin). The results of those effects include hair loss, weight loss, vomiting and bone marrow immune suppression. Thus, standard chemotherapeutics are inappropriate for cancer prevention, particularly if chronic administration is indicated.
Several non-steroidal anti-inflammatory drugs (“NSAIDs”), originally developed to treat arthritis, have shown effectiveness in inhibiting and eliminating colonic polyps. Polyps virtually disappear when the patients take the drug, particularly when the NSAID sulindac is administered. However, the continued prophylactic use of currently available NSAIDs, even in high colon cancer-risk patients, is still marked by severe side reactions that include gastrointestinal irritations, perforations, ulceration and kidney toxicity believed to be produced by inhibition of prostaglandin synthetase activity (“PGE-2”). Such inhibition is a requirement for the NSAIDs anti-inflammatory action since elevated levels of PGE-2 are associated with inflammation. PGE-2 plays a protective function in the gastrointestinal tract, which is the reason such gastric side effects arise with chronic NSAID therapy, which is rarely indicated for arthritis sufferers, acute therapy being the norm for them. However, chronic administration of sulindac is important for high cancer-risk patients to eliminate and prevent future polyps which causes gastric side effects in many such patients. Once NSAID treatment is terminated due to such complications, the neoplasms return, particularly in high risk patients.
Compounds such as those disclosed in U.S. Pat. No. 5,643,959 have exhibited advantages in the treatment of neoplastic lesions since such compounds have been shown to induce apoptosis in neoplastic cells but not in normal cells in humans. Thus, the severe side effects due to induction of apoptosis in normal cells by conventional chemotherapeutics are avoided by these novel therapeutics (see, Van Stolk, et al.,
Gastroenterology
, 112 (4): A673, 1997). In addition, such compounds do not exhibit the gastric side effects associated with NSAIDs since such compounds do not substantially inhibit PGE-2. More potent compounds with such neoplasia specificity but without substantial PGE-2 activity are desirable.
SUMMARY OF THE INVENTION
This invention represents potent compounds that induce apoptosis in neoplastic cells (but not substantially in normal cells), for treating patients with neoplastic lesions without substantially inhibiting PGE-2. This invention also involves methods for inducing such specific apoptosis in neoplastic cells by exposing such cells to a pharmacologically effective amount of those compounds described below to a patient in need of such treatment. Such compositions are effective in modulating apoptosis and modulating the growth of neoplasms, but are not suffering from the side effects of conventional chemotherapeutics and NSAIDs.
DETAILED DESCRIPTION OF THE INVENTION
As discussed above, the present invention utilizes compounds of Formula I below
wherein
R
1
is selected from a group consisting of hydrogen, lower alkyl, —(CH
2
)
x
—C(O)—OR
4
, —(CH
2
)
x
—C(O)—NH—(CH
2
)
y
—R
5
, (CH
2
)
x
—S(O)
m
—R
6
or substituted or unsubstituted benzyl, wherein said substituents are one or two independently selected from a group consisting of halogen, lower alkyl, lower alkoxy or phenyl;
R
2
is substituted or unsubstituted aryl, wherein said aryl group is selected from the group consisting of phenyl, benzyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, indolyl, triazinyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, pyrazolyl, or pyrrolyl, and wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl or lower alkoxy;
R
3
is selected from a group consisting of halogen, lower alkoxy, lower alkyl, lower alkoxy carbonyl, carboxyl, substituted and unsubstituted carbamoyl, wherein said substituents are one or two independently selected from a group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, or benzenesulfonyl;
R
4
is hydrogen or lower alkyl;
R
5
is selected from a group consisting of hydrogen, lower alkyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, indolyl, triazinyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, pyrazolyl, or pyrrolyl;
R
6
is substituted or unsubstituted phenyl, wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl or lower alkoxy;
x is 0, 1, or 2;
m is 0, 1, or 2;
n is 0, 1 or 2; and
y is 0, 1, or 2.
Preferred compounds of Formula I include those wherein:
R
1
is selected from a group consisting of hydrogen, lower alkyl, —(CH
2
)
x
—C(O)—OR
4
, —(CH
2
)
x
—C(O)—NH—(CH
2
)
y
—R
5
, or substituted or unsubstituted benzyl, wherein said substituents are one or two independently selected from the group consisting of halogen, lower alkoxy or phenyl;
R
2
is substituted or unsubstituted aryl, wherein said aryl group is selected fr
Ixkes Ulrich
Pamukcu Rifat
Piazza Gary A.
Sperl Gerhard
Cell Pathways Inc.
Goldberg Jerome D.
Stevenson Robert W.
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