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Lipid analogs for treating viral infections Number:7,129,227 from the United States Patent and Trademark Office (PTO) owispatent

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Title: Lipid analogs for treating viral infections

Abstract: A method of treating viral infections, and in particular HIV-1, hepatitis B virus, and herpesviruses, is disclosed. The method comprises administering to a subject in need of such treatment an infection-combating amount of a phospholipid or phospholipid derivative.

Patent Number: 7,129,227 Issued on 10/31/2006 to Kucera,   et al.


Inventors: Kucera; Louis S. (Pfafftown, NC), Morris-Natschke; Susan L. (Apex, NC), Ishaq; Khalid S. (Chapel Hill, NC)
Assignee: Wake Forest University (Winston Salem, NC)
University of North Carolina at Chapel Hill (Chapel Hill, NC)
Appl. No.: 09/412,539
Filed: October 4, 1999


Related U.S. Patent Documents

Application NumberFiling DatePatent NumberIssue Date
087934705962437
PCT/US95/10111Aug., 1995
08314901Sep., 1994
08297416Aug., 1994

Current U.S. Class: 514/81 ; 514/86; 544/243; 544/244
Current International Class: A61K 31/675 (20060101); A61P 31/00 (20060101); C07F 9/02 (20060101)
Field of Search: 544/243,244 514/81,86


References Cited [Referenced By]

U.S. Patent Documents
2086585 July 1937 Taub et al.
2087132 July 1937 Taub et al.
2108765 February 1938 Domagk
2209383 July 1940 Bock
2439969 April 1948 Fourneau
2445393 July 1948 Fourneau
2513747 July 1950 Sallman et al.
2606909 August 1952 Blicke
2689790 September 1954 Mowry et al.
2950253 August 1960 Kling et al.
3054678 September 1962 Michener et al.
3694473 September 1972 Eibl et al.
4093714 June 1978 Tolman et al.
4096278 June 1978 Queuille
4119714 October 1978 Kny et al.
4159988 July 1979 Eibl et al.
4221732 September 1980 Oette et al.
4235877 November 1980 Fullerton
4291024 September 1981 Turcotte
4329302 May 1982 Hanahan et al.
4426525 January 1984 Hozumi et al.
4444766 April 1984 Bosies et al.
4471113 September 1984 MacCoss
4540521 September 1985 Garst et al.
4559157 December 1985 Smith et al.
4608392 August 1986 Jacquet et al.
4619917 October 1986 Lee et al.
4622392 November 1986 Hong et al.
4661509 April 1987 Gordon et al.
4724232 February 1988 Rideout et al.
4797479 January 1989 Shuto et al.
4816450 March 1989 Bell et al.
4820508 April 1989 Wortzman
4826823 May 1989 Cook et al.
4835263 May 1989 Nguyen et al.
4837023 June 1989 Eibl
4841039 June 1989 Chu et al.
4880782 November 1989 Eckstein et al.
4921951 May 1990 Shuto et al.
4938949 July 1990 Borch et al.
4992478 February 1991 Geria
4997761 March 1991 Jett-Tilton
5026687 June 1991 Yarchoan et al.
5034394 July 1991 Daluge
5138045 August 1992 Cook et al.
5221696 June 1993 Ke et al.
6030960 February 2000 Morris-Natschke et al.
Foreign Patent Documents
3726945 Oct., 1989 DE
3934820 Apr., 1991 DE
4010228 Oct., 1991 DE
0094586 Nov., 1983 EP
0109255 May., 1984 EP
0146258 May., 1985 EP
0142333 Jun., 1985 EP
0145303 Jun., 1985 EP
0252310 Jun., 1987 EP
0335396 Feb., 1989 EP
0310109 Apr., 1989 EP
0 350 287 Jan., 1990 EP
0348859 Jan., 1990 EP
0416401 Aug., 1990 EP
0434450 Dec., 1990 EP
0506704 Jul., 1991 EP
0632048 Jun., 1994 EP
1561630 Mar., 1969 FR
2 239 243 Jun., 1991 GB
42-13841 Aug., 1967 JP
49-100224 Sep., 1974 JP
61-238793 Oct., 1986 JP
1029319 Jan., 1989 JP
10-293129 Nov., 1989 JP
90/00555 Jan., 1990 WO
90/15601 Dec., 1990 WO
90/05736 Mar., 1991 WO
91/05558 May., 1991 WO
91/09602 Jul., 1991 WO
91/18914 Dec., 1991 WO
91/19726 Dec., 1991 WO
92/03462 Mar., 1992 WO
92/06192 Apr., 1992 WO
93/00910 Jan., 1993 WO
93/08807 May., 1993 WO
93/16091 Aug., 1993 WO
93/16092 Aug., 1993 WO
93/17020 Sep., 1993 WO
93/21191 Oct., 1993 WO

Other References

Hirsch et al., Antiviral Agents, Fields Virology, Third Edition, Lippincott--Raven Publishers, p. 431, 1996. cited by examiner .
Aggarwal, "Synthesis and Biological Evaluation of Prodrugs of Zidovudine", J. Med. Chem., 33, 1505-10 (1990). cited by other .
Boldanova, et al., "Protective effect of Phosphatidylcholine-containing Liposomes in Experimental Toxic Hepatitis", Vopr. Med. Khim, 32, No. 3 (1986) Chemical Abstracts, 105, p. 67, Abstract No. 35587k (1986). cited by other .
Bosies, et al., "Chemical Abstracts", 115CA;72142p 1991. cited by other .
Chen, "Design and Synthesis of Novel Nucleoside Analogs as Potential Antiviral Agents", Abstract American Assoc. of Pharmaceutical Scientists, Orlando Fl., (1993). cited by other .
Crumpton, "Novel Lipid Analogs with Cytostatic and Cytocidal Activity", Submitted to Anticancer Res., vol. 8, No. 6, pp. 1361-1366 (Nov.-Dec. 1988). cited by other .
Daniel, "Alkyl-Linked Diglygerides Inhibit Protein Kincase C Activation by Diacylglycerols", Biochemical & Biophysical Res. Comm., 151, 291-97 (Feb. 29, 1988). cited by other .
Dietzfelbinger, "Cytotoxic and Purging Effects of ET-18-OCH3 in Human Malignant Lymphoid Cell Lines in Vitro", Abstract 2472, Proceedings of the American Assoc. for Cancer Res., 31, 416 (Mar. 1990). cited by other .
Fields, "Human Immunodeficiency Virus Induces Phosphorylation of its Cell Surface Receptor", Nature, 333, 278-80 (May 19, 1988). cited by other .
Harada, "Infection of HTLV-III/LAV in HTLV-I-Carrying Cells MT-2 and MT-4 and Application in a Plaque Assay", Science, 229, 563-566 (Aug. 9, 1985). cited by other .
Himmelmann, "Studies on the Cross Resistance Pattern of Membrane-Toxic Lipids in Vitro", Abstract 2448, Proceedings of the American Assoc. for Cancer Res., 31, 416 (Mar. 1990). cited by other .
Hsu, L., et al., "Synthesis of Anti-Restricted Pyramidine Acyclic Nucleosides", Journal of Organic Chemistry, vol. 57, No. 12, pp. 3354-3358, (1992). cited by other .
Kasnar, B., et al., "Synthesis of 2',3'-Dideoxy- and 3'-Azido-2',3'-Dideoxy-Pyridazine Nucleosides as Potential Antiviral Agents", Nucleosides & Nucleotides, 13(1-3), pp. 459-479, (1994). cited by other .
Korba, "Use of a Standardized Cell Culture Assay to Assess Activities of Nucleoside Analogs Against Hepatitus B Virus Replication", Antiviral Res., 19, 55-70 (1992). cited by other .
Krugner-higby, L., et al., "Membrane-Interactive Phosphilipids Inhibit HIV Type 1-Induced Cell Fusion and Surface gp160/gp120 Binding to Monoclonal Antibody", AIDS Research and Human Retroviruses, 11, 705-712, (1995). cit- ed by other .
Krugner-higby, et al., "Novel Membrane Interactive Ether Lipid Analogs Inhibits HIV-1 Glycoprotein Interaction with CD4+ Cells", Abstract from 32nd Interscience Conf on Antimicrobial Agents and Chemotherapy, Anaheim, 164, (Oct. 11-14, 1992). cited by other .
Kucera, L.S., et al., "Activity of Triciribine and Triciribine-5'-Monophosphate Against Human Immunodeficiency Virus Types 1 and 2", Aids Research and Human Retroviruses, vol. 9, No. 4, pp. 307-314, (1993). cited by other .
Kucera, "Effect of Membrane-Active Ether Lipid (EL) Analogues on Human Immunodefiency Virus Production Meausured by Plaque Assay", Annuals of the New York Acad. of Sciences, 546-548 (Dec. 26, 1990). cited by other .
Kucera, "Inhibition of HIV-1 Plaque Formation by a Novel Class of Membrane-Active Ether Lipid Analogs", International Conference on AIDS, Abstract No. W.C.O.21, Jun. 4-9, 1989, p. 528. cited by other .
Kucera, "Inhibition of Human Immunodeficiency Virus-1 (HIV-1) by Novel Membrane Interactive Ether Lipids", Abstract No. 2470, Proceedings of the American Assoc. for Cancer Res., 31, 416 (Mar. 1990). cited by other .
Kucera, L., et al., "Inhibition of Human Immunodeficiency Virus Envelope Glycoprotein-Medicated Cell Fusion by Synthetic Phospholipid Analogs", Antiviral Research (1995). cited by other .
Kucera, "Investigations on Membrane Active Ether Lipid Analogs that Alter Functional Expression of HIV-1 Induces Glycoproteins and Inhibit Pathogenis", Abstract, Innovations in Theraphy of Human Viral Diseases, Symposium, Research Triangle Park, 16, (Dec. 6-9, 1992). cited by other .
Kucera, L., et al., "Novel Ether Lipid Analogs of Platelet Activating Factor with Anti-Hepatitis B Virus Activity", Abstract, ICAAC Orlando, (1994). cited by other .
Kucera, "Novel Membrane-Interactive Ether Lipid Analogs That Inhibit Infectious HIV-1 Production and Induce Defective Virus Formation", AIDS Research and Human Retroviruses, 6, 491-501 (1990). cited by other .
Kumar, R., et al., "Equal Inhibition of HIV Replication by Steroisomers of Phosphatidyl-Azidothymidine--Lack of Stereospecificity of Lysosomal Phospholipase A1", J. Biol. Chem., 267, 20288-20292, (1992). cited by oth- er .
Marasco, Jr., "The Synthesis and Biological Activity of Novel Alkylglycerol Derivatives as Inhibitors of Protein Kinase C Activity, Neoplastic Cell Growth and HIV-1 Infectivity", Dissertation for Ph.D., Univ. of No. Carolina, Chapel Hill 1990. cited by other .
Marasco, et al., "Synthesis and Biological Activity of Novel Quaternary Ammonium Derivatives of Alkylglycerols as Potent Inhibitors of Protein Kincase C", Jour. of Med. Chem., 33, No. 3, pp. 985-992 (Mar. 1990). cite- d by other .
Marasco, "The Synthesis, Biological Evaluation, and Structure Activity of Amido Phosphocholines and Related Analogs as Anti-HIV-1 Agents", 6th Conf. on AIDS, San Francisco, Abstract, (Jun. 20-24, 1990). cited by othe- r .
Marasco, et al., "The Synthesis and Biological Testing of Alkyl Glycerols as Potential Inhibitors of Protein Kinase C", American Assoc. of Pharmaceutical Scientists Abstract, Orlando Fl., (1993). cited by other .
Marx, "Synthesis and Evaluation of Neoplastic Cell Growth Inhibition of 1-N-Alkylamide Analogues of Glycero-3-phosphocholine", J. Med. Chem., 31, 858-863 (Mar. 28, 1988). cited by other .
Meyer, K.L., et al., "In Vitro Evaluation of Phosphocholine and Quaternary Ammonium Containing Lipids as Novel Anti-HIV Agents", J. Med. Chem, 34, 1377-1383, (1991). cited by other .
Meyer, "Synthesis and Evaluation of Anti-HIV-1 Ether Lipids", AAPS Meeting, Atlanta Abstract N. MN-510, p. S-41, (Oct. 22-25, 1989). cited by other .
Mitsuya, "Strategies for Antiviral Therapy in AIDS", Nature, 325, 773-78 (1987). cited by other .
Modest, "Antineoplastic and Antiviral Properties of Ether Lipid Analogs", 15th Intl Cancer Congress, Abstract (Aug. 16-22, 1990). cited by other .
Modest, "Combination Chemotherapy Studies with Antitumor and Antiviral Ether Lipid Analogs", Abstract 2471, Proceedings of the American Assoc. for Cancer Res., 31, 416 Abstract 2471 (Mar. 1990). cited by other .
Modest, E., et al., "Comparison of Cell Kill Induced by Two Ether Lipids in Combination with Hyperthermia", Proceedings of the American Association for Cancer Research; Preclinical Pharmacology Eperimental Therapeutics, vol. 31, pp. 416, Abstract 2467, (Mar. 1990). cited by othe- r .
Modest, "Pharmacological Effects and Anticancer Activity of New Ether Phospholipid Analogs", The Pharmacological Effect of Lipids. III: The Role of Lipids in Carcinogenesis and Therapy, (in Press), pp. 330-337 (1989). cited by other .
Morrey, "Effects of Zidovudine on Friend Virus Complex Infection in Frv-3r/s Genotype-Containing Mice Used as a Model for HIV Infection", J. of Acquired Immune Deficiency Syndromes, 3, 500-10 (1990). cited by other .
Morris-natschke, "Synthesis of Sulfur Analogues of Alkyl Lysophospholipid and Neoplastic Cell Growth Inhibitory Properties", J. of Med. Chem., 29, 2114-17 (1986). cited by other .
Nara, "Simple, Rapid, Quantitative, Syncytium-Forming Microassay for the Detection of Human Immunodeficiency Virus Neutralizing Antibody", Aids Res. and Human Retroviruses, 3, 283-302 (1987). cited by other .
Noseda, "In Vitro Antiproliferative Activity of Combinations of Ether Lipid Analogues and DNA-interactive Agents Against Human Tumor Cells", Journal of Cancer Research, 48, 1788-1791 (Apr. 1988). cited by other .
Noseda, "Neoplastic Cell Inhibition with New Ether Lipid Analogs", Lipids, 22, 878-883 (Nov. 1987). cited by other .
Ostertag, "Induction of Endogenous Virus and of Thymidine Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus", Proc. Nat. Acad. Sci. USA, 71, 4980-85 (Dec. 1974). cited by other .
Piantadosi, "Synthesis and Evaluation of Novel Ether Lipid Nucleoside Conjugates for Anti-HIV-1 Activity", J. Med. Chem., 34, 1408-14 (1991). cited by other .
Sarin, et al., "Effects of a Novel Compund (AL 721) on HTLV-III Infectivity in Vitro", New England J. of Med., 313, 1289-90 (Nov. 14, 1985). cited by other .
Swayze, E.E., et al., "Synthesis of 1-(2-Aminopropyl) Benzimidazoles, Structurally Related to the Tibo Derivative R82150, With Activity Against Human Immunodeficiency Virus", Bioorganic & Medical Cehmistry Letters, vol. 3, No. 4, pp. 543-546, (1993). cited by other .
Thompson, J., et al., "Phospholipid Analog Inhibition of Human Immunodeficiency Virus Envelope Glycoprotein-Mediated Cell Fusion", Abstracts of the 2nd National Conference on Human Retroviruses, Session 18, (1995). cited by other .
Tiollais, P., et al., "Hepatitis B. Virus", Scientific American, 116-123, (Apr. 1992). cited by other .
Van Wijk, G.M., et al., "Spontaneous and Protein-Mediated Intermembrance Transfer of the Antiretroviral Liponucleotide 3'-Deoxythymidine Diphosphate Diglyceride", Biochem, 31, 5912-5917, (1992). cited by other .
Yanagawa, "Spontaneous Formation of Superhelical Strands", J. Am. Chem. Soc., 111, 4567-70 (1989). cited by other .
Yarchoan, "Therapeutic Strategies in the Treatment of AIDS", Annual Reports in Medicinal Chemistry, 253-263 (1988). cited by other .
Miller, et al, 1986, Proc. Natl. 83:2531-2535. cited by other .
Pacheco, 1990, Abstract No. 2446, Proc. Amer. Assoc. Cancer Res. 31:412. cited by other .
Pidgeon, et al. 1994, Chem. Abstract 120:69591. cited by other .
Scolaro, et al. 1992, Chem. Abstract 117:124476. cited by other .
Small, 1990, Abstract No. 2447, Pro Amer. Assoc. Cancer Res. 31:412. cited by other .
Sunamoto, et al, 1992, Chem. Abstract 117:68365. cited by other .
Qui, et al., "Membrane Properties of Antiviral Phospholipids Containing Heteroatoms in the Acyl Chains," Biochemistry 1994, 33(4), 960-72. cited by other .
Hostetler, et al., "Synthesis and Antiretroviral Activity of Phospholipid Analogs of Azidothymidine and Other Antiviral Nucleosides," Journal of Biological Chemistry, vol. 265, No. 11, Apr. 15, 1990, 6112-6117. cited by other .
Jia, et al., "Diamide Analogs of Phosphatidylcholine as Potential Anti-AIDS Agents," J. Chem. Soc. Perkin Trans. 1 (1993), 2521-23. cited by other .
Hostetler, et al., "Phosphatidylazidothymidine, Mechanism of Antiretroviral Action in CEM Cells," Journal of Biological Chemistry, vol. 266, No. 18, Jun. 25, 1991, 11714-11717. cited by other .
Hostetler, et al., "Phosphatidylazidothymidine and Phosphatidyl-ddC: Assessment of Uptake in Mouse Lymphoid Tissues and Antiviral Activities in Human Immunodeficiency Virus-Infected Cells and in Rauscher Leukemia Virus-Infected Mice," Antimicrobial Agents and Chemotherapy, Dec. 1994, 2792-2797. cited by other .
Amari, et al., "Isolation of Experimental Anti-AIDS Glycerophospholipids by Micro-Preparative Reversed-Phase High Performance Liquid Chromatography," Journal of Chromatography, 590 (1992), 153-161. cited by other .
Steim, et al., "Lipid Conjugates of Antiretroviral Agents. I. Azidothymidine-Monophosphate-Digylceride: Anti-HIV Activity, Physical Properties, and Interaction with Plasma Proteins," Biochemical and Biophysical Research Communications, vol. 171, No. 1, 1990, 451-457. cite- d by other .
Painuly, et al., "Preparative HPLC of an Experimental Anti-HIV Analogue of AZT: Azidothymidine Monophosphate Diglyceride (AZT-MP-DG)," Journal of Liquid Chromatography, 16(11), 2237-2248 (1993). cited by other .
Van Wijk, et al., "Synthesis and Antiviral Activity of 3'-azido-3'-deoxythymidine Triphosphate Distearoylglycerol: A Novel Phospholipid Conjugate of the Anti-HIV Agent AZT," Chemistry and Physics of Lipids, 70 (1994) 213-222. cited by other .
Tarnowski, et al., "Effect of Lyso Lecithin and Analogs on Mouse Ascites," Cancer Research, vol. 38 (1978), 339-344. cited by other .
Berdel, et al., "Cyto Toxicity of Thio Ether Lyso Phospho Lipids in Leukemias and Tumors of Human Origin," Cancer Research, vol. 43 (1983), 5538-5543. cited by other .
Runge, et al., "Destruction of Human solid Tumors by Alkyl Lyso Phospho Lipids," Journal of the National Cancer Institute, vol. 64 (1980), 1301-1306. cited by other .
Hayashi, et al., "Antitumor Activity of a Novel Nucleotide Derivative, 5'-(1,2 Dipalmitoyl-sn-glycero-3-phospho)-5-fluorouridine (TJI4026) on Murine Tumors," Biol. Pharm. Bull., 16(8), 778-81 (1993). cited by other .
Sidoti, et al., "Cytostatic Activity of New Synthetic Anti-Tumor AZA-Alkyllysophospholipids," Int. J. Cancer 51, 712-717 (1992). cited by other .
Jahne, et al., "Preparation of Carbocyclic Phosphonate Nucelosides," Tetrahedron Letters, vol. 33, No. 37, 5335-5338 (1992). cited by other .
Coe, et al., "Preparation of Nucleotide Mimics with Potent Inhibitory Activity Against HIV Reverse Transcriptase," J. Chem. Soc. Perkin Trans 1 (1991), 3378-3379. cited by other .
Pajouhesh, et al., "Synthesis of Polar Head Group Homologs of All-trans-cyclopentano-phosphatidylcholine, Phosphatidyl-N, N-Dimethylethanolamine, and Phosphatidylethanolamine," Journal of Lipid Research, vol. 25 (1984), 294-303. cited by other .
Lister, et al., "Cyclopentanoid Analogs of Phosphatidylcholine: Susceptibility to Phospholipase A.sub.2," Journal of Lipid Research, vol. 29 (1988), 1297-1308. cited by other .
Hancock, et al., "Analogs of Natural Lipids. VII. Synthesis of Cyclopentanoid Analogs of Phosphatidylcholine," Journal of Lipid Research, vol. 23 (1982), 183-189. cited by other .
Mertes, et al., "Charge-Spatial Models. cis- and trans-3- and --4-Substituted Cyclohexyl Phosphates as Analogs of 2'-Deoxyuridine 5'-Phosphate," J. Med. Chem (1968), vol. 12(5), 828-832. cited by other .
Jayasuriya, et al., "Design, Synthesis, and Activity of Membrane-Disrupting Bolaphiles," J. Am. Chem. Soc. 1990, 112, 5844-5850. cited by other .
Anderson, L. J. et al., "Antigenic Characterization of Respiratory Syncytial Virus Strains with Monoclonal Antibodies," Journal of Infectious Diseases, 151:626-633, Apr. 1985. cited by other .
Caliendo, A. M. et al., "Combination Therapy for Infection Due to Human Immunodeficiency Virus Type 1", Clinical Infectious Diseases, vol. 18, pp. 516-524, 1994. cited by other .
Daniel, L. W. et al., "Characterization of Cells Sensitive and Resistant to ET-18-OCH.sub.3" Abstract 2447, Proceedings of the American Assoc. for Cancer Res., 31, 416, Mar. 1990. cited by other .
Falsey A. R. et al., "Viral Respiratory Infections in the Institutionalized Elderly: Clinical and Epidemiologic Findings," J Am Geriatric Soc., 40:115-119, 1992. cited by other .
Fujiwara K., et al., "Comparison of Cell Kill Induced by Two Ether Lipids in Combination with Hyperthermia," Proceedings of the American Association for Cancer Research: Preclinical Pharmacology Experimental Therapeutics, vol. 31, pp. 416, Abstract 2467, Mar. 1990. cited by other .
Gill, P. S. et al., "Azidothymidine Associated with Bone Marrow Failure in the Acquired Immunodeficiency Syndrome (AIDS)", Annals of Internal Medicine 107: 502-505, 1987. cited by other .
Glezen, W. P. et al., "Risk of Primary Infection and Reinfection with Respiratory Syncytial Virus," Am J Dis Child, 140:543-546, 1986. cited by other .
Gordeev, K. et al., "Synthesis of Thio Analogs of Platlet Activating Factor (PAF)," Bioorg. Khim., vol. 12, No. 7, pp. 951-955, 1986. cited by other .
Graham, F. L. et al., "A New Technique for the Assay of Infectivity of Human Adenovirus 5-DNA," Virology, vol. 52, pp. 456-467, 1973. cited by other .
Hall, C. B. et al., "Infectivity of Respiratory Syncytial Virus by Various Routes of Inoculation," Infect Immun., 33:779-783, 1981. cited by other .
Hall, C. B. et al., "Nosocomial Respiratory Syncytial Virus Infections," N Engl J Med., 293:1343-1346, 1975. cited by other .
Hall, C. B. et al., "Respiratory Syncytial Virus Infections Within Families," N Engl J Med, 294:414-419, 1976. cited by other .
Henderson, F. W. et al., "Respiratory-Syncytial-Virus Infections, Reinfections, and Immunity: a Prospective, Longitudinal Study in Young Children," N Engl J Med,, 300:530-534, 1979. cited by other .
Hendrickson, H. S. et al., "A Facile Asymmetric Synthesis of Glycerol Phospholipids via Tritylglycidol Prepared by the Asymmetric Epoxidation of Allyl Alcohol, Thiolester and Thioether Analogs of Phosphatidylcholine", Chemistry and Physics Lipids, vol. 53, No. 1, pp. 115-120, 1990. cited by other .
Hong, C. I. et al., "Nucleoside Conjugates. 11. Synthesis and Antitumor Activity of 1-.beta.-D-Arabinofuranosylcytosine and Cytidine Conjugates of Thioether Lipids", Journal of Medicinal Chemistry 33: 1380-1386, 1990. cited by other .
Hong, C. et al., "Formulation, Stability and Antitumor Activity of 1-.beta.-D-Arabinofuranosylcytosine Conjugate of Thioether Phospholipid", Cancer Res. 50: 4401-4406, 1990. cited by other .
Hong, C. I. et al., "Nucleoside-Ether Lipid Conjugates as Biotransformed Prodrugs of Antitumor and Antiviral Nucleosides," J. Lipid Mediators Cell Signaling, vol., 10, No. 1-2, pp. 159-161, 1994. cited by other .
Hostetler, K. et al., "Antiviral Activity of Phosphatidyl-Dideoxycytidine in Hepatitis B-infected Cells and Enhanced Hepatic Uptake in Mice," Antiviral Research., 59-65, 1994. cited by other .
Hruska, J. F. et al., "In Vivo Inhibition of Respiratory Syncytial Virus by Ribavirin," Antimicrob Agents Chemother., 21:125-130, 1982. cited by other .
Kakiuchi, N. et al., "Non-peptide Inhibitors of HCV Serine Proteinase," J. FEBS Letters, 421:217-220, 1993. cited by other .
Kawana, F. et al., "Inhibitory Effects of Antiviral Compounds on Respiratory Syncytial Virus Replication In Vitro," Antimicrob Agents Chemother., (8):1225-30, Aug. 31, 1987. cited by other .
MacCoss, M. et al., "Synthesis and Biological Activity of Novel Nucleoside-Phospholipid Prodrugs," 4th International Round Table Nucleosides, Nucleotides and their Biological Applications, Antwerp, p. 255-263, Feb. 4-6, 1981. cited by other .
Meert, K. L. et al., "Aerosolized Ribavirin in Mechanically Ventilated Children with Respiratory Syncytial Virus Lower Respiratory Tract Disease: a Prospective Double-Blind Randomized Trial," Crit Care Med., Abstract 22:566-572, Apr. 1994. cited by other .
Mufson, M. A. et al., "Two Distinct Subtypes of Human Respiratory Syncytial Virus," The Journal of General Virology, 66:2111-2124, Oct. 1985. cited by other .
Piantadosi, C. et al., "Synthesis and Evaluation of Novel Ether Lipid Nucleoside Conjugates for Anti-HIV-1 Activity," J. Med. Chem., 34, 1408-14, 1991. cited by other .
Pidgeon, C. et al., "Anti-HIV Drugs Conjugated to the Glycerobackbone of Phospholipids," The Journal of Biological Chemistry, 7773-7778, 1993. cit- ed by other .
Poiesz, B. J. et al., "Detection and Isolation of Type C Retrovirus Particles From Fresh and Cultured Lymphocytes of a Patient with Cutaneous T-Cell Lymphoma", Proc. Natl Acad. Sci. U.S.A. 77: 7415-7419, 1980. cited by other .
Prince, G. A. et al., "The Pathogenesis of Respiratory Syncytial Virus Infection in Cotton Rats," Am J Pathol Abstract., 93:771-91, 1978. cited by other .
Raetz, C. R. H. et al., "A Phospholipid Derivative of Cytosine Arabinoside and its Conversion to Phosphatidylinositol by Animal Tissue," Science 196, 303-304, 1977. cited by other .
Richman, D. D. et al., "The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex", New England Journal of Medicine 317: 192-197, 1987. cited by other .
Smith, D. W. et al., "A Controlled Trial of Aerosolized Ribavirin in Infants Receiving Mechanical Ventilation for Severe Respiratory Syncytial Virus Infection," New England Journal of Medicine, 325:24-29, Jul. 1991. cited by other .
Surbone, A. et al., "Treatment of the Acquired Immunodeficiency Syndrome (AIDS)and AIDS-Related Complex with a Regimen of 3'-Azido-2'3'-Dideoxythymidine (Aziodthymidine or Zidovudine) and Acyclovir", Annals of Internal Medicine, 108: 534-540, 1988. cited by oth- er .
Surles, J. R. et al, "Multigram Synthesis of 1-Alkylamido Phospholipids," Lipids, 28, 55-57, 1993. cited by other .
Yamaue, H. et al., "Chemosensitivity Testing with Highly Purified Fresh Human Tumor Cells with the MTT Colorimetric Assay," Abstract. Eur J Cancer, 27:1258-1263, 1991. cited by other.

Primary Examiner: Coleman; Brenda
Attorney, Agent or Firm: Morgan Lewis & Bockius LLP

Parent Case Text



CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No. 08/793,470, filed May 2, 1997, now U.S. Pat. No. 5,962,437 which is a 371 of International Application PCT/US95/10111, filed Aug. 7, 1995, which is a continuation of application Ser. No. 08/314,901, filed Sep. 29, 1994, now abandoned, which is a Continuation-In-Part of application Ser. No. 08/297,416, filed Aug. 29, 1994, now abandoned.
Claims



What is claimed is:

1. A method of treating a viral infection in a subject in need of such treatment comprising administering to said subject an effective infection-combating amount of a compound of 3'-azido-3'-deoxy-5'-(3-dodecanamido-2-decyloxypropyl)-phosphothymidine, or a pharmaceutical salt thereof, wherein the viral infection comprises a virus selected from the group consisting of HIV-1, herpes virus, influenza, respiratory syncytial virus, mumps, measles, and parainfluenze virus.

2. The method according to claim 1, wherein said viral infection is caused by HIV-1 virus.

3. The method according to claim 1, wherein said viral infection is caused by herpes simplex virus.

4. The method according to claim 1, wherein said subject is a human.

5. The method according to claim 1, wherein said administration is oral.

6. The method according to claim 1, wherein said administration is rectal.

7. The method according to claim 1, wherein said administration is topical.

8. The method according to claim 1, wherein said administration is intrathecal.

9. The method according to claim 1, wherein said administration is buccal.

10. The method according to claim 1, wherein said administration is parenteral.

11. The method according to claim 1, wherein said compound is administered in an amount of at least about 0.1 ng/kg to about 1 ng/kg.

12. The method according to claim 1, wherein said compound is administered in an amount of at least about 0.001 .mu.g/kg to about 0.1 g/kg.

13. A method of treating a viral infection in a subject in need of such treatment comprising administering to said subject an effective infection-combating amount of a compound of 3'-azido-3'-deoxy-5'-(3-dodecyloxy-2-decyloxypropyl)-phosphothymidine or a pharmaceutical salt thereof, wherein the viral infection comprises a virus selected from the group consisting of HIV-1, herpes virus, influenza, respiratory syncytial virus, mumps, measles, and parainfluenze virus.

14. The method according to claim 13, wherein said viral infection is caused by HIV-1 virus.

15. The method according to claim 13, wherein said viral infection is caused by herpes simplex virus.

16. The method according to claim 13, wherein said subject is a human.

17. The method according to claim 13, wherein said administration is oral.

18. The method according to claim 13, wherein said administration is rectal.

19. The method according to claim 13, wherein said administration is topical.

20. The method according to claim 13, wherein said administration is intrathecal.

21. The method according to claim 13, wherein said administration is buccal.

22. The method according to claim 13, wherein said administration is parenteral.

23. The method according to claim 13, wherein said compound is administered in an amount of at least about 0.1 ng/kg to about 1 ng/kg.

24. The method according to claim 13, wherein said compound is administered in an amount of at least about 0.001 .mu.g/kg to about 0.1 g/kg.
Description



FIELD OF THE INVENTION

This invention relates generally to the treatment of viral infections, and more specifically to the treatment of viral infections with phospholipids and phospholipid derivatives.

BACKGROUND OF THE INVENTION

A current treatment for combating human immunodeficiency virus type 1 (HIV-1) infections is the administration of the nucleoside analog 3'-azido-3'-deoxythymidine (AZT) to an afflicted subject. See, e.g., U.S. Pat. No. 4,724,232 to Rideout et al. HIV-1 infection treatment methods have also included the administration of ether lipid compounds in an amount effective to inhibit replication of the virus in infected cells, see, e.g., Kucera et al., AIDS Research and Human Retroviruses 6:491 (1990), and ether lipids conjugated with AZT and other antiviral nucleoside analogs. See PCT Application No. US91/04289 (published 26 Dec. 1991). These compounds appear to act at the plasma membrane to block the endocytic process of HIV-1 into CD4.sup.+ cells and the process of virus assembly, cell fusion and pathogenesis. They also can inhibit the activity of protein kinase C. Given the seriousness of HIV-1 infection worldwide, there is an ongoing need for new methods of combating HIV-1 infections.

Another virus of serious concern, hepatitis B virus (HBV), is one of a family of hepadnaviruses that cause acute and chronic liver disease, including liver cancer. HBV, which is found in the body fluids of infected persons, makes three antigenic proteins during multiplication in liver cells: hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). These three virus antigenic proteins are important as markers for determining virus infection, as antibodies against the virus infection are made in response to these virus proteins in the blood. An HBV vaccine is available to prevent infection, and hyperimmune gamma globulin is available for temporary prophylaxis against developing HBV infection in persons at risk. Clearly specific antiviral agents are needed for treatment and control of HBV infections in humans.

Based on the foregoing, it is an object of the present invention to provide a new treatment method for combating the effects of HIV-1.

It is another object of the present invention to provide compounds and pharmaceutical compositions for carrying out HIV-1 treatment methods.

It is also an object of the present invention to provide a new treatment method for combating the effects of HBV.

It is a second object of the present invention to provide compounds and pharmaceutical compositions for carrying out HBV treatment methods.

SUMMARY OF THE INVENTION

These and other objects are satisfied by the present invention, which provides methods of combating viral infections. As a first aspect, the present invention provides a method of combating a viral infection in a subject in need of such treatment comprising administering to the subject an effective infection-combating amount of a compound of Formula I or a pharmaceutical salt thereof.

##STR00001## In the compounds of Formula I, R.sub.1 is a branched or unbranched, saturated or unsaturated C.sub.6 to C.sub.18 alkyl group optionally substituted from 1 to 5 times with --OH, --COOH, oxo, amine, or substituted or unsubstituted aromatic; X is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3; R.sub.2 is a branched or unbranched, saturated or unsaturated C.sub.6 to C.sub.14 alkyl group optionally substituted from 1 to 5 times with --OH, --COOH, oxo, amine, or substituted or unsubstituted aromatic; Y is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3; R.sub.6 is a branched or unbranched C.sub.2 to C.sub.6 alkyl group; and R.sub.3, R.sub.4, and R.sub.5 are independently methyl or ethyl, or R.sub.3 and R.sub.4 together form an aliphatic or heterocyclic ring having five or six members and R.sub.5 is methyl or ethyl. Preferred compounds include 1-dodecanamido-2-decyloxypropyl-3-phosphocholine, 1-dodecanamido-2-octyloxypropyl-3-phosphocholine, and 1-dodecanamido-2-dodecyloxypropyl-3-phosphocholine. The method is particularly preferred as a treatment to combat viral infections caused by HIV-1, HBV, and herpes simplex virus. The present invention also includes pharmaceutical compositions comprising a compound of Formula I and a suitable pharmaceutical carrier.

As a second aspect, the present invention includes a method of combating viral infections in a subject in need of such treatment which comprises the administration to such a subject a compound of Formula II or a pharmaceutical salt thereof in an effective infection-combating amount.

##STR00002## In Formula II, the ring structure is optionally substituted from 1 to 3 times with C.sub.1 to C.sub.3 alkyl; R.sub.1 is an unbranched or branched, saturated or unsaturated C.sub.6 to C.sub.20 alkyl group; R.sub.2, R.sub.3, and R.sub.4 are independently methyl or ethyl, or R.sub.2 and R.sub.3 together form an aliphatic or heterocyclic ring having five or six members and R.sub.3 is methyl or ethyl; X is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3; R.sub.5 is a branched or unbranched C.sub.2 to C.sub.6 alkyl group; m is 1 to 3; and n is 0 to 2. Preferred compounds of Formula II are 3-hexadecanamido-cyclohexylphosphocholine and 3-hexadecylthio-cyclohexylphosphocholine. Adminstration of the compounds of Formula II is particularly useful in treating viral infections caused by HIV-1, HBV, and herpesviruses. The present invention also includes pharmaceutical compositions comprising a compound of Formula II and a suitable pharmaceutical carrier.

A third aspect of the present invention is a method of treating viral infections comprising administering to a subject in need of such treatment an effective infection-inhibiting amount of a compound of Formula III.

##STR00003## In compounds of Formula III, R.sub.1 is a branched or unbranched, saturated or unsaturated C.sub.6 to C.sub.18 alkyl group optionally substituted from 1 to 5 times with --OH, --COOH, oxo, amine, or substituted or unsubstituted aromatic; X is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3; R.sub.2 is a branched or unbranched, saturated or unsaturated C.sub.6 to C.sub.14 alkyl group optionally substituted from 1 to 5 times with --OH, --COOH, oxo, amine, or substituted or unsubstituted aromatic; Y is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3; and Z is a moiety of the Formula V,

##STR00004## wherein:

V is H or N.sub.3;

W is H or F; or

V and W together are a covalent bond; and

B is a purinyl moiety of Formula VI

##STR00005##

optionally substituted at position 2 with .dbd.O --OH, --SH, --NH.sub.2, or halogen, at position 4 with NH.sub.2 or .dbd.O, at position 6 with Cl, --NH.sub.2, --OH, or C.sub.1 C.sub.3 alkyl, and at position 8 with Br or I; or

B is a pyrimidinyl moiety of Formula VII

##STR00006##

substitued at position 4 with .dbd.O or NH.sub.2 and optionally substituted at position 5 with halogen or C.sub.1 C.sub.3 saturated or unsaturated alkyl optionally substituted 1 to 3 times with halogen.

Pharmaceutical compositions comprising these compounds and a pharmaceutical carrier are also encompassed by the present invention.

A fourth aspect of the invention is a method of inhibiting viral infections comprising administering to a subject in need of such treatment an effective infection-inhibiting amount of a compound of Formula IV.

##STR00007## In the compounds of Formula IV, the ring structure is optionally substituted from 1 to 3 times with C.sub.1 to C.sub.3 alkyl; R.sub.1 is an unbranched or branched, saturated or unsaturated C.sub.6 to C.sub.20 alkyl group; X is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3; m is 1 to 3; n is 0 to 2; and Z is a moiety of the Formula V,

##STR00008## wherein:

V is H or N.sub.3;

W is H or F; or

V and W together are a covalent bond; and

B is a purinyl moiety of Formula VI

##STR00009##

optionally substituted at position 2 with .dbd.O --OH, --SH, --NH.sub.2, or halogen, at position 4 with NH.sub.2 or .dbd.O, at position 6 with Cl, --NH.sub.2, --OH, or C.sub.1 C.sub.3 alkyl, and at position 8 with Br or I; or

B is a pyrimidinyl moiety of Formula VII

##STR00010##

substitued at position 4 with .dbd.O or NH.sub.2 and optionally substituted at position 5 with halogen or C.sub.1 C.sub.3 saturated or unsaturated alkyl optionally substituted 1 to 3 times with halogen.

The present invention also includes pharmaceutical compositions comprising a compound of Formula IV and a suitable pharmaceutical carrier.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" is intended to refer to an unbranched or branched alkyl group comprising carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, hexyl, and octyl. The term "pharmaceutical salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects thereto. Examples of such salts are (a) salts formed with cations such as sodium, potassium, NH.sub.4.sup.+, magnesium, calcium polyamines, such as spermine, and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine, and iodine.

A first aspect of the present invention is a method of combating viral infection comprising administering a compound of Formula I, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, X, and Y are defined as stated above, or a pharmaceutical salt thereof. The amphipathic compounds of Formula I, which are generally analogs of phosphatidylcholine, include a glycerol backbone (represented by the chain of three carbon atoms to which other functional groups are bonded), lipophilic moieties (represented by R.sub.1 and R.sub.2) bonded to positions 1 and 2 of the glycerol backbone through functional groups (represented by X and Y) that are generally resistant to phospholipase degradation, and polar phosphate and quaternary amine groups (linked to one another through a short alkyl group) bonded to position 3 of the glycerol backbone. Each of these components of the compounds of Formula I is described separately below.

In Formula I, as described above, R.sub.1 is a lipophilic moiety; the lipophilicity of R.sub.1 allows the compounds of Formula I to bind with the cell membrane of a cell infected with a retrovirus to provide an anchor thereto. R.sub.1 can be an unbranched or branched, saturated or unsaturated C.sub.6 to C.sub.18 alkyl group. Preferably, R.sub.1 is an unbranched saturated or unsaturated C.sub.8 to C.sub.12 alkyl group, and more preferably, R.sub.1 is an unbranched saturated C.sub.10 or C.sub.12 alkyl group.

In compounds of Formula I, X is a functional group that links the lipophilic moiety R.sub.1 and the glycerol backbone of the compound. X is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3; these functional groups are resistant to the hydrolytic activity of cellular lipases, in particular phospholipase A, which is specific for ester linkages at position 1 (as are present in phosphatidyl choline). Preferably, X is S or NHCO, with NHCO being most preferred.

In Formula I, R.sub.2 is a lipophilic moiety which, as is true for R.sub.1, enables the compounds of Formula I to bind with the cell membrane of an infected cell. R.sub.2 can be an unbranched or branched, saturated or unsaturated C.sub.6 to C.sub.14 alkyl group. Preferably, R.sub.2 is an unbranched saturated or unsaturated C.sub.8 to C.sub.12 alkyl group, and more preferably, R.sub.2 is an unbranched saturated C.sub.8 or C.sub.10 alkyl group. It is also preferred that R.sub.1 and R.sub.2 together contain between 18 and 22 carbon atoms.

R.sub.2 is bonded to position 2 of the glycerol backbone through a functional group Y, which is selected from the group consisting of NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, S, SO, SO.sub.2, O, NH, and NCH.sub.3. Like X, Y should be a moiety that is resistant to the hydrolytic activity of cellular lipases, and in particular phospholipase B, as this enzyme is specific for ester linkages at position 2. Preferably, X is S or O, with O being more preferred.

The polar hydrophilic end of the amphipathic compounds of Formula I, which can play a role in membrane interaction, comprises an amphoteric phosphoalkyl quaternary amine group in which the phosphate moiety carries the negative charge and the quaternary amine moiety carries the positive charge. In this group, R.sub.6, which is a branched or unbranched, saturated or unsatured C.sub.2 to C.sub.6 alkyl group, is preferably saturated C.sub.2. R.sub.3, R.sub.4, and R.sub.5 are independently selected from the group consisting of methyl and ethyl, with methyl being preferred, and with R.sub.3, R.sub.4, and R.sub.5 each being methyl being more preferred, or R.sub.3 and R.sub.4 together form an aliphatic or heterocyclic ring having five or six members and R.sub.5 is methyl or ethyl.

Exemplary compounds of Formula I include 1-dodecanamido-2-decyloxypropyl-3-phosphocholine (CP-128), 1-dodecanamido-2-octyloxypropyl-3-phosphocholine (CP-130), 1-dodecanamido-2-dodecyloxypropyl-3-phosphocholine (CP-131), and 1-dodecyloxy-2-decyloxypropyl-3-phosphocholine (CP-129). These compounds of Formula I can be synthesized according to the procedures set forth in Examples 1 and 2 below. Other compounds of Formula I can be synthesized using the same method with the appropriate reagents substituted for those listed.

Another aspect of the invention is a method of combating viral infection by administering compounds of Formula II, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, m, and n are defined as stated above, or a pharmaceutical salt thereof. Compounds of Formula II are amphipathic-moieties having a lipophilic moiety (represented by R.sub.1)-linked to a five- or six-membered ring structure (which is optionally sustituted 1 to 3 times with C.sub.1 to C.sub.3 alkyl) and a hydrophilic moiety that includes phosphate and quaternary amine groups linked by a short alkyl group that is bonded to the ring structure through the phosphate group. The hydrophilic group is linked to the ring at position 1, and the lipophilic group is linked to the ring at positions 2, 3, or 4. Like the compounds of Formula I, the compounds of Formula II are analogs of phosphatidyl choline. However, the ring structure provides a more conformationally restricted framework for the compound than compounds lacking a ring structure; this restricted framework can provide the compound with more favorable interaction with the cellular membrane and thereby increase its efficacy.

In the compounds of Formula II, R.sub.1 can be an unbranched or branched, saturated or unsaturated C.sub.6 to C.sub.20 alkyl group. As with the compounds of Formulas II, R.sub.1 is a lipophilic moiety which binds with the cell membrane of infected cells to provide an anchor thereto. Preferably, R.sub.1 is unbranched saturated or unsaturated C.sub.10 to C.sub.18 alkyl. More preferably, R.sub.1 is unbranched saturated or unsaturated C.sub.16 to C.sub.18 alkyl.

In compounds of Formula II, X is a functional group that links the lipophilic moiety R.sub.1 to position 1 of the ring structure. X should be a functional group, such as NHCO, CH.sub.3NCO, CONH, CONCH.sub.3, NH, NCH.sub.3, S, SO, SO.sub.2, or O, that is able to withstand the hydrolytic activity of cellular lipases. Preferably, Y is S or NHCO.

As stated above, the polar hydrophilic end of the amphipathic compounds of Formula II comprises a phosphate group bonded to the ring structure, a short alkyl group R.sub.5 linked at one end thereto, and a quaternary amine group linked to the opposite end of the short alkyl group. R.sub.5 is a saturated or unsatur


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Linkgrinder is a free service that searches the Internet and indexes all files found so that you may search quickly and easily for shared files. These files are created and made available individually by users whose identity we are not aware of and who we have no control over. In essence we function like a search engine tool; these files ARE NOT STORED OR SERVED BY OUR NETWORK. We are not responsible for any materials obtained by using our service. We do not monitor any of the contents of these files. These files may contain viruses, illegal materials, materials inappropriate for minors, offensive files and the like. BY USING OUR SERVICE, YOU ASSUME FULL RESPONSIBILITY FOR DOWNLOADING THESE MATERIALS AND WILL INDEMNIFY US FOR ANY DAMAGES THAT MAY BE INCURRED.

For More Specific Information VIEW OUR TERMS OF SERVICE.

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