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  Ring-expanded nucleosides and nucleotidesUSPTO Application #: 20060241065Title: Ring-expanded nucleosides and nucleotides Abstract: The present invention relates to compositions comprising analogues of purine nucleosides containing a ring-expanded (“fat”) 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 may be utilized in the treatment of certain cancers, bacterial, fungal, parasitic, and viral infections, including, but not limited to, Acquired Immunodeficiency Syndrome (AIDS), hepatitis, Epstein-Barr and cytomegalovirus. (end of abstract) Agent: Manelli Denison & Selter - Washington, DC, US Inventors: Ramachandra S. Hosmane, Ramesh K. Sood USPTO Applicaton #: 20060241065 - Class: 514043000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20060241065. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] 1. Technical Field [0002] 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. [0003] The concept of the present invention can be extended to include pyrimidine nucleosides and pharmaceutically acceptable derivatives thereof. [0004] 2. Background Information [0005] 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. [0006] 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. [0007] 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. [0008] 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. [0009] 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. [0010] 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. [0011] 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. 1) (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)). [0012] 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/nucleotides, which are described herein are thought to operate by this latter mechanism, as corroborated by molecular modeling studies. (Huckel 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.TM. computer, employing CHARMm.TM., interfaced with QUANTA.TM., obtained from Molecular Simulations, Inc., Boston, Mass. However, several other possible mechanisms of action cannot be ruled out. [0013] Figure II (A) depicts a ten-nucleotide long oligomer containing all 10 natural nucleotides, Figure II (B) shows the corresponding oligomer with 9 natural nucleotides plus a "fat" guanine (fG) nucleotide inserted at position 5 in place of G. Figure II (C) is a space-filling model of Figure II (B). Extensive ABNR (Adopted Basis Newton Raphson) energy minimization performed on each duplex, Molecular modeling studies were performed on a Silicon Graphics.TM. computer, employing CHARMm.TM., interfaced with QUANTA.TM., obtained from Molecular Simulations, Inc., Boston, Mass., that was formed by hybridization of each oligomer with its respective complementary oligomer, shows that incorporation of a fG into a nucleic acid sequence results in considerable distortion of the double helix with severe disruption of base-pair hydrogen bonding leading to unwinding of the double helix starting from the deviant fG residue (see Figures II (B) and II (C)). [0014] Implications are that the incorporation of an fG into the growing DNA chain during reverse transcription would (a) hinder incorporation of subsequent nucleotides, (b) cause base-pair disruption, mismatch, or frameshift, and/or (c) prevent formation of an RNA-DNA hybrid. Any or all of the above events lead to chain termination, and in turn, inhibit viral replication. [0015] Even if an analogue is not a chain-terminator, the incorporation of such an aberrant nucleotide into DNA by HIV reverse transcriptase, could become self destructive, as the analogue may introduce multiple mutations in subsequent rounds of polymerization and accumulations of several such mutations would be lethal to the virus. [0016] Still another possible mode of action that cannot be ignored is if any of the ring-expanded nucleosides turn out to be neither chain terminators nor to be incorporated into DNA. In that case, the inhibitory activity of the analogue may simply be due to its binding to one of the active or allosteric binding sites of HIV reverse transcriptase causing competitive, noncompetitive, or uncompetitive inhibition. [0017] One other major pathogen causing severe consequences is the hepatitis B virus (HBV) which is largely prevalent in third-world countries. It is believed that 80% of the world's liver cancer is caused by HBV. The U.S. currently has 1 million infectious carriers, and chronically active hepatitis will develop in over 25% of carriers and often progresses to cirrhosis. It is estimated that about 5000 people die from cirrhosis each year in the U.S. and about 1000 people die from liver cancer caused by HBV. [0018] Hepatitis B virus (HBV) is a DNA (2'-deoxyribonucleic acid) virus that infects humans. It is a member of the family of viruses, collectively called hepadnaviruses. These closely related viruses selectively infect either mammalian or avian hosts. Mechanistic studies on the replication of these viruses have explored the important role of reverse transcription of an RNA intermediate, strongly suggesting the viability of reverse transcriptase as a logical therapeutic target. [0019] Hepatitis B virus infections continue to be a major worldwide health problem (Centers for Disease Controls and Prevention. Morbid. Mortl. Weekly Rep., 1995:43-963, 1995). HBV infection is known to cause acute and chronic liver hepatitis which can lead to chronicity and liver cirrhosis. Worldwide there are some estimated 350 million chronic carriers of HBV and 1-2% of them die each year from infection related complications. Chronic carriage of HBV has also been strongly associated with hepatocellular carcinoma (Beasley, R. P., et al., Overview on the epidemiology of hepatocellular carcinoma, p. 532-535, In F. B. Hollinger, S. M. Lemon, and M. Margolis (ed.), Viral Hepatitis and Liver Disease, 1991). [0020] Several nucleoside analogs have been shown to inhibit the replication of HBV in cell cultures and in animal models (Colacino, J. M., et al., Prog. Drug Res., 50:260-322, 1998; Chu, C. K., et al., Antimicrob. Agents Chemother., 39:979-981, 1995; Doong, S.-L., et al., Proc. Natl. Acad. Sci. USA., 88:8495-8499, 1991; Genovesi, E. V., et al., Antimicrob. Agents Chemother., 42:3209-3217, 1998; Innaimo, S. F., et al., Antimicrob. Agents Chemother., 41:1444-1448, 1997; Korba, B. E., et al., Antimicrob. Agents Chemother., 40:1282-1284, 1996; Lin, T.-S., et al., J. Med. Chem., 37:798-803, 1994; Lin, T.-S., et al., Biochem. Pharmacol., 47:171-174, 1994; Nicoll, A. J., et al., Agents Chemother., 42:3130-3135, 1998; Yokota, T., et al., Antimicrob. Agents Chemother., 35:394-397, 1991; Zhu, Y-L., et al., Antimicrob. Agents Chemother., 41:1755-1760, 1997). More recently, 2',3'-dideoxy-L-3'-thiacytidine (3TC) has become the first and the only nucleoside analog that has been approved for the treatment of chronic HBV infection in humans. Several other pyrimidine and purine nucleoside analogs with either modified ribose or acyclic alkyl chains as the sugar moiety have been shown to exhibit anti-HBV activity (Colacino, J. M., et al., Prog. Drug Res., 50:260-322, 1998; Lin, T.-S., et al., J. Med. Chem., 37:798-803, 1994; Lin, T.-S., et al., Biochem. Pharmacol., 47:171-174, 1994). Some of these nucleosides are currently being evaluated for their ability to treat HBV infections in humans (Bowden, S., Antivir. Chem. Chemother. 8(supple1):77-82, 1997). For the majority of these nucleosides with anti-HBV activity, the sugar moiety of the molecule is modified to make them inhibitors of the viral polymerases. Some of the modifications which may impart antiviral activity to nucleoside analogs are: removal of 2' and/or 3'-hydroxyl as in 3TC (Doong, S.-L., et al., Proc. Natl. Acad. Sci. USA., 88:8495-8499, 1991); substitution of cyclic ribose with an acyclic side chain as in acyclic phosphonate analogs (Nicoll, A. J., et al., Agents Chemother., 42:3130-3135, 1998); or removal of ring oxygen as in carbocyclic analogs (Genovesi, E. V., et al., Antimicrob. Agents Chemother., 42:3209-3217, 1998; Innaimo, S. F., et al., Antimicrob. Agents Chemother., 41:1444-1448, 1997). [0021] Enzymes play a crucial role in regulating the purine and pyrimidine metabolism of normal as well as rapidly proliferating cells. This fact has led to considerable research in identifying, isolating, characterizing, and studying the specific physiological role of many enzymes. This, in turn, has led to the rational design of inhibitors of a variety of enzymes. The replication of DNA of a cancer cell or a pathogen is dependent upon the availability of the deoxyribonucleoside triphosphates: dTTP, dCTP, dATP, and dGTP. Nucleotides are synthesized as ribo- and/or deoxyribonucleotides either via the de novo pyrimidine and purine pathways or via the salvage pathway using the preformed exogenous nucleobases or nucleosides. These nucleotides are used for the synthesis of new DNA strands. When there are preformed exogenous nucleobases or nucleosides, the de novo pathways are inhibited and nucleotides are synthesized via the more economical salvage pathway. Division of a cancer cell can be significantly altered or stopped by interfering with either of these two pathways. The rapidly proliferating cancer cells are in high demand for nucleotide pools. Inhibition of any of the enzyme-catalyzed biosynthetic pathways by a specific enzyme inhibitor would terminate or significantly reduce the production of purine and pyrimidine nucleotides and this will lead to the death of the cell. Compounds that selectively interfere with malignant cells including nucleoside analogues are of great importance (Sartorelli and David, Springer-Verlag: Berlin (1974); Hirsch and Kaplan Sci. Amer., 256, 76-85 (1987)). [0022] Modifications of natural nucleosides have led to synthesis of therapeutically significant nucleoside analogues which are potent inhibitors of enzymes involved in nucleic acid biosynthesis and are important in the treatment of cancer and pathogenic diseases. [0023] A few patents exist relating to 5:7-fused heterocycles and nucleosides. The compounds described therein have structural features similar to coformycin and pentostatin, the compounds depicted in FIG. 3. Continue reading... Full patent description for Ring-expanded nucleosides and nucleotides Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Ring-expanded nucleosides and nucleotides patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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