Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-30
2002-04-16
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254020, C514S369000, C544S133000, C544S367000, C548S183000
Reexamination Certificate
active
06372742
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the synthesis of substituted indole compounds, to pharmaceutical compositions containing the compounds and to the use of the compounds and compositions to inhibit telomerase activity, 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). Methods for detecting telomerase activity, as well as for identifying compounds that regulate or affect telomerase activity, together with methods for therapy and diagnosis of cellular senescence and immortalization by controlling telomere length and telomerase activity, have also been described. See, Feng, et al., 1995, Science, 269:1236-1241; Kim, et al., 1994, Science, 266:2011-2014; PCT patent publication No. 93/23572, published Nov. 25, 1993; and U.S. Pat. Nos. 5,760,062, 5,767,278, 5,770,613 and 5,863,936.
U.S. Pat. No. 5,656,638 lists compounds that may have anti-telomerase activity. U.S. Pat. No. 5,556,874 discloses substituted 2-thioindoles are inhibitors of the epidermal growth receptor tyrosine kinase. In addition, 2-oxindole-1-carboxamides are disclosed to be inhibitors of cyclooxygenase and lipoxygenase in U.S. Pat. Nos. 4,569,942 and 4,556,672, and as being capable of inhibiting the biosynthesis of interleukin-1 in U.S. Pat. No. 4,861,794.
The synthesis of some isatinylidineacetic acid derivatives is described by Autrey and Tahk (1967) Tetrahedron 23: 901-917, and the structure elucidation of indolmycin, a antibiotic, is described by von Wittenau and Els (1963) J. Am. Chem. Soc. 86: 3425-3431.
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.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to the synthesis and characterization of thiazolidinedione indole and 5-(3-isatinylidenyl)-2,4-thiazolidinedione compounds and the use of these compounds as inhibitors of the telomerase enzyme. 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 thiazolidinedione indole and 5-(3-isatinylidenyl)-2,4-thiazolidinedione inhibit the proliferation of cells that have telomerase activity, such as many cancer cells. Thus, this aspect of the present invention provides methods of inhibiting telomerase activity in a cell, such as a cancer cell. Further, the invention provides methods of inhibiting telomerase activity in a subject (for example a human or other mammalian subject) suffering from a telomerase-mediated condition or disease, comprising administering to the patient a therapeutically effective amount of a telomerase inhibiting thiazolidinedione indole or 5-(3-isatinylidenyl)-2,4-thiazolidinedione compound, or a pharmaceutically acceptable salt thereof. Thus, the compounds are useful as inhibitors of telomerase and as antitumor agents.
More particularly, the invention comprises compounds, and their pharmaceutically acceptable salts, of formula (I):
wherein X
1
is chosen from O, S, CH
2
, or NR
5
where R
5
is H, lower alkyl or aryl;
L
1
is a direct single bond, direct double bond, —CH
2
—, or —CH═;
is a single or a double bond;
R
1
is selected from the group consisting of H, OR
5
, SR
5
, CR
6
R
7
R
8
, and oxo only when
is a single, wherein R
6
, R
7
, and R
8
are independently selected from H, OH, lower alkyl, aryl, or heteroaryl;
R
2
and R
3
are independently selected from the group consisting of H, OH, halogen, mercapto, nitro, cyano, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy, NR
9
R
10
, SO
2
NR
9
R
10
, OCHR
9
R
10
, COR
9
, CO
2
R
9
, NHCONHR
9
, CONHR
9
, NHCOR
9
, aryl, and heteroaryl wherein R
9
and R
10
are independently selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl, and R
2
and R
3
further represent replacement in the ring of ring methine (—CH═) atoms with aza (—N═) atoms;
L
2
is a direct single bond or a linking group having from 1 to 3 atoms independently selected from unsubstituted or substituted carbon, N, O or S; and
R
4
is H, lower alkyl, alkaryl, aryl, or heteroaryl.
In another aspect, the invention relates to isatin compounds comprising formula (II):
wherein X
1
is O or S;
R
2
is H, OH, halogen, lower alkyl, aryl, or heteroaryl;
L
2
is a direct bond, CH
2
, or SO
2
; and
R
11
is H, halogen or lower alkoxy;
or a pharmaceutically acceptable salt thereof.
The new compounds of the invention have many valuable uses as inhibitors of deleterious telomerase activity, such as, for example, in the treatment of cancer in mammals, such as humans. The pharmaceutical compositions of this invention can be employed in treatment regimens in which cancer cells are killed, in vivo, or can be used to kill cancer cells ex vivo. Thus, this invention provides therapeutic compounds and compositions for treating cancer, and methods for treating cancer and other telomerase-mediated conditions or diseases in humans and other mammals (e.g., cows, horses, sheep, steer, pigs and animals of veterinary interest such as cats and dogs).
DETAILED DESCRIPTION
I. Definitions
Unless otherwise defined below, the terms used herein have their normally accepted scientific meanings. Definition of standard chemistry terms may be found in reference works, includ
Chin Allison C.
Holcomb Ryan
Nguyen Mark Q.
Tolman Richard L.
Geron Corporation
Geron Corporation
Solola T. A.
Wright Sonya N.
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