WO1991012260A1 - 6-halo- et 2-amino-6-halo-purine 2',3'-didesoxy nucleosides ainsi que leur emploi en tant qu'agents antiviraux - Google Patents

6-halo- et 2-amino-6-halo-purine 2',3'-didesoxy nucleosides ainsi que leur emploi en tant qu'agents antiviraux Download PDF

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Publication number
WO1991012260A1
WO1991012260A1 PCT/US1991/000886 US9100886W WO9112260A1 WO 1991012260 A1 WO1991012260 A1 WO 1991012260A1 US 9100886 W US9100886 W US 9100886W WO 9112260 A1 WO9112260 A1 WO 9112260A1
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WIPO (PCT)
Prior art keywords
compound
purine
dideoxy
glycero
amino
Prior art date
Application number
PCT/US1991/000886
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English (en)
Inventor
Hiroaki Mitsuya
Takuma Shirasaka
Samuel Broder
Kunichika Murakami
Hidetoshi Yoshioka
Eiji Kojima
Original Assignee
The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce
Sanyo-Kokusaku Pulp Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce, Sanyo-Kokusaku Pulp Co., Ltd. filed Critical The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce
Priority to CA002075490A priority Critical patent/CA2075490A1/fr
Priority to AU73037/91A priority patent/AU644412C/en
Priority to JP91504549A priority patent/JPH05506211A/ja
Publication of WO1991012260A1 publication Critical patent/WO1991012260A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • HIV Human Immunode iciency Virus
  • This virus is one member of a retrovirus family which includes viruses which cause numerous neoplasms and/or immune system abnormalities in humans and animals. Because the virus can destroy cells critical to a person's immune system the person becomes more susceptible to infection by a large number of microorganisms which would otherwise be easily handled by a fully operable immune system.
  • HIV also causes much morbidity and even some mortality by lesser disease states such as by wasting away with ARC.
  • compositions useful for inhibiting viral growth in cells This is done by administering any of the eight novel dideoxynucleoside purine derivatives described below. All of these compounds have demonstrated effec ⁇ tiveness at blocking the infectivity, the cytotoxic effect of a virus against cells, and the synthesis of gag protein in T-cells. Furthermore, these compounds have been shown to inhibit infection of HIV in macrophages.
  • the invention encompasses their use to block any virus which utilizes this enzyme in its life cycle.
  • these compounds are also used to inhibit the replication of hepatitis B virus which has reverse transcriptase and can cause hepatitis, cirrhosis and hepatic cancer in humans.
  • Viruses of particular concern are in the human retrovirus group, particularly HIV of any type.
  • These compounds are more lipophilic than other anti-HIV dideoxynucleoside analogues such as AZT, ddC, ddG, ddl or ddA. Accordingly, these compounds are expected to cross the blood-brain barrier better and therefore may be more effective at blocking viral infection in the central nervous system.
  • These compounds are substrates for adenosine deaminase and convert to ddl or ddG in vivo.
  • these compounds can be used to prevent an infection from becoming established as well as treatment once cells become infected.
  • Examples of such preventative use may be for people potentially exposed to a virus but are uncer ⁇ tain whether or not they are actually infected such as when one has been injured with contaminated equipment or contacted contaminated fluids.
  • Figures la-d and 2a-d show the number of ATH-8 cells remaining upon exposure to various concentrations of various suspected anti-rviral compounds. For each test 2X10 5 ATH-8 cells are exposed to 1,000 HIV virus parti ⁇ cles/cell and cultured in the presence of various concen- trations of a compound. The dark bars represent the cell number after six days of growth following exposure to HIV and the white bars represent the cell number after six days of growth without virus.
  • Figure la shows the data when 6-fluoro, dideoxy- purine is used as the suspected anti-viral compound.
  • Figure lb shows the data when 6-chloro, dideoxy- purine is used as the suspected anti-viral compound.
  • Figure lc shows the data when 6-bromo, dideoxy- purine is used as the suspected anti-viral compound.
  • Figure Id shows the data when 6-iodo, dideoxy- purine is used as the suspected anti-viral compound.
  • Figure 2a shows the data when 2-amiho, 6-fluoro, dideoxypurine is used as the suspected anti-viral com ⁇ pound.
  • Figure 2b shows the data when 2-amino, 6-chloro, dideoxypurine is used as the suspected anti-viral com ⁇ pound.
  • Figure 2c shows the data when 2-amino, 6-bromo, dideoxypurine is used as the suspected anti-viral com ⁇ pound.
  • Figure 2d shows the data when 2-amino, 6-iodo, dideoxypurine is used as the suspected anti-viral com ⁇ pound.
  • X is any hal fluorine, chlorine, bromine or iodine
  • Y is hydrogen or amino
  • Z is hydroxyl, monophosphate, diphosphate or triphosphate.
  • the HIV infectivity assay using ATH-8 cells is now a recognized in vitro test which reasonably accurately predicts biological activity in vivo. See the previous U.S. Patent 4,704,357 by Mitsuya et al. This has been demonstrated with AZT, ddl, ddC and several promising drugs now undergoing the later stages of clinical trials.
  • the compounds of the invention used alone or in combina ⁇ tion with each other or other anti-viral compounds not of this invention would typically be used with a pharmaceuti ⁇ cally acceptable carrier to facilitate administration of the active ingredient. Also esters of the described compounds may also be used.
  • Preferred esters of the anti-viral compounds may include carboxylic acid esters in which the non-carbonyl moiety of the ester grouping is straight or branched chain alkyl, alkoxyalkyl (e.g. methoxymethyl) , aralkyl (e.g benzyl) , aryloxyalkyl (phenoxymethyl) , aryl (e.g.
  • a halogen, C 1-4 alkyl or alkoxy sulphonate esters such as alkyl or aralkylsulphonyl (e.g methanesulphonyl)
  • mono-, di- or tri-phosphate esters Another embodiment of the present invention invol- ves direct delivery of the triphosphate derivative directly to the host cell.
  • triphosphate derivatives generally do not penetrate cell membranes well, it needs to be "packaged" in order to cross the cell membrane.
  • One way is by encapsulating the drug in a small liposome (about l ⁇ to 25 ⁇ in diameter) which permits normally non- absorbable drugs to cross the cell membrane.
  • liposomes for drug delivery is well known in the art and is based on a phospholipid's ability to spontaneously form lipid bilayers in aqueous environments.
  • One method of forming liposomes is by agitating phospholipids in aqueous suspensions at high frequencies; this results in the closed vesicles characteristic of liposomes. Once a liposome contacts a cell membrane it fuses and thereby "dumps" its contents into the cell. This technique will permit the triphosphate form of the dideoxynucleoside purine derivatives to enter the cell and thereby act in the same manner as the same triphosphate compound formed naturally inside the cell from the dideoxynuceloside purine derivatives.
  • any alkyl moiety present preferably contains 1-18 carbon atoms, more preferably 1-4 carbon atoms.
  • the aryl moiety preferably comprises a phenyl or substituted phenyl group.
  • physiologically or pharmaceutically acceptable salts of the compounds or acceptable deriva ⁇ tives thereof include base salts, e.g. derived from an appropriate base, such as alkali metal, alkaline earth metal salts, ammonium, and NX 4 wherein each X is hydrogen or an alkyl with 1-4 carbon atoms.
  • Acceptable salts containing a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, succinic: organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulphonic; and inorganic acids such as hydrochloric, sulfuric, phosphoric, sulfamic acids.
  • Acceptable salts of a compound containing any hydroxy group include the anion of said compound in combination with a suitable cation such as sodium, NX 4 , NHX 3 , NH s 2 , NH 3 X wherein X is alkyl having 1-4 carbon atoms.
  • pharmaceutically acceptable derivatives of the anti-viral compound include sodium salts of 5' esters including mono-, di- and tri- phosphates, acetates, 3-methyl butyrate, octanoate, palmitate, 3-chloro benzo- ate, 4-methyl benzoate, hydrogen succinate, pivalate and mesylate.
  • the pharmaceutically acceptable salts, esters, salts of such esters, nitrile oxides, or any other covalent linked or non-linked compounds which upon administration to the cells or individual, is capable of providing (directly or indirectly) the substituted dideoxynucleoside anti-viral compound described in the invention or a biologically active metabolite thereof. All of these compounds are active and relatively non-toxic at concen- trations sufficient for effective inhibition of viral cytotoxicity.
  • the active ingredient(s) may be used or administered in a pharmaceutical formulation.
  • These formulations comprise at least one active ingredi ⁇ ent, together with one or more pharmaceutically acceptable carriers and possibly other active or inactive therapeutic ingredients.
  • "acceptable” is defined as being compatible with other ingredients of the formulation and relatively non- injurious to the patient or host cell.
  • These carriers include those well known to practitioners in the art as suitable for oral, rectal, nasal, topical, buccal, sublin- gual, vaginal, transdermal, subcutaneous, intradermal, intramuscular, intravenous or other parenteral administra ⁇ tion. Specific carriers suitable for use in the invention are further defined below.
  • a suitable dose in the range of 0.1 to 120 mg per kilogram body weight per day and more preferably in the range of 10-60 mg per kilogram body weight per day.
  • the desired dose is preferably provided in several increments at regular intervals throughout the day or by continuous infusion or sustained release formu ⁇ lations.
  • the doses will need to be modified according to the type of cells being treated, the species of the cells or patient, the particular virus infection one wishes to treat or prevent, the condition of the patient particularly in regard to the hepatic, renal, and bone marrow functions, and the nature of whatever other treatment is being employed,
  • the active ingredient is administered to achieve peak plasma concentrations of the active compound from about 0.5 ⁇ M to about 200 ⁇ M and preferably from about l ⁇ M to lOO ⁇ M. This may be achieved, for example, by intravenous injection of 0.1% to 50% concentration in solution of the active ingredient or may be administered orally in doses of about 0.1-120 mg/kg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient. Ideally, concentrations in the cerebrospinal fluid should reach 10- 100% of the circulating plasma concentration. To attain such levels, the ingredient may be administered intra- thecally or systemically.
  • the antiviral compounds may be administered orally in liquid or in solid form and may include any of the following: antacids, lactose (hydrous, fast flow etc.), microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, stearic acid and other excipients, binders, colorants and other pharmacologically compatible carriers.
  • Compositions for oral use may be administered to patients in fasting or non-fasting states.
  • Formulations of the present invention suitable for oral administration include sustained release formulations and may be presented in discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient(s) .
  • the shape and form of the solid are immaterial and it may be composed of smaller solids such as powders or granules.
  • the formulation may be in liquid form such as a solution, suspension, oil-in- water or water-in-oil emulsion.
  • Other acceptable formula ⁇ tions include a bolus, electuary or paste.
  • the oral dose may optionally be provided with an enteric coating to provide release in any part of the digestive track so desired.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient with an acceptable flavorant such as sucrose and acacia or tragacanth; with an inert ingredient(s) such as gelatin or glycerin; or a combination of both. Mouth- wash comprising the active ingredient and a liquid carrier are also acceptable in accordance with the invention.
  • Formulations for topical and transdermal adminis- tration include a suitable carrier such as a cream or base of other material to facilitate contact with the skin or mucus membranes.
  • a suitable carrier such as a cream or base of other material to facilitate contact with the skin or mucus membranes.
  • the active ingredient(s) contained therein may be charged, or converted into a salt in order to permit crossing the surface under the influence of an electrical field.
  • the active ingredient may be derivatized in order to enhance absorption or transport across the cell layer.
  • Formulations for rectal administration may be presented as a suppository with a suitable base, for exam ⁇ ple, comprising cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulas containing such carriers as are known in the art to be appropriate in addition to the active ingredient(s) .
  • Formulations suitable for parenteral administra- tion include aqueous and non-aqueous, isotonic and isos- motic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the body fluids of the intended recipient and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and may be stored in a freeze-dried (lyophi- lized) condition requiring only the addition of the sterile liquid carrier (e.g. water, saline) for injection immediately prior to use.
  • Extemporaneous injection solu ⁇ tions and suspensions may be prepared from powders, granules and tablets of the kind previously described. In all cases, the final product is preferably free of pyrogens.
  • the compounds of the invention may not be stable in the acid range it may be necessary to buffer or otherwise protect the composition in the neutral range to provide adequate bioavailability.
  • anti-viral compounds of the invention may be used in conjunction with other anti-viral drugs, antibiotics or immuno odulating chemicals.
  • Other forms of therapy such as cell transplants may also be concurrently used.
  • EXAMPLES 2• ,3•-dideoxyuridine (DDU) was chemically synthe ⁇ sized from uridine by a method previously described by Furukawa et al, Chem. Pharm. Bull. 18(3), p. 554-60 (1970) .
  • 6-chloropurine, 6-iodopurine, 2-amino-6-chloro- purine and 2-amino-6-iodopurine were purchased from Sigma Chemical Company.
  • 6-Fluoropurine and 2-amino-6-fluoro- purine were synthesized by the method of Lister et al, J. Chem. Soc. (C) p. 3942-7 (1971) .
  • 6-bromopurine and 2- amino-6-bromopurine were synthesized from the corresponding purine thiols and bromine in the presence of aqueous hydrobromic acid and methanol according to Beamar et al, J. Org. Chem. 27 p. 986 (1962).
  • Escherichia coli JA-300 (Gene 10. p. 157 (1980) was selected as the best strain for the production of the various 2' ,3*-dideoxynucleosides. This is done by a base exchange reaction catalyzed by the microorganism.
  • the cells of E. coli JA-300 were inoculated into five flasks of 100 ml of medium in a 500 ml flask.
  • the medium used consisted of 0.5 g of yeast extract (Oriental Yeast, Tokyo, Japan), 1.0 g of Polypepton (Nippon-Seiyaku, Tokyo, Japan), and 0.5 g NaCl in 100 ml deionized water.
  • the culture was aerobically grown at 37°C for 24 hours. 500 ml of the culture was added to a 30 1 jar-fermenter and 20 1 of fresh medium added followed by 24 hours aerobic cultivation at 37°C. The cells of E. coli JA-300 were then harvested by centrifugation for 10 minutes at 8000 rpm in 10°C. About 150 g of wet cells were recovered and used as the enzyme source below.
  • the supernatant was recovered and chromato- graphed on a DIAION HP-20 column (Mitsubishi Kasei Co.) and eluted with water, 20% methanol and 100% methanol.
  • the fraction of methanol was concentrated and purified by silica gel column chromatography with ethyl acetate used to elute the column, and treated with activated charcoal to yield 180 mg (0.76 mmol) of 6-fluoro-9-(2,3-dideoxy- / 3- D-glycero-pentofuranosyl)-9H-purine (6-F, ddP) a 23% yield.
  • the supernatant was chromato ⁇ graphed on a DIAION HP-20 column (Mitsubishi Kasei Co.) and eluted with water, 10% methanol and 50% methanol. The 50% methanol fraction was evaporated to yield 164 mg 2- amino-6-fluoro-9-(2,3-dideoxy-3-D-glycero-pentofuranosyl)- 9H-purine (2-amino, 6F, ddP) a 21.7% yield.
  • the supernatant was chromato ⁇ graphed on a DIAION HP-20 column (Mitsubishi Kasei Co.) and eluted with water, 20% methanol and 50% methanol.
  • the 50% methanol fraction was treated with activated charcoal and evaporated to give 2-amino-6-bromo-9-(2,3-dideoxy-j8-D- glycero-pentofuranosyl)-9H-purine.
  • the compound was recrystallized from water to yield 1.25 g (3.98 mmol) of pale yellow crystals, a 21.3% yield.
  • the supernatant was chromatographed on a DIAION HP-20 column (Mitsubishi Kasei Co.) and eluted with water, 20% methanol, and 50% methanol. The 50% methanol fraction was evaporated to yield 2-amino-6-iodo-9-(2,3-dideoxy- ⁇ -D- glycero-pentofuranosyl-9H-purine (2-amino, 6-1, ddP) . The compound was recrystallized from water to give 2.0 g (5.5 mmol) of white crystal for a yield of 32.3%.
  • a human tetanus toxoid-specific T-cell line was established by repeated cycles of stimulation with antigen as described by Mitsuya et al, Science, 225, p. 1484-6 (1984), and cloned in the presence of lethally irradiated (12,000 rad) human T-lymphotrophic virus type I (HTLV-I) producing MJ tumor cells in 96-well microtiter culture plates (Costar, Cambridge, MA) . Clone ATH-8 was isolated by limiting dilution when plated at 0.5 cells per well.
  • ATH-8 cells bear several distinct copies of HTLV-I in its genome when assessed by Southern Blot Hybridization using a radiolabelled HTLV-I cDNA probe but does not produce detectable amounts of HTLV-I p24 gag protein.
  • 2 X 10 5 ATH-8 cells were pelleted and exposed to 1,000 HIV viral particles/cell for 40 minutes and resuspended in 2 ml of RPMI medium supplemented with 15% undialysed heat- inactivated fetal calf serum, 4mM L-glutamine, 5X10 "5 M 2- mercaptoethanol, 50 U/ml penicillin, and 50 ⁇ g/ l strepto- ycin, further containing 15% (vol./vol.) IL-2 (lectin- depleted; Cellular Products, Inc.
  • the cells were cultured in culture tubes (3033, Falcon, Oxnard, CA) at 37 C in 5% carbon dioxide humidified air. On day 6 in culture the total viable cells were counted by the trypan blue dye exclusion method. The number of viable cells cultured at concentrations ranging from 0 ⁇ m to 200 ⁇ m with each of 6-F-ddP, 6-Cl-ddP, 6-Br-ddP, 6-I-ddP, 2- amino-6-F-ddP, 2-amino-6-Cl-ddP, 2-amino-6-Br-ddP and 2- amino-6-I-ddP are shown in Figs, la-d and Figs. 2a-d.

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Abstract

Compositions contenant des 6-halo, 2',3'-didésoxy-nucleoside purines et des 2-amino, 6-halo, 2',3'-didésoxy-nucleoside purines, utiles dans le traitement d'infections virales. Ces composés sont particulièrement utiles dans la prévention de la réplication virale et des faits cytotoxiques du virus d'immunodéficience humaine (VIH) et du virus de l'hépatite B chez des individus contaminés par ces virus.
PCT/US1991/000886 1990-02-09 1991-02-08 6-halo- et 2-amino-6-halo-purine 2',3'-didesoxy nucleosides ainsi que leur emploi en tant qu'agents antiviraux WO1991012260A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002075490A CA2075490A1 (fr) 1990-02-09 1991-02-08 6-halo et 2-amino-6-halo-purine 2',3'-didesoxynucleosides et leur utilisation comme agents antiviraux
AU73037/91A AU644412C (en) 1990-02-09 1991-02-08 6-halo- and 2-amino-6-halo-purine 2',3'-dideoxy nucleosides and their use as antiviral agents
JP91504549A JPH05506211A (ja) 1990-02-09 1991-02-08 ６―ハロ―及び２―アミノ―６―ハロ―プリン２′，３′―ジデオキシヌクレオシド及び抗ウイルス剤としてのそれらの使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47740690A 1990-02-09 1990-02-09
US477,406 1990-02-09

Publications (1)

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WO1991012260A1 true WO1991012260A1 (fr) 1991-08-22

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PCT/US1991/000886 WO1991012260A1 (fr) 1990-02-09 1991-02-08 6-halo- et 2-amino-6-halo-purine 2',3'-didesoxy nucleosides ainsi que leur emploi en tant qu'agents antiviraux

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EP (1) EP0544668A1 (fr)
JP (1) JPH05506211A (fr)
CA (1) CA2075490A1 (fr)
WO (1) WO1991012260A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0286425A2 (fr) * 1987-04-09 1988-10-12 The Wellcome Foundation Limited Nucléosides thérapeutiques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR910700054A (ko) * 1988-12-12 1991-03-13 엠. 팔레스 피터 B형 간염 비루스 감염의 예방 및 치료를 위한 방법 및 조성물
JP2619710B2 (ja) * 1989-02-27 1997-06-11 日本製紙 株式会社 ２′，３′−ジデオキシプリンヌクレオシド類の製造方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0286425A2 (fr) * 1987-04-09 1988-10-12 The Wellcome Foundation Limited Nucléosides thérapeutiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Journal of the American Chemical Society, Volume III, issued 1989, NAIR et al., "Novel, Stable, Congeners of Antiretroviral Compound 2', 3' -Dideoxy-Adenosine", pages 8502-8504, see entire document. *
See also references of EP0544668A4 *

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EP0544668A1 (fr) 1993-06-09
EP0544668A4 (fr) 1993-03-03
JPH05506211A (ja) 1993-09-16
CA2075490A1 (fr) 1991-08-10

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