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WO1998005662A1 - Analogues de nucleosides a blocage conformationnel en tant qu'agents antiherpetiques - Google Patents

Analogues de nucleosides a blocage conformationnel en tant qu'agents antiherpetiques Download PDF

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Publication number
WO1998005662A1
WO1998005662A1 PCT/US1996/012800 US9612800W WO9805662A1 WO 1998005662 A1 WO1998005662 A1 WO 1998005662A1 US 9612800 W US9612800 W US 9612800W WO 9805662 A1 WO9805662 A1 WO 9805662A1
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Prior art keywords
virus
herpes
compound
carrier
methanocarba
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Inventor
Victor E. Marquez
Juan B. Rodriguez
Marc C. Nicklaus
Joseph J. Barchi, Jr.
Maqbool A. Siddiqui
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US Department of Health and Human Services
Government of the United States of America
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US Department of Health and Human Services
Government of the United States of America
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Priority to PCT/US1996/012800 priority Critical patent/WO1998005662A1/fr
Priority to AU67664/96A priority patent/AU6766496A/en
Publication of WO1998005662A1 publication Critical patent/WO1998005662A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the present invention relates to the use of conformationally locked nucleoside analogs as antiviral agents. More specifically, the invention relates to the use of 2'-deoxynucleoside analogs locked in the Northern conformation as antiherpetic agents.
  • Nucleoside analogs lacking 2'- and 3' hydroxyl groups can function as chain terminators of DNA synthesis after their incorporation into DNA. This is the basis of the Sanger dideoxynucleotide method for DNA sequencing (Sanger et al, Proc. Natl. Acad. Sci. USA, 1977). Intense effort has focused on the design and use of these compounds as inhibitors of viral replication (Van Roey et al., Ann. N. Y. Acad. Sci., £7/5:29, 1990).
  • the conformation of the sugar moiety in these analogs is believed to play a critical role in modulating biological activity, including the a ⁇ ti-HIV activity mediated by derivatives such as azidothymidine (AZT) and dideoxyi ⁇ osi ⁇ e (ddl), the main problem encountered in correlating a specific type of sugar conformation with the biological activity of nucleoside analogs is that the sugar ring is quite flexible and its conformation in solution can differ markedly from its conformation in the solid state (Jagannadh et al., Biochem. Biophys. Res. Comm ⁇ n., 179:386; Piavec et al., Biochem. Biophys. Methods, 25:253).
  • nucleosides and their analogs can be described by the geometry of the gl ⁇ cosyl link
  • the torsion angles [C2-N1-C1 '- 04' (pyrimidi ⁇ es) or C4-N9-CT-04' (puri ⁇ es)] and y (C3'-C4'-C5'-05') describe, respectively, the orientations of the base and the 5' hydroxyl group relative to the ribose ring.
  • a Southern conformation of the repeating nucleoside unit confers upon the double helix a B-conformation
  • the Northern conformation induces an A conformation double helix.
  • the A and B forms of DNA differ in the number of base pairs per turn, the amount of rotation per base pair, the vertical rise per base pair and the helical diameter.
  • Z-DNA may form.
  • the present invention provides such agents.
  • One embodiment of the present invention is a method of treating a herpes virus infection in an individual in need thereof, comprising the step of administering to said individual an effective herpes antiviral amount of a compound having the formula
  • the herpes virus is Herpes Simplex Virus- 1, Herpes Simplex Virus 2, Epstein-Barr Virus, Cytomegalovirus or Varicella-Zoster Virus.
  • the effective amount is between about 300 mg and about 15,000 mg per day.
  • the administering step is topical, oral, intravenous, intramuscular or subcutaneous.
  • the carrier is a sterile carrier suitable for parenteral administration.
  • the carrier is suitable for topical administration.
  • the carrier may also be suitable for oral administration.
  • the present invention also provide an oligodeoxynucleotide or phosphorothioate derivative thereof comprising at least one deoxynucleoside analog having the formula shown above.
  • Figure 1 illustrates the pseudorotational cycle.
  • Figure 2 illustrates the placement of substituents on the Bicyclo[3.1.0]hexane template for generating the Northern and Southern 2'-methanocarba deoxynucleoside analogs.
  • Figure 3 is a perspective view of compound 4 as found in the crystal structure.
  • C2' and C3' correspond, respectively, to C3' and C2' in a pentofuranose ring.
  • Figure 4 is a graph showing the energy distribution of 14 rotamers of (N)-methanocarba-T with energies of up to 5 kcal/mole above the global minimum.
  • Figure 5 is a graph showing the energy distribution of 9 rotamers of (S) methanocarba-T with energies of up to 5 kcal/mole above the global minimum.
  • Figure 6 is a graph illustrating the substrate disappearance and product formation from the interaction of compound 4 with adenosine deaminase (filled circles) and a hypoxanthine analog (open squares).
  • the present invention includes the observation that carbocyclic 2'-deoxynucleoside analogs locked in the Northern conformation are effective antiherpetic agents. These compounds are described in copending U. S. application Serial No. 08/311,425 and in PCT publication W095/08541. C ⁇ nformationaliy rigid (locked) nucleoside analogs are constructed on a bicyclo[3.1.0]hexane template whose value of P (pseudorotational angle) fits within the range of absolute Northern or Southern conformations.
  • This bicyclo[3.1.0]hexane template exists exclusively as a pseudoboat, and carbocyclic nucleosides built thereon can adopt either a Northern or Southern conformation depending on the relative disposition of substituents on the ring ( Figure 2).
  • a Northern Zl' exo ( 2 E) envelope conformation is obtained when the cyclopropane ring was fused between carbon C4' and the carbon supplanting the ribof ura ⁇ oside oxygen
  • fusion of the cyclopropane ring between carbon C1' and the carbon supplanting the ribofuranoside oxygen provides the opposite Southern conformation.
  • the carbocyclic 2'-deoxynucleoside analogs are referred to herein as (N)-2'-deoxy-methanocarba-A (adenosine analog), (N)-metha ⁇ ocarba-T (thymidine analog), (N)-2'-deoxy-methanocarba-G (gua ⁇ osine analog), (N)-2'-deoxy- methanocarba-C (cytosine analog) and (N)-2'-deoxy-metha ⁇ ocarba-U (uridine analog).
  • the structure of these analogs is indicated below (B-adenine, thymine, cytosine, guanine or uracil).
  • HFF human foreskin fibroblasts
  • EBV Epstein-Barr Virus
  • Cytomegalovirus all members of the Herpesviridae family. N-methanocarba-T is effective against HSV-1, HSV-2 and EBV. (N) methanocarba-A exhibited antiviral effects against Human CMV, EBV and HSV-2. HSV-1 and HSV-2 cause oral (fever blisters) and genital herpes simplex lesions, respectively; however, HSV-1 is the causative agent in approximately 5% of genital herpes cases. HSV-2 infection may lead to cervical cancer. CMV infection leads to cytomegalic inclusion disease (CMV). EBV is the causative agent of Burkitt's lymphoma and mononucleosis.
  • CMV cytomegalic inclusion disease
  • VZV Varicella-Zoster Virus
  • Herpes virus infections can also lead to Herpes Zoster. It is contemplated that the nucleoside analogs described herein may be used to treat any condition caused by a herpes virus.
  • adenosine analogs active against HCMV are also good inhibitors of the enzyme S-adenosylhomocysteine hydrolase (AdoHcy-ase).
  • AdoHcy-ase S-adenosylhomocysteine hydrolase
  • the activity of (N)-methanocarba-A (4) against AdoHcy-ase is very low, exhibiting only 20% inhibition at 100 ⁇ M concentration, indicating that the antiviral activity of the adenosine analog is independent of its interaction with this enzyme.
  • N-benzoyl group Base-catalyzed deprotection of the N-benzoyl group from intermediates 16 and 17 yields the penultimate intermediates 18 and 19, respectively, and simultaneous removal of both O-benzyl and O-t ⁇ /r-butyl groups with BCI3 provide the desired targets (N)- methanocarba-T (20) and N-methanocarba-U (21).
  • (N)-metha ⁇ ocarba-C (22) is prepared from (N)-metha ⁇ ocarba-U via formation of the triazole intermediate as described (Divakar et al., J. Chem. Soc. Perkin Trans, 1, 1171-1176, 1982).
  • the (N)-methanocarba nucleoside analogs may also be incorporated into short oligodeoxynucleotides (ODNs).
  • Standard double helices exist in the classic B-DNA form, in which all sugars have a Southern conformation, or in the
  • A-DNA form wherein the sugars have a N-conformation.
  • the A-form typical of RNA
  • the 2'-deoxy-methanacarbanucleosidesor derivatives thereof, or pharmaceutically acceptable esters or salts of these compounds, may be incorporated into a pharmaceutically acceptable carrier for administration to an individual having a herpes virus infection.
  • Contemplated routes of administration include topical, oral, intravenous, intramuscular and subcutaneous.
  • Nonlimiting examples of particularly preferred nucleoside analog compositions for topical administration include creams, lotions, gels, salves, sprays, dispersions, suspensions, pastes and ointments.
  • the deoxynucleoside analogs may be provided as a tablet, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and may include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives.
  • Tablets may contain the active compound in admixture with non-toxic pharmaceutically acceptable excipients including inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as gl ⁇ ceryl monostearate may be used.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or aca
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions may contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, dispersing or wetting agents, preservatives, coloring agents and sweetening agents.
  • the (N)-methanocarba 2'-deoxy ⁇ ucleoside analogs for parenteral administration may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Suitable diluents include, for example, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may be employed conventionally as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the formation of injectable preparations.
  • the pharmaceutical compositions may also be in the form of oil-i ⁇ -water emulsions.
  • the oily phase may be a vegetable oil, such as olive or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • compositions of the invention may additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
  • the compositions may contain additional compatible pharmaceutically active materials for combination therapy (such as supplementary antimicrobials, antipruritics, astringents, local anesthetics or anti-inflammatory agents), or may contain materials useful in physically formulating various dosage forms of the present invention, such as excipients, dyes, perfumes, thickening agents, stabilizers, skin penetration enhancers, preservatives or antioxidants.
  • additional compatible pharmaceutically active materials for combination therapy such as supplementary antimicrobials, antipruritics, astringents, local anesthetics or anti-inflammatory agents
  • materials useful in physically formulating various dosage forms of the present invention such as excipients, dyes, perfumes, thickening agents, stabilizers, skin penetration enhancers, preservatives or antioxidants.
  • Remington's Pharmaceutical Sciences 15th ed., Mack Publishing Co., Easton, PA (1975
  • acyclovir which is also a nucleoside analog.
  • Detailed information relating to administration and dosages of acyclovir may be found in the Physician's Desk Reference, 47th edition, pp. 844-850, 1993 and in Hayden et al., "Antiviral Agents" in Basic Principles in the Diagnosis of Infectious Diseases, pp. 271-274).
  • contemplated amounts of (N)-2'-deoxy-methanocarba- ⁇ ucleoside analogs for oral administration to treat initial genital herpes range from about 100 mg to about 300 mg about every 4 hours, five times daily for about 10 days (500-1,500 mg/day) or until there is a significant improvement in the condition.
  • For chronic suppressive therapy for recurrent disease between about 300 mg and about 500 mg is orally administered twice a day for up to about 12 months (600-1 ,000 mg/day).
  • For treatment of VZV, EBV and CMV between about 10 mg/kg and about 50 mg/kg is administered four times a day for about 5 days (about 2,800-14,000 mg/day).
  • a topical preparation containing about 50 mg nucleoside analog per gram of preparation is applied in an amount sufficient to adequately cover all lesions.
  • the topical preparation is applied every 3-6 hours 4-6 times daily for about 7 days or until the lesions have disappeared (about 300 mg/day).
  • the dose size per application will vary depending upon the total lesion area, but should approximate a one-half inch ribbon of preparation per four square inch surface area.
  • about 5 mg/kg is infused at a constant rate over 1 hour, every 8 hours (15 mg/kg/day) for about 7 days (about 1,050 mg/day).
  • VZV For intravenous administration to treat VZV, about 10 mg/kg is infused at a constant rate over 1 hour, every 8 hours for about 7 days in adult patients (about 2,100 mg/day).
  • IV administration to treat Herpes Zoster about 5-10 mg/kg /8 h is administered for about 5 days (about 1,050-2,100 mg/day).
  • the nucleoside analogs locked in the N conformation can also be incorporated into oligodeoxynucleotides (ODNs) to increase the thermal stability of the ODN with its target RNA. This observation has implications in targeted gene therapy.
  • ODNs oligodeoxynucleotides
  • An ODN containing (N)-locked oligonucleosides targeted to a particular gene can be introduced into a cell and will bind to its target RNA.
  • the increased stability of the DNA/RNA heteroduplex makes the RNA unavailable for translation into its corresponding protein.
  • Example 3 (1S.4R,5S)-1 -(rgf-Butyldimethylsilyloxy)-3-[(Benzyloxy)methvn-4-fg/-t butyloxy-5-hvdroxy-2-cvcloDentene(8)
  • a solution of 7 (8.04 g, 27.5 mmol) and imidazole (7.05 g, 103.55 mmol) in anhydrous DMF (80 ml) was mixed with . ⁇ rf-butyldimethyisilyl chloride (6.70 g, 44,45 mmol). The mixture was stirred at room temperature under a blanket of argon for 40 min and quenched by the slow addition of water (100 ml).
  • reaction mixture was cooled to -78°C and treated with chloroiodomethane (1.15 ml, 15.71 mmol).
  • the resulting mixture was continuously stirred starting at -78°C and allowed to reach ambient temperature during the night.
  • the reaction was quenched with a saturated solution of K C0 3 (50 ml) and extracted with ether (3 x 75 ml).
  • the combined organic extract was washed with brine (2 x 75 ml), dried over Na 2 S0 4 , filtered and evaporated to dryness.
  • GUANOSINE AND CYTIDINE The synthetic steps described below in Examples 11-17 are summarized in Schemes 3 (thymidine, uridine and cytidine analogs) and 4 (guanosine analog).
  • the solvent was evaporated at reduced pressure and the residue was purified first by flash chromatography (silica gel, 0%40% ethyl acetate in hexane) to give a mixture of N- and O-alkylated products, which were re-chromatographed (silica gel, 0% to 5% ether in CH 2 CI 2 to give 0.87 g (27%) of the desired N- alkylated product 16 as a semisolid and 1.30 g (40%) of the O-alkylated product as an oil.
  • the N-alkylated product (16) was dissolved in methanol (200 ml), treated with concentrated NH 4 0H (15 ml) and stirred at room temperature overnight.
  • the compound was reacted with a freshly made solution of PhCH 2 0Na (prepared from 10 ml benzyl alcohol and 0.30 g of Na) and stirred at room temperature for 30 min. The mixture was quenched with water and extracted with CH 2 CI 2 (2 x 75 ml). The combined organic extract was washed with water until the pH of the washings was neutral, dried over MgS0 2 and concentrated under reduced pressure.
  • PhCH 2 0Na prepared from 10 ml benzyl alcohol and 0.30 g of Na
  • Example 18 X-ray analysis of compound 4 X-ray crystallographic data was generated for compound 4-2H 2 0 (C 12 H 15 N 5 0 2 -2H 2 0), FW-297.32, mp 259-261 °C (dec). Triclinic, space group PI, a-6.1740(10), b-8.270(2), c- 14.760(2) A, ⁇ -94.280(10), ⁇ - 100.250(10), y- 102.240(10)°, V-719.812) A 3 , Z-2, D-- 1.372 mg mm '3 , l(CuK ⁇ )- 1.54178 A. . -0.881 mm "
  • the unit cell of the crystal contained two nearly identical molecules (A and B) which differ only in terms of the value of the torsion angle y that determines the orientation of the free primary hydrox ⁇ group.
  • the pseudorotational parameters calculated from the crystal structure were as follows: P-339.25 0 , v ma ⁇ -31.80°, x— 167.6° (molecule A); and P- 342.78°, v ma ⁇ - 30.46°, ⁇ - U ⁇ ° (molecule B). These values are in perfect agreement with a 2'-exo/3'-endo conformation with a theoretical value of P-342°. The value of for both molecules corresponds to the characteristic and orientation about the glycosyl bond.
  • Conformational analysis of N-2'-deoxy-methanocarba-T The complete definition of the conformation of a nucleoside usually involves the determination of three groups of structural parameters: (a) the orientation about the glycosyl bond as syn or anti, which is more precisely defined by the value of the torsion angle ⁇ ; (b) the orientation of the hydroxymethyl group determined by the value of the torsion angle y, and (c) the deviation from planarity of the sugar ring measured by the angle of pseudorotation P.
  • the pseudorotational angle P is calculated according to equation (1)
  • the endocyclic torsion angles vg-v 4 were measured directly from the X-ray structures. For the cyclopentane ring, these angles correspond to equivalent torsion angles as defined for a sugar moiety in Saenger et al., ibid.
  • the torsion angles x (pseudoglycosyl bond) and y correspond, respectively, to C 2 -N 1 -C 4 --C 5 . and HO-CH ⁇ C ⁇ C ⁇ . These torsion angles are equivalent to C ⁇ N ⁇ -C -O ⁇ and 0g -Cg'-C 4 '-C 3 ', in pyrimidine nucleotides.
  • the rotational barrier for x (E syn
  • the combination of higher energy barriers for the S conformer revealed in the potential energy map a much stiffer molecule with fewer low energy conformational states available when compared to the (N) conformer.
  • HPLC conditions were as follows: pump, Waters 6000A; detector, Perkin-Elmer LC 235 Diode Array @ 260 nm, AUFS 0.05; column, Becka /Altex 5 ⁇ ODS, 250 x 4.6 mm; mobile phase, CHgCN 7.5% in 0.01 M phosphate buffer, pH 7.0; flow rate, 1 ml/min. Curve fitting of the data to an exponential decay equation (y-Aexp' ') for substrate disappearance and an exponential association equation (y « A[1-exp' ']) for the inosi ⁇ e analog product formation yielded the curves shown in Figure 6.
  • HFF human foreskin fibroblasts
  • FBS fetal bovine serum
  • HSV-1 herpes simplex type 1
  • HSV-2 herpes simplex type 2
  • HCMV human cytomegalovirus
  • EBV Epstein- Barr virus
  • b HFF human foreskin fibroblasts.
  • c EC 5 n - inhibitory concentration in ⁇ g/mL required to reduce virus- induced cytopathogenicity (or viral capsid antigen for EBV) by 50%.
  • CC 50 cytotoxic concentration in ⁇ g/mL that produces 50% of cell death.
  • SI selectivity index (CC 50 /EC 50 ).
  • HSV-1 herpes simplex type 1
  • HSV-2 herpes simplex type 2.
  • EC 50 inhibitory concentration required to reduce the number of virus plaques by 50%.
  • c CC 5 n - cytotoxic concentration that produces 50% of cell death.
  • d SI - selectivity index (CC 50 /EC 50 ).
  • e ACV - acyclovir control. f These values correspond to a drug pre-treated plaque reduction assay.
  • Table 5 provides antiherpetic data for the (N) and (S) methanocarba analogs of adenosine, cytidine, uracil and guanine.
  • the (S) conformers of all these analogs exhibited little, if any activity with the exception of the adenosine analog which was active against HCMV.
  • the (N) cytidine analog was very active against HSV-1, and active against HCMV. Little activity was seen against HSV-2.
  • the (N) uridine analog was inactive against all three -24- viruses.
  • the (N) guanosine analog was active against HSV-1 and HSV-2, but exhibited little activity against HCMV.
  • the (N) adenosine analog results are discussed in regard to Table 3. The results indicate that the (N)-methanocarba adenosine, thymidine, cytidine and guanosine analogs are effective antiherpetic agents.
  • HSV-1 herpes simplex type 1
  • HSV-2 herpes simplex type 2
  • HCMV human cytomegalovirus.
  • EC 50 inhibitory concentration required to reduce virus-induced cytopathogenicity or virus plaques by 50%.
  • C CC 50 - cytotoxic concentration that produces 50% cell death.
  • SI SI - selectivity index (CC 50 /EC 50 ).
  • e ACV - acyclovir control; GCV - gancyclovir control, plaque reduction assay. Because several adenosine analogs active against HCMV are also good inhibitors of the enzyme S- adenosylhomocysteine hydrolase (AdoHcy-ase), the activity of 4 was tested against it. The activity of 4 against
  • AdoHcy-ase was very low (20% inhibition at a concentration of 100 ⁇ M), indicating that its antiviral activity is independent of its interaction with the enzyme. Accordingly, it is expected that 4 should be inactive against viruses which are sensitive to the inhibition of the enzyme.
  • T m was measured using the complementary RNA strand in 5 mM Na 2 HP0 , pH 7.2, 140 mM KCI, 1 mM MgCI 2 .
  • Table 6 the increase in thermody ⁇ amic stability of the heteroduplex due to the presence of multiple (N)-methanocarba-T nucleotides resulted in an average stabilization per substitution of about 1.3°C relative to thymidine.
  • ODN - 5'-CTTCA T - an pos tions are completely substituted with: (N)-methanocarba-T, thymidine (T), 5-propynyl-2'-deoxyuridine (pU), 5-propynyl-2'-deoxycytidine (pC), or 5-methyl-2'-deoxycytidine (5-Me-C).
  • b T m was measured using the complementary RNA strand in the buffer, 140 mM KCI/5 mM Na 2 HP0 /1 mM MgCI 2 , pH 7.2.
  • DNA/RNA heterodupexes wherein the DNA contains one or more [H) methanocarba- nucleoside analogs are also useful as antisense therapeutic agents and as in situ hybridization probes for detecting a particular RNA of interest in, for example, a tissue sample.
  • the increased stability of the resulting heteroduplex will allow hybidization to occur under more stringent conditions, thus increasing the signal to noise ratio of the desired RNA.
  • Example 23 Treatment of genital or oral herpes An individual having genital or oral herpes is treated with a topical preparation containing 50 mg of (N)- methanocarba-A, T, G, or C in a polyethylene glycol base. A sufficient amount is applied to adequately cover all lesions every 3 hours six times a day for seven days.
  • Example 24 Treatment of chicken pox, Burkitt's lymphoma or cytomeoalovirus inclusion disease
  • CORRESPONDENCE ADDRESS (A) ADDRESSEE: Knobbe, Martens, Olson & Bear (B) STREET: 620 Newport Center Drive, 16th Floor

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Abstract

Procédé de traitement de l'infection due à l'herpèsvirus, qui consiste à administrer une quantité, efficace pour inhiber le virus, d'un 2'-désoxynucléoside carbocyclique cyclopropané à un patient ayant besoin dudit traitement. Lesdits analogues de nucléoside sont efficaces contre l'herpès simplex de type 1 et 2, le virus d'Epstein-Barr et le cytomégalovirus humain.
PCT/US1996/012800 1996-08-07 1996-08-07 Analogues de nucleosides a blocage conformationnel en tant qu'agents antiherpetiques Ceased WO1998005662A1 (fr)

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PCT/US1996/012800 WO1998005662A1 (fr) 1996-08-07 1996-08-07 Analogues de nucleosides a blocage conformationnel en tant qu'agents antiherpetiques
AU67664/96A AU6766496A (en) 1996-08-07 1996-08-07 Conformationally locked nucleoside analogs as antiherpetic agents

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WO2001051490A1 (fr) * 2000-01-14 2001-07-19 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Analogues nucleosidiques de methanocarba cycloalkyle
WO2002008204A3 (fr) * 2000-07-26 2002-05-16 Us Gov Health & Human Serv Derives de pyrimidine 5-substituee d'analogues de nucleosides a blocage conformationnel
WO2006091905A1 (fr) * 2005-02-25 2006-08-31 Gilead Sciences, Inc. Derives de bicyclo(3.1.0) hexane utilises comme composes antiviraux
WO2006113204A3 (fr) * 2005-04-15 2009-09-03 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Utilisation de north-2'-desoxy-methanocarbathymidines comme agents antiviraux dans le traitement l'herpesvirus lie au sarcome de kaposi
US8518957B2 (en) 2009-12-02 2013-08-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methanocarba adenosine derivatives, pharmaceutical compositions, and method of reducing intraocular pressure

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Publication number Priority date Publication date Assignee Title
WO2001051490A1 (fr) * 2000-01-14 2001-07-19 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Analogues nucleosidiques de methanocarba cycloalkyle
US7087589B2 (en) 2000-01-14 2006-08-08 The United States Of America As Represented By The Department Of Health And Human Services Methanocarba cycloakyl nucleoside analogues
US7790735B2 (en) 2000-01-14 2010-09-07 The United States Of America As Represented By The Department Of Health And Human Services Methanocarba cycloalkyl nucleoside analogues
WO2002008204A3 (fr) * 2000-07-26 2002-05-16 Us Gov Health & Human Serv Derives de pyrimidine 5-substituee d'analogues de nucleosides a blocage conformationnel
US7009050B2 (en) 2000-07-26 2006-03-07 The United States Of America As Represented By The Department Of Health And Human Services 5-Substituted pyrimidine derivatives of conformationally locked nucleoside analogues
WO2006091905A1 (fr) * 2005-02-25 2006-08-31 Gilead Sciences, Inc. Derives de bicyclo(3.1.0) hexane utilises comme composes antiviraux
WO2006113204A3 (fr) * 2005-04-15 2009-09-03 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Utilisation de north-2'-desoxy-methanocarbathymidines comme agents antiviraux dans le traitement l'herpesvirus lie au sarcome de kaposi
US8518957B2 (en) 2009-12-02 2013-08-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methanocarba adenosine derivatives, pharmaceutical compositions, and method of reducing intraocular pressure

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