Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-22
2002-09-17
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S394000, C548S182000, C548S186000, C548S189000
Reexamination Certificate
active
06452014
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to thiazolidinone compounds that inhibit telomerase activity, to pharmaceutical compositions containing the compounds and to the use of the compounds and compositions, alone or in combination with other pharmaceutically active agents, in the treatment of telomerase-mediated conditions or diseases, such as cancer.
BACKGROUND OF THE INVENTION
Telomerase catalyzes the synthesis of telomeres. Telomeres are characteristic tandem repeats (TTAGGG in mammals) found at the ends of most eukaryotic chromosomes, that may be 15-25 kilobases long in human germline cells. With each cell division, about 60-100 bases are lost from the ends of the chromosomes, and as the telomeres shorten, cells eventually reach crisis and apotosis is triggered. See Harley et al., (1991) Mutation Res. 256: 271-282. Telomerase acts to maintain the telomere length just above the crisis level, and are thus responsible for chromosome stability and are involved in the regulation of the cell cycle.
Telomerase is a ribonucleoprotein reverse transcriptase that contains its own RNA template for the synthesis of telomeric DNA. See Blackburn, 1992, Annu. Rev. Biochem., 61:113-129. Telomerase is present in stem and germline cells of normal tissues, and at much higher levels in over 85% of tumors (Kim et al., 1994, Science, 266:2011-2014). Thus, drugs targeted towards telomerase potentially will have a high selectivity for tumor over healthy tissues. Consequently, telomerase inhibition has been proposed as a new approach to cancer therapy.
The inhibition of telomerase activity by antisense strategies directed towards the telomerase RNA component, for example peptide nucleic acids (Norton et al., (1996) Nature Biotech. 14: 615-619) and phosphorothioate oligonucleotides has been reported. Since telomerase is a reverse transcriptase, the use of inhibitors of reverse transcriptases, such as AZT, and other nucleosides has also been reported. Telomerase inhibition by cisplatin, possibly due to crosslinking of the telomeric repeat sequences, is also known (Burger et al., (1997) Eur. J. Cancer 33: 638-644).
We are interested in inhibitors of telomerase that are small molecules, such as thiazolidinediones (see U.S. Ser. No. 09/608,636). Thiazolidinediones comprise a group of structurally related antidiabetic compounds that increases the insulin sensitivity of target tissues (skeletal muscle, liver, adipose) in insulin resistant animals. In addition to these effects on hyperglycemia, thiazolidinediones also reduce lipid and insulin levels in animal models of NIDDM. Recently, the thiazolidinedione troglitazone was shown to have these same beneficial effects in human patients suffering from impaired glucose tolerance, a metabolic condition that precedes the development of NIDDM, as in patients suffering from NIDDM (Nolan et al., (1994) N. Eng. J. Med. 331, 1188-1193). While their mechanism of action remains unclear, it is known that the thiazolidinediones do not cause increases in insulin secretion or in the number or affinity of insulin receptor binding sites, suggesting that thiazolidinediones amplify post-receptor events in the insulin signaling (Colca, J. R., and Morton, D. R. (1990) in New Antidiabetic Drugs (C. J. Bailey and P. R. Flatt, eds.). Smith-Gordon, New York, 255-261; Chang et al. (1983) Diabetes 32, 839-845).
Thiazolidinediones have been found to be efficacious inducers of differentiation in cultured pre-adipocyte cell lines (Hiragun et al. (1988) J. Cell Physiol. 134, 124-130; Sparks et al. (1991) J. Cell. Physiol. 146, 101-109; Kleitzien et al. (1992) Mol. Pharmacol. 41, 393-398). Additionally, thiazolidinediones have been implicated in appetite regulation disorders (see WO 94/25026 A1), and in increase of bone marrow fat content. In addition, thiazolidinedione compounds have been suggested for use in the treatment of psoriasis (U.S. Pat. No. 5,824,694) and climacteric symptoms and mesenchymal tumors (U.S. Pat. No. 5,814,647).
The identification of compounds that inhibit telomerase activity provides important benefits to efforts at treating human disease. Compounds that inhibit telomerase activity can be used to treat telomerase-mediated disorders, such as cancer, since cancer cells express telomerase activity and normal human somatic cells do not possess telomerase activity at biologically relevant levels (i.e., at levels sufficient to maintain telomere length over many cell divisions). Unfortunately, few such compounds, especially compounds with high potency or activity and compounds that are orally bioavailable, have been identified and characterized. Hence, there remains a need for compounds that act as telomerase inhibitors that have relatively high potency or activity and that are orally bioavailable, and for compositions and methods for treating cancer and other diseases in which telomerase activity is present abnormally. The present invention meets these and other needs.
SUMMARY OF THE INVENTION
The present invention provides methods, compounds and compositions that are specific and effective for treating telomerase-mediated disorders, such as malignant conditions by targeting cells having telomerase activity. The methods, compounds, and compositions of the invention can be applied to a wide variety of malignant cell types and avoid the problems inherent in current cancer treatment modalities which are non-specific and excessively toxic.
In a first aspect, the present invention is based on the finding that thiazolidinone compounds are effective in the inhibition of telomerase enzyme activity, in vitro, ex vivo and in vivo. Thus, in certain aspects, the present invention provides methods of inhibiting telomerase by contacting telomerase with the compounds described herein. In particular embodiments, the telomerase to be inhibited is a mammalian telomerase, such as a human telomerase. A related aspect of the present invention is the discovery that thiazolidinone compounds inhibit the proliferation of cells that have telomerase activitiy, such as many cancer cells. Thus, this aspect of the present invention provides methods of inhibiting telomerase activity in a patient, preferably a mammal, suffering from a telomerase-mediated condition or disease, comprising administering to the patient a therapeutically effective. amount of a telomerase inhibiting thiazolidinone compound, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides compounds having the formula:
or their pharmaceutically acceptable salts, wherein X is O or S; L
1
is a direct bond, —CHR
1
—, or ═CR
1
—, wherein R
1
is H or alkyl; L
2
is a direct bond or a linking group having from 1 to 3 atoms independently selected from unsubstituted or substituted carbon, N, O or S; A is aryl or heteroaryl; W is selected from the group consisting of O, NR
5
, and S, wherein R
5
is selected from the group consisting of H, alkyl, aryl, and aralkyl; Y and Z are independently selected to be C or N; and R
2
and R
3
are independently selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, aryl, alkoxyl, cyano, nitro, alkylthio, arylthio, aralkyl, and heteroaryl. The compounds find use in methods and compositions for inhibiting a telomerase enzyme, where the telomerase enzyme is contacted with a compound or a composition containing the compound of the invention.
In another aspect, the present invention provides compounds, or their pharmaceutically acceptable salts, having the formula:
wherein L
1
is a direct bond, —CHR
1
—, or ═CR
1
—, wherein R
1
is H or alkyl; A is aryl or heteroaryl; L
2
is a direct bond or a linking group having from 1 to 3 atoms independently selected from unsubstituted or substituted carbon, N, O or S; W is selected from the group consisting of O, NR
5
, and S, wherein R
5
is selected from the group consisting of H, alkyl, aryl, and aralkyl; Y and Z are independently selected to be C or N; and R
2
and R
3
are independently selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, aryl, alkoxyl, cyan
Akama Tsutomu
Holcomb Ryan
Tolman Richard L.
Earp David J.
Geron Corporation
Schiff J. Michael
Seaman D. Margaret
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