Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-05-26
2001-11-13
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06316425
ABSTRACT:
This invention relates to certain nucleoside derivatives which have been found to have valuable properties for the treatment of tumors.
The nucleoside derivatives are esters of 1-&bgr;-D-arabinofuranosyicytosine (Ara-C) of formula A:
Ara-C is also sometimes known as cytosar.
Ara-C has long been known as a chemotherapeutic agent in the treatment of acute myelogenous leukemia but has limited efficiency against solid tumors (Fre et al., Cancer Res. 29 (1969), 1325-1332; Davis et al., Oncology, 29 (1974), 190-200; Cullinan et al., Cancer Treat. Rep. 61 (1977), 1725-1726). However, even in the treatment of leukemia Ara-C has found only limited use due to its very short biological half-life and its high toxicity.
With a view to overcoming these difficulties, a number of workers have prepared and tested pro-drug derivatives of Ara-C. For example, Hamamura et al. investigated 3′-acyl and 3′,5′-diacyl derivatives of Ara-C (J. Med. Chem. 19 (1976) No. 5, 667-674). These workers prepared and tested numerous Ara-C derivatives with saturated or unsaturated ester groups containing from 2 to 22 carbon atoms, and they found that many of the compounds showed a higher activity against L1210 Leukemia in mice than the parent nucleoside alone.
The work by Hamamura et al., and others, on pro-drug analogs of Ara-C was reviewed by Hadfield et al. in Advances in Pharmacology and Chemotherapy, 20, 1984, pages 21-67. In discussing 5′-esters of Ara-C, these authors conclude (page 27):
“ . . . though many of these agents appear to function as very efficient depot forms of ara-C in mice, the analogous action in man has not been demonstrated.”
Although work has continued on pro-drugs based on Ara-C, including 3′- and 5′-acyl derivatives (see, for instance, Rubas et al. in Int. J. Cancer, 37, 1986, pages 149-154 who tested liposomal formulations of, inter alia, 5′-oleyl-Ara-C against L1210 Leukemia and Melanoma B16) to date no such drugs have become available to the clinician.
The mode of action of Ara-C relies on its enzymatic recognition as a 2′-deoxy-riboside and subsequent phosphorylation to a nucleoside triphosphate which competes with the normal CTP for incorporation into DNA. The 2′-hydroxyl group causes steric hindrance to rotation of the pyrimidine base around the nucleosidic bond. The bases of polyarabinonucleotides cannot stack normally, as do the bases of polydeoxynucleotides. Ara-C inhibits DNA repair and DNA synthesis both by slowing down chain elongation and movement of newly replicated DNA through the matrix-bound replication apparatus. The mechanism of action of Ara-C results in an “unbalance growth” in dividing cells. Ara-C acts in the S-phase of the cell cycle. for continuous inhibition of the DNA synthesis and finally cell death, it is crucial that Ara-C be present at a sufficiently high concentration during at least one cell cycle.
A main reason why Ara-C is not used in the treatment of solid tumors is again the rapid clearance of the active drug from cancer cells and plasma. It is apparently not possible to achieve significant intracellular levels of of drug in the neoplastic tissue, even though the tumor in question is sensitive to Ara-C in vitro. The surprisingly prolonged half life and altered tissue distribution of the products of this invention will be of great importance for the therapeutic effect of these products.
REFERENCES:
patent: 5641758 (1997-06-01), Kluge et al.
patent: 5691319 (1997-11-01), Kaneko et al.
patent: 6153594 (2000-11-01), Børretzen et al.
patent: WO 94/22887 (1994-10-01), None
Stephen K. Carter, et al., “Integration of Chemotherapy into Combined Modality Treatment of Solid Tumors”, Cancer Treatment Reviews, vol. 1, (1974), pp. 1-13.
W.J. Wechter, et al., “The Continuing Search for the Magic Bullet: Cytarabine”, Abstracts, Amer. Pharm. Assoc., vol. 3, No. 1, (1973), p. 70.
Duane T. Gish, et al., “Nucleic Acids. 11. Synthesis of 5′-Esters of 1-&bgr;-D-Arabinofuranosylcytosine Possessing Antileukemic and Immunosuppresive Activity”, J. of Med. Chem., vol. 14, No. 12, (1971), pp. 1159-1161.
Robert B. Livingston, et al., “Cytosine Arabinoside”, Cancer Chemo. Rpts. Part 3, vol. 1, No. 1 (1968), pp. 179-205.
Gary D. Gray, et al., ImmunoSuppressive, Antiviral and Antitumor Activities of Cytarabine Derivatives,Biochemical Pharmacology,vol. 21, pp. 465-475, Pergamon press, 1972.
Donald T. Warner, et al., Nucleic Acids. 13. 3′-O-and 2′-O-Esters of 1-&bgr;-D-Arabinofuranosylcytosine as Antileukemic and Immunosuppressive Agents,Journal of Medicinal Chemistry,vol. 15, No. 8, pp. 790-792, 1972.
J.G. Moffatt, et al., Synthesis and Biological Examination of Some Derivatives of 2,2′-Anhydro-1-(&bgr;-D-arabinofuranosyl)cytosine Hydrochloride (NSC-145668),Cancer Chemotherapy Reports,Part 1, vol. 58, No. 4, pp. 451-469, Jul./Aug. 1974.
Ernest K. Hamamura, et al., Reactions of 2-Acyloxyisobutyryl Halides with Nucleosides. 8. Synthesis and Biological Evaluation of Some 3′-Acyl and 3′,5′-Diacyl Derivatives of 1-&bgr;-D-Arabinofuranosylcytosine,Journal of Medicinal Chemistry,vol. 19, No. 5, pp. 667-674, 1976.
R.A. Schwendener, et al., Liposomes as carriers for lipophilic antitumor prodrugs. Incorporation characteristics and in vivo cytotoxic activity.Liposomes Drug Carriers,Symp. (1986), Meeting Date 1984, 170-81. (Abstract Only).
W. Rubas, et al., Treatment of Murine L1210 Lymphoid Leukemia and Melanoma B16 with Lipophilic Cytosine Arabinoside Prodrugs Incorporated into Unilamellar Liposomes,Int. J. Cancer,37, pp. 149-154, 1986.
R.A. Schwendener, Liposome als Träger vol lipophilen Cytosinarabinosid-und Fluorodeoxyuridin-Derivaten,Onkologie,10, pp. 232-239, Apr. 1987. (English Abstract).
W.J. Wechter, et al., “Ara-Cytidine Acylates. Use of Drug Design Predictors in Structure-Activity Relationship Correlation”, Journal of Medicinal Chemistry, vol. 18, No. 4, pp. 339-344, 1975.
Stedman's Medical Dictionary, 24TH Edition, 1982, p. 817, Balto., MD.*
R.L. Merriman, et al., “Comparison of the Antitumor Activity of Gemcitabine and Ara-C in a Panel of Human Breast, Colon, Lung and Pancreatic Xenograft Models”, Investigational New Drugs, vol. 14, (1996) pp. 243-247.
W. Plunkett, et al., “Preclinical Characteristics of Gemcitabine”, Anti-Cancer Drugs, vol. 6, Suppl. 6, (1995) pp. 7-13.
R. Ohno, et al., “Treatment of Leukemia and Myelodysplastic Syndromes with Orally Administered N4-palmitoyl-1-&bgr;-D-arabinofuranosylcytosine”, Cancer Chemother. Pharmacol., vol. 17, (1986) pp. 161-164.
N. Kemeny, et al., “Phase II Study of 2,2′-Anhydro-1-&bgr;-D-arabinofuranosylcytosine-5-fluorocytosine in Advanced Colorectal Carcinoma”, Cancer Treatment Reports, vol. 62, No. 3, (1978).
G.P. Bodey, et al., “Clinical Studies of &bgr;-Thioguanine Deoxyriboside Alone and in Combination with Arabinosyl Cytosine”, Medical and Pediatric Oncology, vol. 2, (1976) pp. 199-205.
Børretzen Bernt
Dalen Are
Myhren Finn
Stokke Kjell Torgeir
Fitzpatrick ,Cella, Harper & Scinto
Goldberg Jerome D.
Norsk Hydro ASA
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