Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-09-22
2001-08-14
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S217030, C514S422000
Reexamination Certificate
active
06274601
ABSTRACT:
BACKGROUND OF THE INVENTION
Patients undergoing chemotherapy or radiotherapy for treatment of malignancies are almost invariably faced with moderate or severe side effects due to their therapy. One of the common side effects faced by cancer patients is the induction of ulcerative mucositis of the mucosal membranes. This mucositis is especially prominent in the oral cavity. This side effect, although not as life threatening as other side effects such as anemia or immunosuppression, nonetheless often becomes the dose limiting factor in the continuation of therapy in many cancer patients.
Ulcerative mucositis is marked by the formation of slowly healing open ulcers in the oral cavity causing a great deal of pain and discomfort to the patient. Eating, drinking, and swallowing become difficult and painful and additionally, the salivary glands are often effected compounding the discomfort. The presence of open ulcers in the mouth often lead to opportunistic infections of bacterial, viral, and fungal origin in these patients, who are often immunologically suppressed due to their therapy. These oral infections must be carefully monitored to avoid their spreading to life-threatening, systemic infections.
As yet, there is no treatment for such mucositis except either cessation of the therapy or palliative and supportive interventions. Some of the palliative treatments in current use include the use of antibiotics to reduce the chance of infection, the use of anti-histamines and anti-inflammatory drugs, and the use of pain reducing medications. All of these treatments are either unacceptable, as with the case of cessation of cancer therapy or partially successful in relieving the suffering from the mucositis.
For a more detailed description of radio- and chemotherapy induced mucositis, its treatment, management, and causes see Holland, J. F. et al.; Cancer Medicine, Third Ed., Lea & Febiger, Philadelphia Pa., 1993; Vol.2, Section XL, pp. 2382-2385 and references therein.
The current understanding of the mechanism which causes ulcerative mucositis in cancer patients undergoing radio- or chemotherapy is that both normal mucosal cells and malignant cancer cells share one common property, i.e., these are cells which are rapidly growing or cycling. Normally the mucosal lining turns over at a very rapid rate compared to most other tissue compartments in the body. This rapid mucosal turnover is also shared by several other normal tissues such as cellular blood elements, hair, skin, etc. It is not surprising to find that these tissues are also targets of various cancer therapies, because the governing strategy for the treatment of cancer has been aimed at targeting rapidly proliferated cancer cells by a variety of cellular mechanisms. Thus, cancer drugs which are most effective at interrupting the growth of cancer cells are often the most damaging agents to the normal, proliferating cells in the body, such as the mucosal lining. Other tissue compartments of the body whose cells are not as rapidly cycling, such as muscle and nerve cells, are not as prone to the rapid and deleterious effects of such cancer therapies.
Recently there has been a report in the literature, suggesting that Transforming Growth Factor-B 3 (TGF-B 3) may be useful in treating patients suffering from ulcerative mucositis induced by cancer therapy. The authors hypothesis is that TGF-&bgr;3 slows the rate of turnover of epithelial cells (epithelial cells are the predominant cell type in the mucosal lining) and thus these cells might be spared the effects of the cancer therapy. The authors give experimental data both in cell culture and in animal models which support their hypothesis. (Sonis, et al., Prevention Of Chemotherapy-Induced Ulcerative Mucositis by Transforming Growth Factor-&bgr;3., Abst., NIH Symposia on TGF-&bgr;s, Bethesda Md., May 3, 1994).
TGF-&bgr; is a peptide growth factor which refers to a generic family of peptides, often called isoforms meaning that members of the family either share amino acid homology and/or have similar physiological actions. Of particular interest to the subject of wound healing are: TGF-&bgr;s 1, 2, and 3. For further discussion of the TGF-&bgr; family of peptides, the subject is reviewed in: Roberts et al., The transforming growth factor-&bgr;s. In: Sporn and Roberts, eds. Peptide growth factors and their receptors I. Berlin: Springer Verlag, 1990: 419-472.
It would seem reasonable that an agent which might slow the rapid rate of turnover of the mucosal lining may be useful in protecting that tissue from the effects of the commonly used cancer therapies.
SUMMARY OF THE INVENTION
This invention provides methods of inhibiting ulcerative mucositis comprising administering to a human in need thereof an effective amount of a compound of formula I
wherein R
1
and R
3
are independently hydrogen,
wherein Ar is optionally substituted phenyl;
R
2
is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof.
REFERENCES:
patent: 4133814 (1979-01-01), Jones et al.
patent: 4380635 (1983-04-01), Peters
patent: 4418068 (1983-11-01), Jones
patent: WO93/10113 (1993-05-01), None
patent: WO93/1074 (1993-06-01), None
Sato et al., “DEXA Analysis of Raloxifene Effects on the Bones From Ovariectomized Rats”, Am. Soc. for Bone and Min. Res., Tampa, Sep. 18-22, 1993.
Yang et al., “Raloxifene an Anti-Estrogen, Simulates the Effects of Estrogen in Inhibiting Bone Resorption Through Regulating TGFB-3 Expression in Bone;” .Am Soc. for Bone and Min. Res., Tampa, Sep. 18-22, 1993.
Black et al., “Distinct, Structure-Related Profiles of Estrogenic and Anti-Estrogenic Activity in the Tamoxifen and LY117018 Series;” The Endocrine Society, Abstract 1982.
Black et al., “Uterine Bioassay of Tamoxifen, Trioxifene, and New Estrogen Antagonist (LY117018) in Rats and Mice,” Life Sciences, 26:1980, 1453-1458.
Black et al., “Differential Interaction of Antiestrogens with Cytosol Estrogen Receptors,” Molecular and Cellular Endocrinology, 22:1981, 95-103.
Black et al., “Evidence for Biological Action of the Antiestrogens LY117018 and Tamoxifen by Different Mechanisms,” Endocrinology 109;1981, 987-989.
Black, L.J. “Biological Actions and Binding Properites of a New Estrogen Antagosist LY117018,” In: Homone Antagonists, 129-82, 1982 (M.K. Agarwal ed.) Walter de Gruyter and Co., Berlin New York.
Black et al., LY156758: A Unique Antiestrogen Displaying High Affinity for Estrogen Receptors, Negligible Estrogenic Activity and Near-Total Estrogen Antagonism in Vivo. Presented at the Fifth Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, Nov. 5-6, 1982.
Black et al., The Antiestrogenic Action of LY139481: Species Uniformity Duration of Action and Kinetics of 3H-LY139481 Distribution In Vivo. Sixty-fifth Annual Meeting of the Endocrine Society, San Antonio, Texas, Jun. 8-10, 1983, abs. 93.
Black et al., Antagonism of Estrogen Action with a New benzothiophene Derived Antiestrogen, Life Sciences, 32:1983. 1031-1036.
Black et al., The Relationship of the Antiestrogenic Efficacy of LY156758 to its Pharmacokinetics and Metabolism Following Oral Administration to Adult Ovariectomized Rats, Seventh International Congress of Endocrinology, Quebec City, Canada, Jul. 1-7, 1984, abs. 323.
Black et al., Synthesis and Antiestrogenic Activity of [3,4-Dihydro-2(4-methoxyphenyl)-1-napthalenyl] [4-[2-pyrrolidinyl)ethoxyl]-phenyl] methanone, methanesulfonic acid salt, Journal of Medicinal Chemistry 22;1979, 962-966.
Black et al., Antiestrogens 2. Structure Activity Studies in a Series of 3-Aroyl-2-arylbenzo[b]thiophene Derivatives Leading to [6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone Hydrochloride (LY156758), a Remarkably Effective Estrogen Antagonist with Only Minimal Intrinsic Estrogenicity, J. Med. Chem. 27(8), 1984, 1057-1066.
Sonis et al., “Prevention of Chemotherapy Induced Ulcerative Mucositis By Transforming G
Boudreaux William R.
Eli Lilly and Company
Goldberg Jerome D.
Sales James J.
LandOfFree
Methods of inhibiting ulcerative mucositis does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods of inhibiting ulcerative mucositis, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of inhibiting ulcerative mucositis will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2495040