Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1996-02-05
1997-01-07
Bernhardt, Emily
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544244, 546 23, 548112, 548117, C07F 96512, C07F 96503, C07F 9653, C07F 96539
Patent
active
055918514
ABSTRACT:
The internally cyclized congeners of hydroxy-substituted nucleotide analogues have been found to exhibit substantially lower toxicity in vivo than their uncyclized analogues, while retaining essentially the same antiviral activity. This was unexpected because the prior art suggested that the cyclic analogues offered no significant advantages in respect to toxicity. This finding permits the administration of much greater doses of the cyclic congeners than otherwise would have been possible and allows the clinician to omit toxicity ameliorating interventions. Novel compounds are provided for use in the method of this invention. Novel methods for the preparation of these compounds also are provided.
REFERENCES:
patent: 3524846 (1970-08-01), Moffatt et al.
patent: 4369181 (1983-01-01), Miller et al.
patent: 4590269 (1986-05-01), Prisbe et al.
patent: 4670424 (1987-06-01), MacCoss et al.
patent: 4724233 (1988-02-01), De Clercq et al.
patent: 4801710 (1989-01-01), MacCoss et al.
patent: 5043339 (1991-08-01), Beauchamp
patent: 5047533 (1991-09-01), Reist et al.
patent: 5142051 (1992-08-01), Holy et al.
patent: 5208221 (1993-05-01), Kim et al.
patent: 5247085 (1993-09-01), Harnden et al.
patent: 5386030 (1995-01-01), Kim et al.
Trost et al, Comprehensive Organic Synthesis 2, pp. 777-778 (1991).
Orchin, The Vocabulary of Organic Chemistry p. 283 (1980).
Alexander et al, Collect. Czech. Chem. Commun. 59 p. 1853 (1994).
Starrett et al, J. Med. Chem. 37 p. 1857 (1994).
Nelson et al, J. Am. Chem. Soc. 109 p. 4058 (1987).
Snoeck et al, Progress in Cytomrgolovirus Research p. 337 (1991).
Bai et al, "Structural Specificity of Mucosal-Cell Transport and Metabolism of Peptide Drugs: Implication for Oral Peptide Drug Delivery," Phar. Res. 9:969-979 (1992).
Barnard et al, "Selective inhibition of cytomegaloviruses by 9-(3'-ethylphosphono-1'-hydroxymethyl-1'-propyloxy-methyl)guanine," Antiviral Research 22:77-89 (1993).
Bronson et al, "Synthesis and Biological Activity of Carbocyclic Derivatives of the Potent Antiviral Agent 9-[2-(Phosphonomethoxy)Ethyl]Guanine (PMEG)," Bioorganic & Medicinal Chemistry Letters 2:685-690 (1992).
Colla et al, "Synthesis and Antiviral Activity of Water-Soluble Esters of Acyclovir [9-[(2-Hydroxyethoxy)methyl]guanine]," J. Med. Chem. 26:602-604 (1983).
Curley et al, "Synthesis and anti-HIV evaluation of some phosphoramidate derivatives of AZT: studies on the effect of chain elongation on biological activity," Antiviral Research 14:345-356 (1990).
Davies et al, "2'-Nor'2'-deoxyguanosine is an effective therapeutic agent for treatment of experimental herpes keratitis," Antiviral Research 7:119-125 (1987).
Duke et al., "In vitro and in vivo activities of phosphate derivatives of 9-(1,3-dihydroxy-2-propoxymethyl)-guanine against cytomegaloviruses," Antiviral Res 6:299-308 (1986).
Farquhar et al, "Biologically Reversible Phosphate-Protective Groups," Journal of Pharmaceutical Sciences 72:324-325 (1983).
Farrow et al, "Syntheis and Biological Properties of Novel Phosphotriesters: A New Approach to the Introduction of biologically Active Nucleotides into Cells," J. Med. Chem. 33:1400-1406 (1990).
Feng et al, "Combined treatment with 2'-nor-cGMP and ganciclovir against cytomegalovirus infection in a guinea pig model," Antiviral Research 19:193-206 (1992).
Field et al, "Efficacy of 2'-nor-cyclicGMP in treatment of experimental herpes virus infections," Antiviral Research 6:329-341 (1986).
Freed et al, "Evidence for Acyloxymethyl Esters of Pyrimidine 5'-Deoxyribonucleotides as Extracellular Sources of Active 5'-Deoxyribonucleotides in cultured Cells," Biochemical Pharmacology 38:3193-3198 (1989).
Freeman et al, "3'-Azido-3',5'dideoxythymidine-5'-methylphosphonic Acid Diphosphate: Synthesis and HIV-1 Reverse Transcriptase Inhibition," J. Med. Chem. 35:3192-3196 (1992).
Gumport et al, "Structure of the DNA Ligase-Adenylate Intermediate: Lysine (epsilon-amino)-Linked Adenosine Monophosphoramidate," Proc. Nat. Acad. Sci. 68(10):2559-2563 (1971).
Harnden et al, "Snythesis and Antiviral Activity of 9-Alkoxypurines. 1.9-(3-Hyroxypropoxy)- and 9-[3-Hydroxy-2-(hydroxymethyl)propoxy]purines," J. Med. Chem. 33:187-196 (1990).
Ho et al, "Intracellular Metabolism of the Antiherpes Agent (S)-1-[3-Hyroxy-2-(phosphonylmethoxy)propyl]cytosine," Molecular Pharmacology 41:197-202 (1992).
Holy et al, "Acyclic nucleotide analogues: synthesis antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro," Antiviral Research 13:295-312 (1990).
Holy et al, "Synthesis of (3-Hydroxy-2-Phosphonylmethoxypropyl) Derivatives of Heterocyclic Bases," Coll. Czech. Chem. Comm. 54:2470 (1989).
Juodka et al, "Synthesis of Diribonucleoside phospho-(P->N)-Amino Acid Derivatives," Coll. Czech. Chem. Comm. 39:963-968 (1974).
Karkas et al, "Stereochemical considerations in the enzymatic phosphorylation and antiviral activity of acyclonucleosides. I. Phosphorylation of 2'-nor-2'-deoxyguanosine," Biochemica et Biophysica Acta 911:127-135 (1987).
Keim et al, "Amphotericin B Methyl Ester Hydrochloride and Amphotericin B: Comparative Acute Toxicity," Science 179(4073):584-585 (1973).
Kim et al, "A Novel Synthesis of 1-OXA-HPMPA: A Potent Antiviral Agent Against Herpes Viruses," Tetrahedron Letters 33 (1):pp. 25-28 (1992).
Kim et al., "Acyclic Purine Phosphonate Analogues as Antivral Agents. Synthesis and Structure--Activity Relationships," J Med Chem 33:1207-1213 (1990).
Kim et al., "Synthesis and HIV Activity of Phosphonate Isosteres of D4T Monophosphate," Bioorg Med Chem Lett 2:367-370 (1992).
Kumar et al, "Synthesis and Biological Evaluation of Some Cyclic Phosphoramidate Nucleoside Derivatives," J. Med. chem. 33:2368-2375 (1990).
McGuigan et al, "Phosphoramidate derivatives of AZT as inhibitors of HIV: studies on the carboxyl terminus," Antiviral Chemistry & Chemotherapy 4(2):97-101 (1993).
McGuigan et al, "Synthesis and anti-HIV activity of some haloalkyl phosphoramidate derivatives of 3'-azido-3'deoxythymidine (AZT): potent activity of the trichloroethyl methoxyalaninyl compound," Antiviral Research 15:255-263 (1991).
Mukaiyama et al, "Synthesis of Oligothymidylates and Nucleoside Cyclic Phosphates by Oxidation--Reduction Condensation," Journal of the American Chemical Society 94(24):8528-8532 (1972).
Palu et al, "Cellular uptake of phosphonylmethoxyalkylpurine derivatives," Antiviral Research 16:115-119 (1991).
Rosenberg et al, "Phosphonylmethoxyalkyl and Phosphonylalkyl Derivatives of Adenine," Coll. Czech. Chem. Comm. 53:2753-2777 (1988).
Rosenberg et al, "Synthesis of Potential Prodrugs and Metabolites of 9-(S)-(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenines," Coll. Czech. Comm. 52:2792-2800 (1987).
Sastry et al, "Membrane-Permeable Dideoxyuridine 5'-Monophosphate Analogue Inhibits Human Immunodeficiency Virus Infection," Molecular Pharmacology 41:441-445 (1992).
Snoeck et al, "Antiviral activity of anit-cytomegalovirus agents (HPMPC, HPMPA) assessed by a flow cytometric method and DNA hybridization technique," Antiviral Research 16:1-9 (1991).
Srivastva et al, "Bioreversible Phosphate Protective Groups: Synthesis and Stability of Model Acyloxymethyl Phosphates," Bioorganic Chemistry 12:118-129 (1984).
Starrett et al, "Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine," Antiviral Research 19:267-273 (1992).
Tolman et al, "2'-nor-cGMP: A seco-Cyclic Nucleotide with Powerfuf Anti-DNA-Viral Activity\," Biochemical and Biophysical Research Communications 128(3):1329-1335 (1985).
Wolff-Kugel et al, "Synthesis of New Carbocyclic Phosphonate Analogs of Dideoxypurine Nucleotides," Tetrahedron Letters 32(44):6341-6344 (1991).
Yu et al, "Synthesis and Antiviral Activity of Methyl Derivatives of 9-[2-(Phosphonomethoxy)ethyl]guanine," J. Med. Chem. 35:2958-2969 (1992).
Andrei et al, "Comparative Activity of Selected Antiviral Compounds against Clinical Isolates of Human Cytomegalovirus," Eur J Clin Microbiol Infect Dis 10(12):1026-1033 (1991).
Li et al, "Activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC)
Bernhardt Emily
Gilead Sciences, Inc.
Hensley Max D.
LandOfFree
Method for synthesis does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for synthesis, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for synthesis will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1765362