Ring-expanded nucleosides and nucleotides

Details Ring-expanded nucleosides and nucleotides Ring-expanded nucleosides and nucleotides

1999-04-21

2004-01-13

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S081000, C514S045000, C514S048000, C514S393000, C514S421000, C536S027130, C536S026700, C536S026230, C536S026260

Reexamination Certificate

active

06677310

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to compositions comprising analogues of purine nucleosides containing a ring-expanded (“fat” or “REN”, used interchangeably) heterocyclic ring, in place of purine, and an unmodified or modified sugar residue, pharmaceutically acceptable derivatives of such compositions, as well as methods of use thereof. In particular, these compositions can be utilized in the treatment of certain cancers, bacterial, fungal, parasitic, and viral infections, including, but not limited to, Acquired Immunodeficiency Syndrome (AIDS) and hepatitis.
The concept of the present invention can be extended to include pyrimidine nucleosides and pharmaceutically acceptable derivatives thereof.
2. Background Information
Acquired Immunodeficiency Syndrome (AIDS) has become the deadliest epidemic of the closing years of the 20th century (Benditt, J., Ed., “AIDS, The Unanswered Questions,”
Science
260:1253-93 (1993); Mitsuya, et al.,
Science
249:1533-44 (1990); Fauci,
Proc. Natl. Acad. Sci. USA
83:9278 (1986);
Chemical and Engineering News
Jan. 19, 1987, p. 30, Jan. 26, 1987, p. 18, Jun. 8, 1987, p. 6, Jun. 29, 1987, p. 25; Nov. 23, 1989, pp. 12-70; Jun. 26, 1989, pp. 7-16; and Jul. 5, 1993, pp.20-27). It is caused by a retrovirus called the human immunodeficiency virus (HIV). Retroviruses contain ribonucleic acid (RNA) in their genomes instead of deoxyribonucleic acid (DNA) as is the case with mammals, including humans, and many other bacteria and viruses.
When the virus infects host cells, it uses its own enzyme called reverse transcriptase to transcribe its RNA blue-print into a double-stranded DNA, using the host nucleotide pool. The newly synthesized viral DNA, known as provirus, then gets incorporated into host cellular DNA. The host genetic machinery is then utilized to crank out new viral particles which further infect other cells, and so on.
Several approaches are currently being undertaken to confront the virus, for example, immunological reconstitution, development of a vaccine, and antiretroviral therapy. This third approach is described herein.
While the most desirable approach to check the AIDS viral epidemic would be the development of a vaccine, there are compelling factors to suggest that this approach alone will not be adequate to halt the epidemic. These factors are: (a) unlike other retroviruses, by infecting T4-lymphocytes, the HIV eliminates the very component of the immune response that recognizes antigens, and (b) the virus undergoes continually rapid mutation, resulting in several variations of viral envelope proteins, and hence viral antigenicity. This is believed to be due to high error rates intrinsic to reverse transcriptase-catalyzed genome replication (i.e., 10 times as compared with that catalyzed by human DNA polymerases) (Presson, et al.,
Science
242: 1168 (1988); Roberts, et al.,
Science
242:1171 (1988)). Therefore, simply restoring an AIDS patient's immune system, without eliminating or at least checking the extent of HIV infection, is unlikely to prove effective therapeutically. Thus, with the unlikelihood that the exponential growth and spread of the disease will be halted in the very near future by vaccine development, it is of the utmost importance to pursue antiretroviral therapy.
An antiretroviral therapeutic approach involves developing agents that can potentially suppress the replication of human immunodeficiency virus (HIV) by any of a number of mechanisms including, but not limited to, the following: (a) blocking the viral attachment to the target cell, (b) inhibiting the enzyme reverse transcriptase, and/or (c) blocking transcription and/or translation. While progress is being made on several fronts, the principal obstacle has been the non-specificity and/or toxicity of many otherwise promising antiviral agents. In this respect, exploitation of the intrinsically high error rate; Presson, et al.,
Science
242: 1168 (1988); Roberts, et al.,
Science
242:1171 (1988), of HIV reverse transcriptase to incorporate a chain-terminating nucleotide residue into the developing DNA (approach c) has good prospects for specificity.
As mentioned above, HIV reverse transcriptase makes 10 times as many errors as compared to other cellular polymerases (Presson, et al.,
Science
242: 1168 (1988); Roberts, et al.,
Science
242:1171 (1988)). Thus, the incorporation of the chain-terminating nucleotide residue has the potential advantage of specificity in that it is less likely that the normal cellular DNA polymerases would easily accept an aberrant nucleotide analogue. In fact, AZT (Mitsuya, et al.,
Proc. Natl. Acad. Sci. USA
82:7096 (1985)) (3′-azido-3′-deoxythymidine), DDI (2′, 3′-dideoxyinosine) (Mitsuya et al.,
Nature
353:269 (1991)) and DDC (2′,3′-dideoxycytidine) (Nasr et al.,
Antiviral Res
. 14:125 (1990); Merigan et al.,
Am. J. Med
. 88:11 (1990); Meng et al.,
Ann. Intern. Med
. 116:13 (1992)), the currently approved therapy for AIDS, are known to operate by this chain termination mechanism. The other prospective drugs, for example, DDA and CS-87, are also known to be chain-terminators (Johnston et al.,
Science
260:1286-93 (1993); Mitsuya et al.,
Science
249:1533-44 (1990);
Chemical and Engineering News
Jan. 19, 1987, p. 30, Jan. 26, 1987, p. 18, Jun. 8, 1987, p. 6, Jun. 29, 1987, p. 25; Nov. 23, 1989, pp. 12-70, Jun. 26, 1989, pp. 7-16, and Jul. 5, 1993, pp. 20-27). Unfortunately, they all suffer from either unacceptable levels of toxicity or in vivo non-efficacy, e.g. AZT is toxic to bone marrow, DDC causes painful feet, and DDA & CS-87 are not adequately efficacious in vivo (Johnston et al., supra (1993); Mitsuya et al., supra (1990);
Chemical and Engineering News
Jan. 19, 1987, p. 30, Jan. 26, 1987, p. 18, Jun. 8. 1987, p. 6, Jun. 29, 1987, p. 25; Nov. 23, 1989, pp. 12-70; Jun. 26, 1989, pp. 7-16, and Jul. 5, 1993, pp. 20-27). Therefore, the search must continue for efficient chain-terminators with minimum toxicity so as to arrive at an ideal anti-AIDS drug.
Chain termination can occur by different mechanisms: AZT and the other drugs mentioned above, for example, lack the crucial 3′-OH function necessary for chain elongation. It is also possible that base-mispairing accompanied by considerable deviation of base-ribose conformation from the natural array leads to chain termination (see FIG. I) (Chidgeavadze, et al.,
FEBS LETT
, 183:275 (1985); Chidgeavadze, et al.,
Biochim. Biophys. Acta
, 868:145 (1986); Beabealashvilli et al.,
Biochim. Biophys. Acta
, 868:136 (1986)).
Significant deviation of the 3′-OH group from the natural array would hinder incorporation of subsequent nucleotides into the growing polynucleotide chain and/or formation of the RNA-DNA hybrid, an important event occurring during reverse transcription. The potentially planar and aromatic nucleosides
ucleotides, which are described herein are thought to operate by this latter mechanism, as corroborated by molecular modeling studies. (Hückel MO calculations on potential aromaticity of several heterocyclic aglycons were performed using the program “HMO”, available from Trinity Software, Campton, N.H.) Molecular modeling studies were performed on a Silicon Graphics™ computer, employing CHARMm™, interfaced with QUANTA™, obtained from Molecular Simulations, Inc., Boston, Mass. However, several other possible mechanisms of action cannot be ruled out.
FIG. II(A) depicts a ten-nucleotide long oligomer containing all 10 natural nucleotides, FIG. II(B) shows the corresponding oligomer with 9 natural nucleotides plus a “fat” guanine (fG) nucleotide inserted at position 5 in place of G. FIG. II(C) is a space-filling model of FIG. II(B). Extensive ABNR (Adopted Basis Newton Raphson) energy minimization performed on each duplex, Molecular modeling studies were performed on a Silicon Graphics™ computer, employing CHARMm™, interfaced with QUANTA™, obtained from Molecular Simulations, Inc., Boston, Mass., that was formed by hybridization of each oligomer with its

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