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WO1994026273A1 - Derives d'acyclovir a usage topique - Google Patents

Derives d'acyclovir a usage topique Download PDF

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Publication number
WO1994026273A1
WO1994026273A1 PCT/US1993/004450 US9304450W WO9426273A1 WO 1994026273 A1 WO1994026273 A1 WO 1994026273A1 US 9304450 W US9304450 W US 9304450W WO 9426273 A1 WO9426273 A1 WO 9426273A1
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acyclovir
beta
nucleoside analogue
formulation
monophosphate
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PCT/US1993/004450
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Karl Y. Hostetler
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Priority to CA002162574A priority Critical patent/CA2162574A1/fr
Priority to PCT/US1993/004450 priority patent/WO1994026273A1/fr
Priority to JP6525361A priority patent/JPH08510236A/ja
Priority to EP93913832A priority patent/EP0746319A4/fr
Priority to AU43721/93A priority patent/AU701574B2/en
Publication of WO1994026273A1 publication Critical patent/WO1994026273A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention relates to the topical treatment of cutaneous virus infections. It relates particularly to the topical treatment of herpes simplex infections, including herpes simplex types 1 and 2, using formulations comprising phosphate esters of anti-herpes antiviral nucleoside analogues such as acyclovir.
  • Acyclovir is an antiviral nucleoside analogue of guanosine which contains an unusual incomplete (acyclic) sugar moiety. Nucleoside analogues interrupt the process of DNA replication in cells, and are for that reason useful as antiviral and antineoplastic agents.
  • ACV is particularly effective in treating herpes simplex virus infections of types I and II.
  • the antiherpes virus activity of ACV in cells occurs with low toxicity because ACV is selectively phosphorylated by HSV thymidine kinase, but not host cell thymidine kinase. As a consequence, only cells infected with HSV can form ACV monophosphate (ACV-MP) .
  • ACV-MP is then anabolically converted by cellular enzymes to ACV triphosphate, the active agent that interferes with viral replication.
  • the anti-herpes virus activity of acyclovir has been demonstrated in inhibiting the replication of herpes simplex virus in tissue culture cells (O'Brien, W. , et al., Antimicrob. Agents and Chemother. 34:1178-1182 (1990) ; it has also been demonstrated in clinical studies wherein patients infected with HSV were treated with orally administered ACV (Whitley, R., Immunobiol . and Prophylaxis of Human Herpesvirus Infections, C. Lopez et al, (eds) Plenum Press, NY 1990; and Straus, S., Sexually Transmitted Diseases 16 (2) : 107-113 (1989) .
  • Acyclovir is the treatment of choice for mucosal and cutaneous HSV infections, although, patients receiving topical acyclovir therapy experience some reductions of their symptoms, healing is slow and incomplete (Spruance, S., et al., J. Infect. Pis. 146:85-90 (1982) ; and Spruance, S., et al . , Antimicrob. Agents Chemother. 25:553-555 (1984) . Combination treatment using ACV together with interferon for herpes virus infected cultured cells (O'Brien, . , et al . , Antimicrob. Agents and Chemother.
  • Acyclovir has been used with qualified success in a clinical trial to treat another viral disease, varicella (chickenpox) (Whitley, R.,et al . , Immunobiology and Prophylaxis of Human Herpesvirus Infections, C. Lopez (ed) , Plenum Press, New York (1990) pp. 243-253. It has also been used experimentally but without success in treating other disorders in which a viral etiology was hypothesized, such as aplastic anemia (Gomez-Almaguer, D., et al. Amer. J. of Hematology 29:172-173 (1988) and duodenal ulcer (Rune, S.J., et al. , Gut 31:151-152 (1990) ) .
  • Acyclovir phosphates have been shown to be efficacious against wild type or laboratory isolates of HSV-1 infected cultured cells in vitro, but have little or no efficacy against thymidine kinase defective mutants of HSV under the same conditions. (See data of Figures 1 and 2 ) .
  • acyclovir phosphate esters and other antiherpes antiviral nucleoside analogue phosphate esters that are effective in the treatment of mucosal and cutaneous herpetic lesions due to herpes virus infections.
  • These agents surprisingly show antiviral activity against lesions due to thymidine kinase defective herpes virus infections, even though they are relatively inactive against these mutant viruses in cultured cells.
  • the invention also provides pharmaceutical formulations, comprising an effective, antiviral concentration of an acyclovir derivative which can be acyclovir monophosphate, acyclovir diphosphate, acyclovir monophosphate glycerol, acyclovir diphosphate glycerol, acyclovir monophosphate morpholidate, acyclovir monophosphate glycerol, acyclovir diphosphate glycerol, acyclovir monophosphate isopropylidene glycerol, acyclovir diphosphate isopropylidene glycerol, or a mixture thereof, in a pharmaceutical carrier suitable for topical use.
  • an acyclovir derivative which can be acyclovir monophosphate, acyclovir diphosphate, acyclovir monophosphate glycerol, acyclovir diphosphate glycerol, acyclovir monophosphate morpholidate, acyclovir monophosphate
  • antiherpes simplex nucleosides which rely on phosphorylation by viral thymidine kinase will also exhibit enhanced activity when applied to the skin of infected patients as their phosphate esters in a suitable topical formulation.
  • a method for the topical treatment of a viral infection comprising applying a formulation comprising any of the acyclovir phosphate derivatives of the invention, or a mixture thereof, to the mucosal or cutaneous lesions of a virus infected animal, including a human or other mammal.
  • the animal is infected with a herpes virus.
  • the animal is infected with a herpes virus strain that is resistant to acyclovir.
  • the acyclovir resistant herpes virus strain can be a viral strain in which resistance to the antiviral agent is due to an alteration or defect in the thymidine kinase gene.
  • an anti-herpes nucleoside analogue monophosphate is used in the preparation of a medicament for the treatment of a mucosal or cutaneous viral infection-
  • the nucleoside monophosphate is a water soluble salt.
  • the viral infection is herpes simplex virus, type 1 or type 2.
  • the anti ⁇ herpes nucleoside analogue monophosphate is used together with a pharmaceutically acceptable carrier in the preparation of a medicament for the treatment of a mucosal or cutaneous viral infection.
  • the pharmaceutically acceptable carrier is selected from the group consisting of an aqueous cream and polyethylene glycol .
  • Figure 1 illustrates the comparative effect of acyclovir and acyclovir monophosphate on herpes simplex virus replication in Wi38 fibroblasts .
  • Figure 2 illustrates the comparative effect of acyclovir and acyclovir monophosphate on the replication of HSV-DM.21 TK mutant in vitro.
  • Figure 3 illustrates the comparative effect of topical acyclovir and acyclovir phosphate esters on acyclovir- resistant HSV-1 infections of the TK-deficient type in HRS/J mice.
  • Figure 4 illustrates the comparative effect of topical acyclovir and acyclovir phosphate esters on acyclovir- resistant HSV-1 infections of the TK-altered type in HRS/J mice.
  • Figure 5 illustrates the comparative effect of topical acyclovir and acyclovir monophosphate on acyclovir-resistant HSV-1 infections of the wild type in HRS/J mice.
  • Figure 6 illustrates the comparative effect of topical acyclovir and acyclovir monophosphate on acyclovir-resistant HSV-1 infections of the TK-altered type in HRS/J mice.
  • the present invention provides acyclovir phosphate derivatives that demonstrate excellent topical activity against herpes simplex virus (HSV) infections, particularly against ACV-resistant mutants of HSV.
  • Acyclovir is an analogue of the purine base, guanine, having a substituent group at the 9-position, and having an acyclic sugar group from which the common name is derived.
  • the chemical name of acyclovir is 9- (2-hydroxyethoxymethyl) - guanine, which has the structure:
  • acyclovir phosphate derivatives of the invention have a substituent, R, at the terminal O-locant of the acyclic sugar group, as follows:
  • acyclovir monophosphate ACV- MP
  • acyclovir diphosphate ACV-DP
  • acyclovir monophosphate glycerol ACV-MP-G
  • acyclovir diphosphate glycerol ACV-DP- G
  • acyclovir monophosphate morpholidate ACV-MP-morpholine
  • acyclovir monophosphate isopropylidene glycerol ACV-MP-isoP- G
  • acyclovir diphosphate isopropylidene glycerol ACV-DP- isoP-G
  • V-araU 5-vinyl-l-beta-D-arabinofuranosyluracil
  • Ara-T 1-beta-D-arabinofuranosulthymine
  • the various phosphate esters of these compounds may be prepared essentially as described below for acyclovir.
  • the present invention provides methods for the synthesis of acyclovir mono- and diphosphates, acyclovir monophosphate morpholidates, acyclovir mono- and diphosphate glycerols, and acyclovir mono- and diphosphate 1, 2-isopropylidene glycerol.
  • Acyclovir monophosphate can be prepared from acyclovir according to the method of Yoshikawa, M. , et al . , Bull. Chem.
  • Acyclovir diphosphate can be prepared, in the manner of other nucleoside analogues, by the method of Ott, D.G. , et al. , Anal. Biochem. 21:469-472 (1967), using either tributylammonium phosphate or tributylammonium pyrophosphate as the phosphate donor. Methods for the preparation of acyclovir diphosphate glycerol are presented in Examples 2 through 4.
  • nucleoside phosphate glycerols are prepared ir- a manner similar to that for the preparation of phosphatidyl nucleosides.
  • acyclovir phosphate is activated by the addition of a leaving group, for example, morpholine, according to Example 2, and condensed with glycerol-3-phosphate dicyclohexylammonium salt in the presence of N,N' -dicyclohexylcarbodiimide (DCC) .
  • DCC N,N' -dicyclohexylcarbodiimide
  • glycerol phosphate having the reactive hydroxyl groups protected by an isopropylidene moiety, is activated by addition of morpholidate, and then condensed with acyclovir monophosphate under the conditions described for Example 2.
  • a number of acyclovir-diphosphate-diglycerides (ACV-DP- DG) containing various acyl chains have been prepared in the past by the condensation of the appropriate diacylphosphatidic acid morpholidate (PA-Morpholidate) and acyclovir monophosphate (ACV-MP.)
  • PA-Morpholidate diacylphosphatidic acid morpholidate
  • ACV-MP acyclovir monophosphate
  • a method by which the procedure can be carried out is described by Agranoff, B. and Suomi, W. , Biochem. Prep. 10:47-51 (1963) .
  • the morpholidate of the nucleoside monophosphate is prepared and condensed with a phosphatidic acid as described in U.S. Patent Application Serial No. 07/706,873 entitled "Liponucleotide Synthesis," and by Hong, et al. , British Patent Application No. 2,168,350.
  • acyclovir derivatives of the invention comprising ACV-MP, ACV-DP, ACV-MP-glycerol, ACV-DP-glycerol, ACV-MP- isopropylidene glycerol, and ACV-DP isopropylidene glycerol were found to have particular efficacy in topically treating the herpetic lesions of acyclovir-resistant HSV-1 infections.
  • Example 7 demonstrates that infection of cultured cells with wild type isolates and laboratory strains of HSV can be treated with equal success using acyclovir, acyclovir monophosphate (Example 7; Figure 1) .
  • both acyclovir and acyclovir monophosphate have the same IC 50 of about 1 or 2 ⁇ M concentration.
  • HSV- DM.21 lacking the thymidine kinase necessary to convert acyclovir to acyclovir monophosphate
  • acyclovir and acyclovir monophosphate are ineffective in reducing the number of viral plaques (Example 7; Figure 2) .
  • Acyclovir phosphate esters applied in an aqueous cream to the herpetic lesions of mice infected with acyclovir-resistant HSV-1 were substantially more effective than native acyclovir in reducing the number of such lesions (Example 9; Figures 3 and 4) .
  • the nucleoside analogue derivatives of the invention as previously described can be prepared for topical use by incorporation into a variety of formulations known to those in the art as useful and convenient for dermatological use .
  • the nucleoside analogue derivatives are water soluble, and accordingly an aqueous solution, water-in-oil emulsion, or an aqueous cream are highly preferred formulations.
  • Water solubility of the acyclovir and other nucleoside monophosphates can be enhanced through the preparation of salts, such as sodium, potassium, ammonium, or hydrogen.
  • the active ingredient is prepared in a polyethylene glycol (PEG) vehicle.
  • the active ingredients can be topically applied in a dry powder formulation, using an insoluble powder, such as starch or talc as a diluent or carrier.
  • the vehicle is an important component of some topical formulations, because it can be selected to enhance penetration, to prolong the duration of activity, or to meet requirement of the site of application.
  • a formulation for application to the callous parts of the body can include a penetration enhancing agent such as dimethylsulfoxide propylene glycol or azoneTM;
  • a powdery formulation can be selected for application to the intertriginous zones such as the crotch, inner elbow or between the fingers or toes.
  • the formulation can also be made up to contain various organic polymers or other compositions known to those of skill in the art to give sustained release of the active antiviral acyclovir derivatives.
  • compositions include for example, powders, pastes, ointments, jelly, waxes, oils, lipids, anhydrous absorption bases, oil-in-water or water-in-oil emulsions, emulsions carbowax (polyethylene glycols of a variety of molecular weights) , semi-solid gels, and semi-solid mixtures containing carbowax.
  • the concentration of active ingredient in the topical formulations of the invention can be from about 0.01 gm% to 100 gm%; preferably from about 0.1 gm% to 50 gm%; most preferably from about 1 gm% to about 15 gm%.
  • the formulations can further comprise effective concentrations of other agents which help to promote penetration of the skin and healing, as described in the above-referenced formulary and are well known to those of ordinary skill in the art .
  • Efficacy of topical formulations containing the active phosphate esters of the invention can be evaluated using conventional testing procedures, known to those of skill in the art.
  • a particularly expeditious procedure is the murine "orofacial model," as described by Ellis, M. , et al., Antimicrobial Agents and Chemotherapy 33:304-310 (1989) .
  • the pathogenesis of HSV in mice scarified and inoculated on the snout has been shown to be a reasonable model of the disease cycle of cutaneous HSV infection in the immunocompromised host.
  • the formulations can be applied to the herpetic lesions of the affected skin repeatedly; for example once, twice, or several times a day, and the treatment can be extended for several days until healing is achieved.
  • the risk of incidence of toxicity and irritation is minimal.
  • Acyclovir-monophosphate (5 mmol) and morpholine (20 mmol) were suspended in t-butanol (50 ml) and heated under gentle reflux while N,N' -dicyclohexylcarbodiimide (DCC, 20 mmol) dissolved in t-butanol (50 mmol) was added dropwise over a period of 1 hour.
  • the mixture was stirred under reflux for 12 to 36 hours and evaporated to dryness .
  • the residue was triturated with ether and washed by decantation with the same solvent.
  • the product was purified by recrystallization from methanol-ether mixtures.
  • Phosphorous oxychloride 25 mmol was added dropwise over a period of 30 minutes to a mixture of 1, 2-Isopropylidene- - 13 -
  • acyclovir nucleoside derivatives through the following methods. Unprotected acyclovir was reacted with P0C1 3 in trimethyl phosphate ((CH 3 0) 3 PO) was performed essentially as described by Yoshikawa et al . Tetrahedron Letters 50:5065-5068 (1967) ; and Yoshikawa, M. , Kato et al . Bull Chem. Soc. Japan 42:3205-3208 (1967) . To a cooled solution (0°C) of 2 M P0C1 3 in 300-400 ml trimethyl phosphate, acyclovir (1 M) was added dropwise with stirring, the reaction temperature being held constant between 0° and 5°C.
  • the progress of the reaction was monitored by means of HPLC using a Mono Q HR 5/5 anion exchange column (Pharmacia, Uppsala, Sweden) .
  • 5 ⁇ l of the reaction mixture was neutralized with aqueous sodium hydroxide (final pH 7) and injected on the column.
  • Elution was performed as follows: washing with water, elution with 0.1 M ammonium carbonate, NH 4 HC0 3 , which elutes the acyclovir monophosphate, followed by a linear gradient of 0.1-0.6 M NH 4 HC0 3 which elutes some higher phosphorylated products.
  • the reaction was mostly completed within 45 to 75 minutes as determined by this method, and the reaction product was hydrolyzed and neutralized with 2 volumes of aqueous sodium hydroxide to final pH of 7.
  • EXAMPLE II Preparation Of Acvclovir-monophosphomorpholidate glycerol (20 mmol) (Sigma, St. Louis, MO.) and triethylamine (100 mmol) that was cooled to 0°C. After stirring the mixture at 0°C for 10 to 90 minutes. Water (1 ml) was added to stop the reaction. The mixture was then dissolved chloroform (500 ml) and washed with water (3 x 100 ml) . The water wash solutions were combined and back extracted with chloroform (50 ml) and lyophilized. The product was used immediately for subsequent reactions without any additional purification.
  • EXAMPLE V Preparation Of sn- ⁇ lycero-3-phospho-acvclovir 1,2-Isopropylidene-s/i-glycero-3-phosphate, 1 mM (prepared as in Example 4B) , and acyclovir (1 mM) , were suspended in dry pyridine (10 ml) and DCC (4 mmol) . Dissolved pyridine (4 ml) was added and the mixture stirred at 25°C to 60°C for 12 to 72 hours. The solvent was evaporated and the residue was titrated with ether. The crude product was purified by ion exchange chromatography as described in Example 3.
  • the isopropylidene-protecting group was then removed from the product by treating with aqueous acetic acid to furnish the title compound.
  • the title compound was also prepared by using 2,4, 6-triisopropylbenzenesulfonyl chloride (TPS-Cl) as the condensing agent.
  • Acyclovir-diphosphate-dipalmitoylglycerol (1 mmol) was dissolved in chloroform, to which methanolic sodium hydroxide
  • HSV herpes simplex virus
  • DM.21 a mutant strain of HSV
  • the DM.21 mutant lacks the thymidine kinase enzyme which usually converts ACV to ACV- MP, and is therefore resistant to acyclovir.
  • the results for HSV-1 are shown in Figure 1, and those for HSV-DM.21 are shown in Figure 2.
  • An IC 50 is that concentration of antiviral agent which inhibits viral plaque formation 50%.
  • acyclovir and acyclovir monophosphate In wild type isolates and laboratory strains of herpes simplex virus (HSV-1) , acyclovir and acyclovir monophosphate have IC 50 s of 0.1 ⁇ M ( Figure 1) . In contrast, both acyclovir and acyclovir monophosphate have IC 50 s in excess of 100 ⁇ M against mutant HSV strains in this assay ( Figure 2) .
  • mice were inoculated on the snout by scarification with a 25-gauge needle, followed by 10 seconds of rubbing with a cotton-tipped applicator soaked in diluted virus.
  • the virus used for infection was a TK-deficient strain, referred to in Ellis, M. et al. (TK D ) .
  • TK D TK-deficient strain
  • the animals were treated topically, 3 times daily, for 4 days, with formulations of acyclovir or acyclovir phosphates, in a aqueous cream (AC) , according to the Ellis reference cited above.
  • Example 8 The procedure of Example 8 was repeated using an acyclovir-sensitive, wild type HSV-1 and a formulation having only acyclovir monophosphate (ACV-MP) as the acyclovir derivative.
  • ACV-MP acyclovir monophosphate
  • Two creams were formulated, one having ACV-MP present in the aqueous cream at 14.5 millimoles/100 ml and the other having acyclovir present at 22.2 millimoles/100 ml (both 5 gm%, however, because of the addition of the phosphate group the number of moles of acyclovir present in the monophosphate is reduced relative to neat acyclovir) .
  • mice Treatment was initiated 24 hours after infection and continued 4 times daily for four days.
  • the ten untreated mice developed stage 4 lesions by the 5th day and all died by day 14 ( Figure 5) .
  • the acyclovir monophosphate-treated animals did not develop lesions and 10 of 10 animals survived ( Figure 5) .
  • In the acyclovir-treated group several animals developed mild lesions on days 7-9 which resolved; 9 of 10 ten animals survived.
  • Example 8 The procedure of Example 8 was repeated using a formulation having only acyclovir monophosphate (ACV-MP) as the acyclovir derivative. Treatment was begun 3 hours post- infection, with treatments occurring twice on the day of infection, and thereafter, three times a day through day 4.
  • ACV-MP at 14.5 mmol/100 ml is clearly more effective than acyclovir at 22.2 mmol/100 ml in reducing lesion scores in animals infected with acyclovir- resistant (TK altered) HSV-1.
  • TK altered acyclovir-resistant
  • Acyclovir in polyethylene glycol (ACV-PEG) for treatment of a primary genital herpes was studied.
  • a genital herpes infection of guinea pigs caused by an ACV-resistant HSV-2 was studied.
  • acyclovir treatments in two carrier systems were placebo-controlled and uninfected animals were treated with each ACV preparation to assess skin and vaginal irritation.
  • Intravaginal inoculation of weanling guinea pigs with HSV-2 results in a primary genital infection is characterized by initial replication of virus in the vaginal tract followed by the development of external vesicular lesions.
  • Virus titers peak on days one to three in the vaginal tract and gradually clear by days 7-10.
  • the external genital lesions first appear on day four, peak lesion severity occurs on days 6-8, and the lesions generally heal by days 15-18.
  • Animals were inoculated with the HSV-2 strain 12247, which has an altered thymidine kinase and is resistant to in vitro treatment with ACV.
  • mice Female Hartley guinea pigs (Charles River, Springfield, NY) weighing 250-300 grams were first vaginally swabbed to remove vaginal secretions. After one hour, the animals were inoculated intravaginally with 2.4 x 10 A plague forming units (pfu) . Inoculation was accomplished by inserting a swab soaked with virus into the vaginal tract and rotating approximately six times.
  • HSV-2 replication in the vaginal tract swabs of vaginal secretions were obtained during the primary infection on days 1, 3, 5, 7, and 10 after HSV-2 inoculation.
  • the swabs were placed in tubes containing 2.0 ml of media, vortexed, and frozen at -70°C until titrated for HSV. When all samples were collected, they were thawed, diluted serially, and HSV-2 titers were determined using rabbit kidney cells in a microtiter CPE assay.
  • Topical and intravaginal treatment was initiated 24 hours after viral inoculation and was continued three times daily for 7 days.
  • Acyclovir content on a molar basis was lower in the tests conducted with acyclovir monophosphate (14.5 ⁇ mol/100 ml) versus those conducted with the neat acyclovir (22.2 ⁇ nol/100 ml).
  • Topical and intravaginal treatment was initiated 24 hours after viral inoculation and was continued three times daily for 7 days.
  • Acyclovir content on a molar basis was lower in the tests conducted with acyclovir monophosphate (14.5 mmol/100 ml) versus those conducted with the neat acyclovir (22.2 mmol/100 ml).
  • NS Not Statistically Significant when compared to the appropriate placebo-treated group.
  • ACV-MP significantly reduced vaginal viral replication.
  • the ACV-MP-PEG treated group had the lowest virus titer-day and mean peak titer values.
  • the drugs in PEG had lower scores than those in AC.
  • animals receiving ACV-MP-PEG had the lowest lesion score-day and mean peak lesion scores .
  • Example 8 The procedure of Example 8 is repeated using a formulation having only acyclovir diphosphate (ACV-DP) as the acyclovir derivative. Efficacy superior to that of ACV alone is observed.
  • ACCV-DP acyclovir diphosphate
  • EXAMPLE XIII Activity Of Acyclovir Monophosphate Glycerol
  • the procedure of Example 8 is repeated using a formulation having only acyclovir monophosphate glycerol (ACV- MP-G) as the acyclovir derivative- Efficacy superior to that of ACV alone is observed.
  • EXAMPLE XIV. Activity Of Acyclovir Diphosphate Glycerol The procedure of Example 8 is repeated using a formulation having only acyclovir diphosphate glycerol (ACV- DP-glycerol) as the acyclovir derivative. Efficacy superior to that of ACV alone is observed.
  • Example 8 The procedure of Example 8 is repeated using a formulation having only acyclovir monophosphate morpholidate (ACV-MP-morpholidate) as the acyclovir derivative. Efficacy superior to that of ACV alone is observed.
  • Example XVI. Activity Of Acyclovir Monophosphate Isopropylidene Glycerol The procedure of Example 8 is repeated using a formulation having only acyclovir monophosphate isopropylidene glycerol (ACV-MP-isoP-G) as the acyclovir derivative. Efficacy superior to that of ACV alone is observed.
  • Example XVII Activity Of Acyclovir Diphosphate Isopropylidene Glycerol
  • the procedure of Example 8 is repeated using a formulation having only acyclovir diphosphate isopropylidene glycerol (ACV-DP-isoP-G) as the acyclovir derivative. Efficacy superior to that of ACV alone is observed.

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Abstract

Compositions destinées à l'usage topique dans les cas d'infection à l'herpèsvirus, comprenant des esters de phosphate d'analogue de nucléosides anti-herpès tels que du monophosphate et du diphosphate d'acyclovir. Ces compositions démontrent une activité accrue contre les souches natives de l'herpèsvirus ainsi que contre les souches résistantes, notamment les souches négatives de thymidine-kinase du virus. Cette invention concerne également des procédés d'utilisation de ces compositions topiques dans le traitement de la maladie de l'herpès.
PCT/US1993/004450 1993-05-12 1993-05-12 Derives d'acyclovir a usage topique Ceased WO1994026273A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002162574A CA2162574A1 (fr) 1993-05-12 1993-05-12 Derives d'acyclovir pour applications topiques
PCT/US1993/004450 WO1994026273A1 (fr) 1993-05-12 1993-05-12 Derives d'acyclovir a usage topique
JP6525361A JPH08510236A (ja) 1993-05-12 1993-05-12 局所使用のためのアシクロビル誘導体
EP93913832A EP0746319A4 (fr) 1993-05-12 1993-05-12 Derives d'acyclovir a usage topique
AU43721/93A AU701574B2 (en) 1993-05-12 1993-05-12 Acyclovir derivatives for topical use

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US6444652B1 (en) 1998-08-10 2002-09-03 Novirio Pharmaceuticals Limited β-L-2'-deoxy-nucleosides for the treatment of hepatitis B
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WO2004002999A2 (fr) 2002-06-28 2004-01-08 Idenix (Cayman) Limited Promedicaments a nucleosides 2' et 3' destines a traiter les infections aux flavivirus
US6723728B2 (en) 2001-03-01 2004-04-20 Gilead Sciences, Inc. Polymorphic and other crystalline forms cis-FTC
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WO2005003147A2 (fr) 2003-05-30 2005-01-13 Pharmasset, Inc. Analogues de nucleosides fluores modifies
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US7192936B2 (en) 2002-06-28 2007-03-20 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
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US7601820B2 (en) 2004-07-21 2009-10-13 Pharmasset, Inc. Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
US7608597B2 (en) 2000-05-23 2009-10-27 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
US7824851B2 (en) 2002-11-15 2010-11-02 Idenix Pharmaceuticals, Inc. 2′-branched nucleosides and Flaviviridae mutation
EP2251015A1 (fr) 2000-10-18 2010-11-17 Pharmasset, Inc. Nucléosides modifiés pour traiter des infections virales et une prolifération cellulaire anormale
EP2390257A1 (fr) 1998-02-25 2011-11-30 Emory University 2'-Fluoronucléosides
EP2574341A1 (fr) 2004-03-29 2013-04-03 University Of South Florida Traitement efficace des tumeurs et du cancer avec de la triciribine et composés apparentés
WO2013082476A1 (fr) 2011-11-30 2013-06-06 Emory University Inhibiteurs de jak antiviraux utiles dans le traitement ou la prévention d'infections rétrovirales et autres infections virales
US8492539B2 (en) 2004-09-14 2013-07-23 Gilead Pharmasset Llc Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8569478B2 (en) 2005-09-26 2013-10-29 Gilead Pharmasset Llc Modified 4′-nucleosides as antiviral agents
US8580765B2 (en) 2007-03-30 2013-11-12 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8629263B2 (en) 2009-05-20 2014-01-14 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
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US8742101B2 (en) 2003-07-25 2014-06-03 Idenix Pharmaceuticals, Inc. Purine nucleoside analogues for treating flaviviridae including hepatitis C
US8841275B2 (en) 2010-11-30 2014-09-23 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
EP3042660A2 (fr) 2008-04-15 2016-07-13 RFS Pharma, LLC. Dérivés de nucléosides pour le traitement d'infections de caliciviridae, y compris des infections de norovirus
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
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US5576313A (en) * 1994-08-29 1996-11-19 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6245749B1 (en) 1994-10-07 2001-06-12 Emory University Nucleosides with anti-hepatitis B virus activity
US7468357B2 (en) 1994-10-07 2008-12-23 Emory University Nucleosides with anti-hepatitis B virus activity
EP2392580A1 (fr) 1998-02-25 2011-12-07 Emory University 2'-Fluoronucléosides
EP2390257A1 (fr) 1998-02-25 2011-11-30 Emory University 2'-Fluoronucléosides
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US9290533B2 (en) 1998-08-10 2016-03-22 Novartis Ag β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
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JPH08510236A (ja) 1996-10-29
CA2162574A1 (fr) 1994-11-24
AU4372193A (en) 1994-12-12
EP0746319A1 (fr) 1996-12-11
AU701574B2 (en) 1999-02-04
EP0746319A4 (fr) 1997-11-05

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